Active ingredients: Aripiprazole
ABILIFY 5 mg tablets
Abilify package inserts are available for packs:- ABILIFY 5 mg tablets
- ABILIFY 10 mg tablets
- ABILIFY 15 mg tablets
- ABILIFY 30 mg tablets
- ABILIFY 10 mg orodispersible tablets
- ABILIFY 15 mg orodispersible tablets
- ABILIFY 30 mg orodispersible tablets
- ABILIFY 1 mg / ml oral solution
- ABILIFY 7.5 mg / ml solution for injection
Why is Abilify used? What is it for?
ABILIFY contains the active substance aripiprazole and belongs to a group of medicines called antipsychotics. It is used to treat adults and adolescents from 15 years of age who have a disease characterized by symptoms such as hearing, seeing or sensing things that are not present, suspiciousness, mistaken beliefs, incoherent speech and behavior, and flattening of emotions. . People with this condition may also feel depressed, guilty, anxious, or tense.
ABILIFY is used to treat adults and adolescents from 13 years of age who have a condition characterized by symptoms such as feeling "high", having too much energy, not needing to sleep than usual, talking very quickly. with "flight of ideas" and sometimes severe irritability. It also prevents this condition in adults who have responded to treatment with ABILIFY.
Contraindications When Abilify should not be used
Do not take ABILIFY
- If you are allergic to aripiprazole or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Abilify
Talk to your doctor before taking ABILIFY if you suffer from
- High blood sugar levels (characterized by symptoms such as excessive thirst, production of large amounts of urine, increased appetite and feeling tired) or a family history of diabetes
- Convulsions
- Irregular, involuntary muscle movements, especially of the face
- Cardiovascular disorders, family history of cardiovascular disorders, stroke or transient ischemic attack, abnormal blood pressure
- Blood clots (blood clots in the veins) or family history of blood clots, as antipsychotics have been associated with blood clots
- Past excessive gambling experience
If you notice that your weight is gaining, if you develop unusual movements, if you feel sleepy that interferes with your normal daily activities, if you have difficulty swallowing or if you have allergic symptoms, please tell your doctor.
If you are an elderly patient with dementia (loss of memory and other mental skills), you or your caregiver should tell your doctor if you have had a stroke or transient ischemic attack (TIA) in the past. ).
Tell your doctor immediately if you are thinking about harming yourself. Suicidal ideation and behaviors have been reported during treatment with aripiprazole.
Tell your doctor immediately if you have muscle numbness or stiffness with a high fever, sweating, altered mental status or a very fast or irregular heartbeat.
Children and adolescents
ABILIFY should not be used in children and adolescents under 13 years of age.
Ask your doctor or pharmacist for advice before taking ABILIFY.
Interactions Which drugs or foods can change the effect of Abilify
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Medicines that lower blood pressure: ABILIFY may increase the effect of medicines used to lower blood pressure. Tell your doctor if you take a medicine to control blood pressure.
When taking ABILIFY with other medicines it may be necessary to change the dosage of ABILIFY. It is important to tell your doctor especially if you are taking the following medicines:
- Medicines that correct the heart rhythm
- Antidepressants or herbs used to treat depression and anxiety
- Antifungal agents
- Some medicines for the treatment of HIV infection
- Anticonvulsants used to treat epilepsy
Medicines that increase serotonin level: triptans, tramadol, tryptophan, Selective Serotonin Reuptake Inhibitors (SSRIs) (such as paroxetine and fluoxetine), tricyclics (such as clomipramine, amitriptyline), pethidine, St. John's wort ( hypericum) and venlafaxine. These medicines increase the risk of side effects; if you get any unusual symptoms while taking any of these medicines together with ABILIFY, you should see your doctor.
ABILIFY with food, drink and alcohol
ABILIFY can be taken regardless of food. The use of alcohol should be avoided when being treated with ABILIFY.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
The following symptoms may occur in newborn babies, of mothers who have used ABILIFY in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your child has any of these symptoms, you may need to contact your doctor.
Tell your doctor immediately if you are breastfeeding.
If you are taking ABILIFY you should not breast-feed.
Driving and using machines
Do not drive or use any tools or machines until you know how ABILIFY can affect you.
ABILIFY contains lactose
If you have been told by your doctor that you are intolerant to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Abilify: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist
The recommended dose for adults is 15 mg once a day. However, your doctor may prescribe a lower or higher dose up to a maximum of 30 mg once a day.
Use in children and adolescents
ABILIFY can be started with a lower dosage using the oral (liquid) solution. The dose may be gradually increased to the recommended dose for adolescents of 10 mg once daily. However, your doctor may prescribe a lower or higher dose up to a maximum of 30 mg once a day.
If you have the impression that the effect of ABILIFY is too strong or too weak, talk to your doctor or pharmacist.
Try to take your ABILIFY tablet at the same time each day. It does not matter if you take it with food or not. Always take the tablet with water and swallow it whole.
Even if you feel well, do not change or stop your daily dose of ABILIFY without first consulting your doctor.
Overdose What to do if you have taken an overdose of Abilify
If you take more ABILIFY than you should
If you realize that you have taken more ABILIFY tablets than your doctor has recommended (or if someone else has taken some of your ABILIFY tablets), contact your doctor immediately. If you cannot reach the doctor, go to the nearest hospital and take the pack with you
If you forget to take ABILIFY
If you forget a dose, take it as soon as you remember but do not take two on the same day.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Abilify
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Common side effects (may affect up to 1 in 10 people): uncontrollable twitching or jerking movements, headache, tiredness, nausea, vomiting, an uncomfortable feeling in the stomach, constipation, increased saliva production, light-headedness , difficulty sleeping, restlessness, feeling anxious, sleepy, agitated and blurred vision.
Uncommon side effects (may affect up to 1 in 100 people): some people may feel dizzy, especially when getting up from a lying or sitting position, or a fast heart rhythm or double vision. Some people may feel depressed. Some people may experience an "alteration or increase in" sexual interest. The following side effects have been reported since the start of marketing of ABILIFY but the frequency with which they occurred is not known (cannot be estimated from the available data):
Changes in the levels of some blood cells unusual heartbeat, sudden unexplained death, heart attack; allergic reaction (e.g. swelling in the mouth, tongue, face and throat, itching, rash); high blood sugar, onset or worsening of diabetes, ketoacidosis (ketones in the blood and urine) or coma, low blood sodium; weight gain, weight loss, anorexia; nervousness, agitation, anxiety excessive gambling; thoughts of suicide, attempted suicide and suicide; speech disturbances, seizures, serotonin syndrome (a reaction which can cause feeling of great happiness, drowsiness, clumsiness, restlessness, feeling of being drunk, fever, sweating or muscle stiffness), combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness and sudden changes in blood pressure and heart rhythm; fainting; high blood pressure; blood clots (blood clots in the veins), especially in the legs (symptoms include swelling, pain and redness of the leg), which can travel through blood vessels to the lungs causing chest pain and difficulty breathing (if you notice any of these symptoms , ask your doctor for advice immediately); spasm of the muscles around the vocal cords, accidental inhalation of food with risk of pneumonia, difficulty in swallowing; inflammation of the pancreas; liver failure, inflammation of the liver, yellowing of the skin and whites of the eyes, cases of abnormal liver function tests; abdominal discomfort and stomach discomfort, diarrhea; skin rash and sensitivity to light, unusual hair loss or brittle hair, excessive sweating; stiffness or cramps, muscle pain, weakness; involuntary loss of urine, difficulty passing urine; prolonged and / or painful erection; difficulty in controlling core body temperature or conditions of excessive heat, chest pain, swelling of the hands, ankles or feet.
More fatal cases have been reported in elderly patients with dementia while taking aripiprazole. In addition, strokes or "mini" strokes have been reported.
Additional side effects in children and adolescents
Adolescents from 13 years of age have experienced similar side effects in frequency and type to those in adults, except for drowsiness, uncontrollable muscle twitching or jerking movements, restlessness and tiredness which were very common (more than 1 patient in 10) and for pain in the upper abdomen, dry mouth, increased heart rate, weight gain, increased appetite, muscle twitching, uncontrolled limb movements and a feeling of dizziness, especially when rising from a lying or sitting position, which were common (more than 1 in 100 patients).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister and carton.
The expiry date refers to the last day of that month.
Store in the original package to protect the medicine from moisture.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Contents of the pack and other information
What ABILIFY contains
- The active ingredient is aripiprazole. Each tablet contains 5 mg of aripiprazole.
- The other ingredients are lactose monohydrate, maize starch, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate, indigo carmine (E132) aluminum lake.
Description of how ABILIFY looks and contents of the pack
ABILIFY 5 mg tablets are rectangular and blue debossed with "A-007" and "5" on one side.
They are available in perforated unit dose blisters in cartons containing 14, 28, 49, 56 or 98 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ABILIFY 5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of aripiprazole.
Excipient with known effects: 67 mg of lactose per tablet.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
Rectangular and blue embossed with "A-007" and "5" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
ABILIFY is indicated for the treatment of schizophrenia in adults and adolescents from 15 years of age.
ABILIFY is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in adults who have had predominantly manic episodes that have responded to treatment with aripiprazole (see section 5.1). .
ABILIFY is indicated for the treatment, up to 12 weeks, of moderate to severe manic episodes in Bipolar I Disorder in adolescents from 13 years of age (see section 5.1).
04.2 Posology and method of administration
Dosage
Adults
Schizophrenia: The recommended starting dose for ABILIFY is 10 or 15 mg / day with a maintenance dose of 15 mg / day administered once daily, regardless of meals.
ABILIFY is effective at a dosage between 10 and 30 mg / day. Increased efficacy at doses higher than a daily dose of 15 mg has not been demonstrated, although some 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 once daily with or without meals, as monotherapy or in combination (see section 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.
Prevention of relapses of manic episodes in Bipolar I Disorder: For the prevention of relapse of manic episodes in patients who have been treated with aripiprazole alone or in combination therapy, continue therapy at the same dose. Daily dose adjustments, including dose reduction, should be considered based on the patient's clinical status.
Pediatric population
Schizophrenia in adolescents from 15 years of age: The recommended dose for ABILIFY is 10 mg / day administered once daily with or without meals. Treatment should be started with 2 mg (using ABILIFY oral solution 1 mg / ml) for 2 days, titrated to 5 mg for a further 2 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).
ABILIFY is effective at doses of 10 to 30 mg / day. Greater efficacy has not been demonstrated with doses higher than a daily dose of 10 mg, although individual patients may benefit from a higher dose.
The use of ABILIFY is not recommended in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1).
Manic episodes in Bipolar I Disorder in adolescents from 13 years of age: the recommended dose for ABILIFY is 10 mg / day administered once daily with or without meals. Treatment should be started with 2 mg (using ABILIFY 1 mg / ml oral solution) for 2 days, titrated to 5 mg for a further 2 days, to reach the recommended daily dose of 10 mg.
The duration of treatment should be the minimum necessary for symptom control and should not exceed 12 weeks. With doses higher than the 10 mg daily dose, greater efficacy has not been demonstrated, and a 30 mg daily dose is associated with a substantially higher incidence of significant side effects including events related to extrapyramidal symptoms, somnolence, fatigue and increased weight (see section 4.8). Doses higher than 10 mg / day should therefore only be used in exceptional cases and under close clinical monitoring (see sections 4.4, 4.8 and 5.1).
Younger patients are at increased risk of reporting adverse events associated with aripiprazole. Therefore, ABILIFY is not recommended for use in patients below 13 years of age (see sections 4.8 and 5.1).
Irritability associated with autistic disorder: The safety and efficacy of ABILIFY in children and adolescents below 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.
Tics associated with Tourette's syndrome: the safety and efficacy of ABILIFY in children and adolescents aged 6 to 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.
Patients with hepatic insufficiency
No dosage adjustment is required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the available data are insufficient to make recommendations. In such patients, dosing should be managed with caution. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section 5.2).
Patients with renal insufficiency
No dosage adjustment is required in patients with renal insufficiency.
Older people
The efficacy of ABILIFY in the treatment of schizophrenia and Bipolar I Disorder in patients 65 years of age and older has not been established. Given the increased sensitivity of this population,
when clinical conditions permit, a lower starting dose should be considered (see section 4.4).
Sex
No dosage adjustment is required for female patients compared to male patients (see section 5.2).
Smoker status
According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (see section 4.5).
Dosage adjustments due to interactions
When aripiprazole is co-administered with potent inhibitors of CYP3A4 or CYP2D6, the dose of aripiprazole should be reduced. When the CYP3A4 or CYP2D6 inhibitor is cleared from the combination therapy, then the aripiprazole dosage should be increased (see section 4.5).
When aripiprazole is administered concomitantly with a potent CYP3A4 inducer, the dose of aripiprazole should be increased. When the CYP3A4 inducer is removed from the combination therapy, then the dose of aripiprazole should be reduced to that recommended (see section 4.5).
Method of administration
ABILIFY tablets are for oral use.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
During antipsychotic treatment, improvement in the patient's clinical condition may take several days to several weeks. Patients must be closely monitored for the entire period.
Suicidality
The onset of suicidal behavior is inherent in psychotic illness and mood disturbances and, in some cases, has been reported soon after initiation or switch to antipsychotic therapy, including treatment with aripiprazole (see section 4.8). Closer supervision of high-risk patients should accompany antipsychotic therapy. Results from an epidemiological study suggested that there is no increased suicidal risk with aripiprazole compared to other antipsychotics in adult patients with schizophrenia or bipolar disorder. There are insufficient pediatric data to assess 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 "aripiprazole.
Cardiovascular alterations
Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disorder, conditions that may predispose to hypotension (dehydration, hypovolaemia and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant.
Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, any possible risk factors for VTE should be identified before and during treatment. treatment with ABILIFY and preventive measures must be taken.
Conduction anomalies
In clinical trials with aripiprazole, the incidence of QT prolongation was comparable to placebo. As with other antipsychotics, aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia
In clinical trials lasting one year or less, there have been uncommon reports of treatment-related dyskinesia during aripiprazole therapy. If signs and symptoms of tardive dyskinesia appear in patients receiving ABILIFY, dose reduction or discontinuation should be considered. These symptoms may worsen over time or may even occur after discontinuation of treatment.
Other extrapyramidal symptoms
In pediatric clinical trials of aripiprazole akathisia and parkinsonism were observed. If signs and symptoms of other extrapyramidal symptoms appear in a patient taking ABILIFY, a reduction in dosage and close clinical monitoring should be considered.
Neuroleptic malignant syndrome (NMS)
NMS is a life-threatening symptom complex associated with antipsychotic medicinal products. In clinical studies, rare cases of NMS have been 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 or cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis have been reported, not necessarily associated with NMS. If a patient develops signs and symptoms suggestive of NMS, or has high fever of unknown origin without further clinical manifestations of NMS, all antipsychotic medicinal products, including ABILIFY, should be discontinued.
Convulsions
Uncommon cases of convulsions have been reported in clinical studies during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients with a history of seizure disorders or who exhibit conditions associated with seizures.
Elderly patients with dementia-related psychosis
Increased mortality
In three placebo-controlled clinical trials of aripiprazole (n = 938; mean age: 82.4 years; range: 56-99 years) in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole reported a increased risk of death compared to those taking placebo. The death rate in patients treated with aripiprazole was 3.5% compared to 1.7% in the placebo group. Although the causes of deaths were varied, most of them were found to be cardiovascular (e.g. myocardial infarction, sudden death) or infectious (e.g. pneumonia).
Cerebrovascular adverse reactions
Cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack) were reported in the same studies, including cases with fatal outcome (mean age: 84 years; range: 78-88 years). Overall in these studies, 1.3% of patients treated with aripiprazole reported cerebrovascular adverse reactions compared to 0.6% of patients treated with placebo. This difference was not statistically significant. However, in one of these studies, a fixed dose, in patients treated with aripiprazole there was a significant dose-response relationship for cerebrovascular adverse reactions.
ABILIFY is not approved for the treatment of dementia-related psychosis.
Hyperglycemia 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 medicinal products, including ABILIFY. Risk factors that can predispose patients to serious complications include obesity and family history of diabetes. In clinical trials with aripiprazole, no significant differences were reported in the incidence rate of adverse reactions related to hyperglycaemia (including diabetes) or in the occurrence of abnormal blood glucose values compared to placebo. No precise risk estimates are available for hyperglycaemia-related adverse reactions in patients treated with ABILIFY and other atypical antipsychotic medicinal products to allow direct comparison. Patients treated with any antipsychotic drug, including ABILIFY, 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 glycemic control.
Hypersensitivity
As with other medicinal products, hypersensitivity reactions, characterized by allergic symptoms, may occur with aripiprazole (see section 4.8).
Weight gain
Weight gain, due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed lifestyle, is commonly seen in schizophrenic and bipolar mania patients and can lead to serious complications. Post-marketing, it has been reported weight gain in patients receiving ABILIFY. When detected, these were usually patients with significant risk factors such as a history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials, aripiprazole was not shown to cause weight gain clinically relevant in adults (see section 5.1). In clinical studies in 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, a dose reduction should be considered (see section 4.8).
Dysphagia
Disorders of esophageal motility and aspiration have been associated with treatment with antipsychotics, including ABILIFY. Aripiprazole and other antipsychotic active substances should be used with caution in patients at risk for pneumonia ab ingestis.
Pathological gambling
Post-marketing reports of pathological gambling have been reported among patients who were prescribed ABILIFY, regardless of whether these patients had a previous history of gambling. Patients with a previous history of pathological gambling may be at increased risk and should be monitored closely (see section 4.8).
Lactose
ABILIFY tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients with Attentive Deficit Disorder with Hyperactivity Disorder (ADHD) comorbidities
Despite the high comorbid frequency of Bipolar I Disorder and ADHD, very limited safety data are available on the concomitant use of ABILIFY and stimulants; therefore, extreme caution should be exercised when these drugs are administered concomitantly.
04.5 Interactions with other medicinal products and other forms of interaction
Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of some antihypertensives.
Given the primary effect of aripiprazole on the central nervous system, caution should be exercised when taken in combination with alcohol or other centrally acting medicinal products with overlapping adverse reactions such as sedation (see section 4.8).
Caution should be exercised when administering aripiprazole concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance.
Possibility for other medicinal products to affect ABILIFY
The H2 antagonist famotidine, a gastric acid blocker, reduces the rate of absorption of aripiprazole but this effect is not thought to be clinically relevant.
Aripiprazole is metabolised via several pathways involving CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Consequently, no dosage adjustment is required for smokers.
Quinidine and other CYP2D6 inhibitors
In a clinical study in healthy subjects, a strong CYP2D6 inhibitor (quinidine) increased the AUC of aripiprazole by 107% while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32% and 47%, respectively. In the event of concomitant administration of ABILIFY and quinidine, the dosage of ABILIFY should be decreased by approximately half the prescribed dosage. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are expected to have similar effects and similar dose reductions should be applied.
Ketoconazole and other CYP3A4 inhibitors
In a clinical study with healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased the AUC and Cmax by 63% and 37%, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77% and Cmax, respectively. 43%. In poor CYP2D6 metabolisers, concomitant use of potent CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole than those of CYP2D6 extensive metabolisers. When considering concomitant administration of ketoconazole or other potent CYP3A4 inhibitors with ABILIFY , the potential benefits to the patient must outweigh the potential risks. In the event of concomitant administration of ketoconazole and ABILIFY, the dosage of ABILIFY should be decreased by approximately half the prescribed dosage. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, are expected to have similar effects and similar dosage reductions should be applied.
Following discontinuation of the CYP2D6 and CYP3A4 inhibitor administration, the dosage of ABILIFY should be increased to the level prior to initiation of combination therapy.
When weak inhibitors of CYP3A4 (e.g. diltiazem or escitalopram) or CYP2D6 are used concomitantly with ABILIFY, modest increases in aripiprazole concentrations may occur.
Carbamazepine and other CYP3A4 inducers
Following concomitant administration of carbamazepine, a potent CYP3A4 inducer, the geometric means of aripiprazole Cmax and AUC were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) was was administered alone. Similarly, for dehydro-aripiprazole, the geometric means of Cmax and AUC after concomitant administration of carbamazepine were 69% and 71% lower, respectively, than those observed following treatment with aripiprazole alone.
The dosage of ABILIFY should be doubled in case of concomitant administration of ABILIFY and carbamazepine. Other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and Hypericum perforatum) have the same effects, therefore, similar dosage increases should be made. Following discontinuation of the use of potent CYP3A4 inducers, the dosage of ABILIFY should be reduced to the recommended dosage.
Valproate and lithium
There were no clinically significant changes in aripiprazole concentrations when lithium and valproate were co-administered with aripiprazole.
Serotonin syndrome
Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms of this condition may occur especially in cases of concomitant use with other serotonergic drugs, such as SSRIs / SNRIs, or with other drugs that are known to increase concentrations. aripiprazole (see section 4.8).
Possibility for ABILIFY to affect other medicines
In clinical studies, aripiprazole doses of 10-30 mg / day have not been shown to have significant effects on the metabolism of substrates of CYP2D6 (dextromethorphan / 3-methoxymorphine ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP3A4 (dextromethorphan) . Furthermore, aripiprazole and dehydro-aripiprazole have not been shown to potentially alter the metabolic activity. in vitro mediated by CYP1A2. Therefore, it is considered unlikely that aripiprazole will cause clinically relevant drug interactions mediated by these enzymes.
When aripiprazole was co-administered with valproate, lithium or lamotrigine, there was no clinically significant change in the concentrations of the latter.
04.6 Pregnancy and lactation
Pregnancy
There are no specific and adequately controlled studies with aripiprazole in pregnant women. Congenital anomalies have been reported; however, a causal relationship with aripiprazole cannot be established. Animal studies cannot exclude potential developmental toxicity (see section 5.3). Patients should be advised to report to their physician if they are pregnant or intend to become pregnant during treatment with aripiprazole. Given the insufficient information on safety in humans and the questions raised by animal reproduction studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the fetus.
Infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk for adverse reactions including extrapyramidal and / or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, difficulty breathing, or feeding disturbances. Consequently, neonates should be monitored closely.
Feeding time
Aripiprazole is excreted in breast milk. Patients should be advised not to breast-feed if they are taking aripiprazole.
04.7 Effects on ability to drive and use machines
As with other antipsychotics, patients should be warned about the use of hazardous machinery, including motor vehicles until they are reasonably certain that aripiprazole does not adversely affect them. Some pediatric patients with Bipolar I Disorder have an increased incidence of somnolence and fatigue (see section 4.8).
04.8 Undesirable effects
Summary of the safety profile
The most common adverse reactions reported in placebo-controlled clinical trials are akathisia and nausea, each occurring in more than 3% of patients treated with oral aripiprazole.
Table of adverse reactions
The following adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as adverse reactions with possible medical relevance (*).
The frequency listed below is described using the following convention: common (≥ 1/100 to
Description of particular adverse reactions
Extrapyramidal symptoms
Schizophrenia - in a 52-week controlled long-term study, patients treated with aripiprazole had an overall lower (25.8%) incidence of extrapyramidal symptoms including parkinsonism, akathisia, dystonia and dyskinesia than those treated with haloperidol (57, 3%). In a 26-week long-term, placebo-controlled study, the incidence of extrapyramidal symptoms was 19% for patients treated with aripiprazole and 13.1% for patients treated with placebo. In another 26-week controlled long-term study, the incidence of extrapyramidal symptoms was 14.8% for patients treated with aripiprazole and 15.1% for patients treated with olanzapine. Manic Episodes in Bipolar I Disorder - in a 12-week controlled study, the incidence of extrapyramidal symptoms was 23.5% in patients treated with aripiprazole and 53.3% in patients treated with haloperidol. In another 12-week study, the incidence of extrapyramidal symptoms was 26.6% in patients treated with aripiprazole and 17.6% in those treated with lithium. In a long-term placebo-controlled study, in the 26-week maintenance phase, the incidence of extrapyramidal symptoms was 18.2% in patients treated with aripiprazole and 15.7% in patients treated with placebo.
Akathisia
In placebo-controlled studies, the incidence of akathisia in patients with bipolar disorder 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
Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in sensitive individuals during the first days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressive to narrowing of the throat, difficulty in swallowing, difficulty in breathing and / or protrusion of the tongue. While these symptoms may occur at low doses, they may occur more frequently and with greater severity with high potency and higher dose first generation antipsychotic drugs. High risk of acute dystonia was observed in male patients and younger patient groups.
Comparison between aripiprazole and placebo in the proportion of patients who exhibited changes in routine laboratory and lipid parameters (see section 5.1) of potential clinical significance did not show medically important differences. Elevations in creatine phosphokinase (CPK), generally transient and asymptomatic, were observed in 3.5% of patients treated with aripiprazole compared to 2.0% of patients given placebo.
Other results
Adverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizures, cerebrovascular adverse reactions and increased mortality in elderly patients with dementia, hyperglycaemia and diabetes mellitus (see section 4.4).
Pediatric population
Schizophrenia in adolescents from 15 years of age
In a short-term, placebo-controlled clinical study of 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, reported more frequently in adolescents treated with aripiprazole than in adults treated with aripiprazole (and more frequently than with placebo):
Somnolence / sedation and extrapyramidal disorders were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100, serum prolactin was in females (
Manic episodes in Bipolar I Disorder in adolescents from 13 years of age
The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: somnolence (23.0%), extrapyramidal disorders (18.4%), akathisia (16 , 0%), and fatigue (11.8%) were very common (≥ 1/10); upper abdominal pain, increased heart rate, weight gain, increased appetite, muscle twitching and dyskinesia were common (≥ 1/100,
The following adverse reactions have a possible dose relationship; extrapyramidal disorders (incidences were 9.1% with 10 mg, 28.8% with 30 mg, 1.7% with placebo); and akathisia (incidences were 12.1% with 10 mg, 20.3% with 30 mg, 1.7% with placebo).
The mean body weight changes in adolescents with Bipolar I Disorder at 12 and 30 weeks were 2.4 kg and 5.8 kg with aripiprazole and 0.2 kg and 2.3 kg with placebo, respectively.
In the pediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder than in those with schizophrenia.
In the bipolar pediatric population (10-17 years) with exposure up to 30 weeks, the incidence of low serum prolactin levels in females (
Post-marketing experience
The following adverse reactions have been reported during post-marketing surveillance. The frequency of these reactions is considered unknown (cannot be estimated from the available data).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
Signs and symptoms
In clinical studies and post-marketing experience, acute accidental or intentional overdose of aripiprazole alone has been identified in adult patients with reported dosages greater than 1,260 mg with no fatal outcome. The potentially important signs and symptoms from a viewpoint medically observed have included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhea In addition, there have been reports of accidental overdose with aripiprazole alone (with doses up to 195 mg) in children with no fatal outcome. Potentially clinically serious reported signs and symptoms have included somnolence, transient loss of consciousness and extrapyramidal symptoms.
Treatment of overdose
Treatment of overdose should focus on supportive care, maintaining adequate airway clearance, adequate oxygenation and ventilation, and symptom control. The possibility of multiple drug involvement should be considered. Then, initiation should be made. immediate cardiovascular monitoring including continuous electrocardiographic monitoring for possible arrhythmias Following a confirmed or suspected aripiprazole overdose, continued medical monitoring is required until the patient is recovered.
Activated charcoal (50 g), administered one hour after aripiprazole, decreased Cmax by approximately 41% and AUC by approximately 51%, suggesting that charcoal may be effective for the treatment of overdose.
Hemodialysis
Although no information is available on the effect of hemodialysis in the treatment of aripiprazole overdose, it is unlikely to be useful in the treatment of overdose due to the high plasma protein binding of aripiprazole.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antipsychotics.
ATC code: N05AX12.
Mechanism of action
It has been proposed that the efficacy of aripiprazole in schizophrenia and Bipolar I Disorder is mediated by a combination of a partial agonist activity on dopamine D2 and serotonergic 5HT1a receptors and an antagonist action on serotonergic 5HT2a receptors. animal models of dopaminergic hyperactivity Aripiprazole has shown antagonistic and agonist properties in animal models of dopaminergic hypoactivity. In vitro, aripiprazole shows a high binding affinity for the dopaminergic receptors D2 and D3, for the serotonergic receptors 5HT1a and 5HT2a and a moderate affinity for the dopaminergic D4, for the serotonergic 5HT2c and 5HT7, the alpha1-histamine H1 and the alpha1-histaminergic ones. Aripiprazole also showed moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptor subtypes other than dopaminergic and serotonergic subtypes may explain some of the other clinical effects of aripiprazole. Aripiprazole doses ranging from 0.5 to 30 mg administered once daily to healthy subjects for 2 weeks resulted in a dose-dependent reduction in the binding of 11C-raclopide, 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-week) placebo-controlled clinical trials involving 1,228 adult schizophrenic patients with positive or negative symptoms, aripiprazole was associated with larger, statistically significant improvements in psychotic symptoms than placebo. .
ABILIFY is effective in maintaining clinical improvement during continuation of therapy in adult patients who have shown a response to initial treatment. In a controlled study with haloperidol, the proportion of patients who respond and maintain a response to treatment at 52 weeks was similar in both groups (aripiprazole 77% and haloperidol 73%). The total study completion rate was significantly higher for patients on aripiprazole (43%) than for those on haloperidol (30%). Current scores on the rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg depression rating scale, showed significant improvement over haloperidol.
In a 26-week placebo-controlled study in adult patients with stabilized chronic schizophrenia, the aripiprazole group had a significantly greater reduction in relapse rate, 34% in the aripiprazole group and 57% in the placebo group.
Weight gain - in clinical trials, aripiprazole was not shown to induce clinically relevant weight gain. In a 26-week multinational, double-blind, olanzapine-controlled schizophrenia study involving 314 adult patients and in which the primary end-point was was weight gain, significantly fewer patients had weight gain of at least 7% from baseline (i.e. gain of at least 5.6 pounds for mean baseline weight of ≈ 80.5 kg) in patients treated with aripiprazole (n = 18, or 13% of evaluable patients) compared to patients treated with olanzapine (n = 45, or 33% of evaluable patients).
Lipid parameters - in a pooled analysis of placebo-controlled clinical trials in adults, aripiprazole was not shown to induce clinically relevant changes in total cholesterol, triglycerides, HDL and LDL levels.
• Total cholesterol: the incidence of changes in levels from normal (
• Fasting triglycerides: the incidence of changes in levels from normal (
• HDL: the incidence of changes in levels from normal (
• Fasting LDL: the incidence of changes in levels from normal (
Manic Episodes in Bipolar I Disorder
In two 3-week, flexible-dose, placebo-controlled monotherapy studies in Bipolar I Disorder patients with manic or mixed episode, aripiprazole demonstrated superior efficacy to placebo in reducing manic symptoms after 3 weeks. . These studies included patients with or without psychotic symptoms and with or without rapid cycles.
In a 3-week, fixed-dose, placebo-controlled, monotherapy study in Bipolar I Disorder patients with a manic or mixed episode, aripiprazole did not demonstrate greater efficacy than placebo.
In two 12-week, placebo- or active-controlled monotherapy studies in patients with Bipolar I Disorder, manic or mixed episode, with or without psychotic symptoms, aripiprazole demonstrated superior efficacy to placebo at 3 weeks. and maintenance of comparable efficacy to lithium or haloperidol at 12 weeks. In addition, aripiprazole has reported a comparable proportion of patients in symptom remission from mania to lithium or haloperidol at 12 weeks.
In a 6-week, placebo-controlled study in Bipolar I Disorder patients with manic or mixed episode, with or without psychotic symptoms, partially responsive to treatment with lithium or valproate, as monotherapy for 2 weeks at therapeutic serum levels , the combination with aripiprazole resulted in superior efficacy to lithium or valproate alone in reducing manic symptoms.
In a 26-week, placebo-controlled study followed by a 74-week extension phase, in manic patients who had achieved remission on aripiprazole during a stabilization phase prior to randomization, aripiprazole demonstrated superiority over placebo in preventing relapse into the manic phase, but has not been shown to be superior to placebo in preventing relapse into depression.
In a 52-week, placebo-controlled study in Bipolar I Disorder patients with manic or mixed episode who achieved prolonged remission (Y-MRS and MADRS total score ≤ 12) with aripiprazole (from 10 mg / day at 30 mg / day) combined with lithium or valproate for 12 consecutive weeks, the combination with aripiprazole was superior to placebo with a 46% decrease in risk (hazard ratio 0.54) on relapse prevention for any episode of "mood and a 65% decrease in risk (hazard ratio 0.35) on the prevention of manic relapse compared to" the combination with placebo, but the combination was not superior to placebo on the prevention of depressive relapses. The combination with aripiprazole was superior to placebo in CGI-BP Disease Severity (Mania) (secondary outcome measure).
In this study, patients were assigned by the investigators to either open-label lithium or valproate monotherapy to determine partial non-responses. Patients were stabilized for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer.
The stabilized patients were then randomized to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were evaluated in the randomized phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate.
For the combination arm, the Kaplan-Meier relapse rates for any mood episode were 16% with aripiprazole + lithium and 18% with aripiprazole + valproate compared to 45% with placebo + lithium and 19% with placebo + valproate. .
Pediatric population
Schizophrenia in adolescents
In a 6-week placebo-controlled study involving 302 adolescent schizophrenic patients (13-17 years), who presented with positive or negative symptoms, aripiprazole was associated with larger, statistically significant improvements in psychotic symptoms than placebo.
In a sub-analysis of adolescent patients aged 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed during the 26-week open-label extension study.
Manic episodes in children and adolescents with Type I Bipolar Disorder
Aripiprazole was studied in a 30-week placebo-controlled study 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 manifestations. psychotic and with a baseline Y-MRS score ≥ 20. Among patients included in the primary efficacy analysis, 139 patients were diagnosed with ADHD comorbidity.
Aripiprazole was superior to placebo in changing the total Y-MRS score from baseline at week 4 and week 12. In a "post-hoc analysis, improvement versus placebo was more pronounced in patients with associated ADHD comorbidities than in patients with associated ADHD comorbidity. to the group without ADHD, in which there was no difference from placebo. Relapse prevention has not been established.
Table 1: Mean improvement from baseline in YMRS score for psychiatric comorbidity
n = 51 at Week 4
bn = 46 at Week 4
The most common adverse events emerging from treatment among patients receiving 30 mg were extrapyramidal disorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). ). The mean weight gain over the 30-week treatment interval was 2.9 kg compared to 0.98 kg in the placebo-treated patients.
Irritability associated with autistic disorder in pediatric patients (see section 4.2)
Aripiprazole has been studied in patients aged 6-17 years in two placebo-controlled, 8-week studies [one flexible-dose (2-15 mg per day) and one fixed-dose (5, 10 or 15 mg per day) mg per day)] and in an open label study lasting 52 weeks. In these studies, the starting dosage is 2 mg per day, increased to 5 mg per day after one week, and increased by 5 mg per day every week until the established dosage is reached. More than 75% of the patients were under 13 years of age. Aripiprazole showed statistically superior efficacy to placebo in the Irritability subscale Aberrant Behavior Checklist. However, the clinical relevance of these findings 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 group of clinical studies performed, the incidence of low serum prolactin levels in females (
Aripiprazole was also studied in a long-term, placebo-controlled maintenance study.After a stabilization of 13-26 weeks with aripiprazole (2-15 mg daily), patients with a stable response were either maintained on aripiprazole treatment or switched to placebo for an additional 16 weeks. Kaplan-Meier relapse rates at week 16 were 35% for aripiprazole and 52% for placebo; the 16-week relapse risk rate (aripiprazole / placebo) was 0.57 (non-statistically significant difference). The mean weight gain beyond the stabilization phase (up to 26 weeks) with aripiprazole was 3.2 kg, and an additional mean weight gain of 2.2 was observed during the second phase (16 weeks) of the study. kg for aripiprazole compared to 0.6 kg for placebo Extrapyramidal symptoms were reported mainly during the stabilization phase in 17% of patients, with tremor in 6.5% of patients.
Tics associated with Tourette's syndrome in pediatric patients (see section 4.2)
The efficacy of aripiprazole was studied in pediatric subjects with Tourette's syndrome (aripiprazole: n = 99, placebo: n = 44) in an 8-week randomized, double-blind, placebo-controlled study using a design with weight-based fixed dose treatment groups, for a dose range of 5 mg / day to 20 mg / day with a starting dose of 2 mg. Patients were 7 to 17 years of age and had a mean score of 30 on the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) at baseline. Aripiprazole demonstrated an improvement in TTS change in YGTSS between baseline and week 8 of 13.35 in the low-dose group (5 mg or 10 mg) and 16.94 in the high-dose group (10 mg or 20 mg) ) compared to an improvement of 7.09 in the placebo group.
The efficacy of aripiprazole in pediatric subjects with Tourette's syndrome (aripiprazole: n = 32, placebo: n = 29) was also studied over a flexible dose range between 2 mg / day and 20 mg / day with a single dose initial 2 mg, in a 10-week, randomized, double-blind, placebo-controlled study conducted in South Korea. Patients were aged 6 to 18 years and had a mean score of 29 at TTS of YGTSS at entry. The aripiprazole group demonstrated an improvement of 14.97 in the change in YGTSS TTS between baseline and week 10 compared with an improvement of 9.62 in the placebo group.
Considering the magnitude of the treatment effect relative to the large placebo effect and the unclear effects on psychosocial functioning, the clinical relevance of the efficacy results has not been established in both of these short-term studies. There are no long-term data on the efficacy and safety of aripiprazole in this fluctuating disorder.
The European Medicines Agency has deferred the obligation to submit the results of studies with ABILIFY in one or more subsets of the pediatric population in the treatment of schizophrenia and bipolar affective disorder (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
Aripiprazole is well absorbed, with peak plasma concentrations reached within 3-5 hours after administration. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. A high-fat meal has no effect on the pharmacokinetics of aripiprazole.
Distribution
Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l / kg, indicating extensive extra-vascular distribution. At therapeutic concentrations aripiprazole and dehydro-aripiprazole are bound to plasma proteins to a greater extent than 99%, mainly albumin.
Biotransformation
Aripiprazole is extensively metabolised by the liver, mainly via three biotransformation pathways: dehydrogenation, hydroxylation and N-dealkylation. Based on the studies in vitro, the enzymes CYP3A4 and CYP2D6 are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant molecule in the systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, accounts for approximately 40% of the AUC of aripiprazole in plasma.
Elimination
The mean elimination half-lives for aripiprazole are approximately 75 hours in strong CYP2D6 metabolisers and approximately 146 hours in CYP2D6 weak metabolisers.
Total body clearance of aripiprazole is 0.7 ml / min / kg, primarily via the liver.
After a single oral dose of 14C-labeled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of the unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.
Pharmacokinetics in special patient groups
Pediatric population
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients aged 10-17 years were similar to those in adults after correcting for body weight differences.
Older people
There are no differences in the pharmacokinetics of aripiprazole between healthy elderly subjects and young adults nor was there any detectable effect of age in the population pharmacokinetic analysis of schizophrenic patients.
Sex
There are no differences in the pharmacokinetics of aripiprazole between healthy men and women nor was any effect of sex detected in the pharmacokinetic analysis in a population of schizophrenic patients.
Smoke and Race
A population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences or effects of smoking on the pharmacokinetics of aripiprazole.
Kidney disease
The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were similar in patients with severe renal disease compared to healthy young subjects.
Liver disease
In a single dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B and C) a significant effect of hepatic dysfunction on the pharmacokinetics of aripiprazole and dehydro-aripiprazole was not shown, but the study included only 3 patients with class C liver cirrhosis, which is not sufficient to draw conclusions about its metabolic capacity.
05.3 Preclinical safety data
Non-clinical safety data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity.
Significant effects from the point of view of toxicity were observed only at doses or exposures well in excess of the maximum human ones, indicating that these effects have little or no clinical relevance. These included: dose-dependent adrenocortical toxicity (accumulation of lipofuscin pigment and / or loss of cell parenchyma) in rats after 104 weeks at doses ranging from 20 to 60 mg / kg / day (3 to 10 times the mean AUC at steady state at the maximum recommended dose in humans) and increase in adrenal cortex carcinomas and carcinomas in combination with adrenocortical adenomas in female rats at 60 mg / kg / day (10 times the mean AUC at steady state at maximum dose recommended in man).
The highest non-carcinogenic exposure in female rats was 7 times the human exposure at the recommended dose.
An additional finding was biliary lithiasis as a result of the precipitation of aripiprazole hydroxymetabolite sulfoconjugates in monkey bile after repeated oral doses ranging from 25 to 125 mg / kg / day (1 to 3 times the steady state mean AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose in mg / m2). above 6% of the bile concentrations found in monkeys in the 39-week study and are well below (6%) their solubility limits in vitro.
In repeat dose clinical studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals and there was no evidence of neurotoxicity or developmental adverse reactions.
Based on the results of a full set of standard genotoxicity tests, aripiprazole is considered non-genotoxic. Aripiprazole did not affect fertility in reproductive toxicity studies. Signs of developmental toxicity, including dose-dependent delayed fetal 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 3 to 11-fold exposure. the mean AUC at steady state at the maximum recommended clinical dose. Maternal toxicity occurred at dosages similar to those triggering developmental toxicity of the fetus.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate
Cornstarch
Microcrystalline cellulose
Hydroxypropyl cellulose
Magnesium stearate
Indigo carmine (E132) aluminum lake
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in the original package to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
Aluminum perforated unit dose blisters of 14 x 1, 28 x 1, 49 x 1, 56 x 1, 98 x 1 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Otsuka Pharmaceutical Europe Ltd.
Gallions, Wexham Springs, Framewood Road,
Wexham, SL3 6PJ - United Kingdom
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/04/276 / 001-005
036582017
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 04 June 2004
Date of most recent renewal: 04 June 2009
10.0 DATE OF REVISION OF THE TEXT
D.CCE February 2015
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