Date of approval.
Date of revision.
Aripiprazole Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
WARNING
WARNING
Death is increased in patients with Alzheimer’s-related psychosis.
Atypical antipsychotics used in Alzheimer’s-related psychosis increase the risk of death in patients compared to placebo. Seventeen placebo-controlled studies of the same drug class found that mortality was 1.6 to 1.7 times greater in the drug-treated group than in the placebo group. The mortality rate in the medication group was about 4.5% in a typical 10-week placebo-controlled trial compared to about 2.6% in the placebo group. Although the causes of death vary, most appear to be related to cardiovascular disease (e.g., heart failure or sudden death) or infection (e.g., pneumonia). Aripiprazole should not be used in the treatment of dementia-related psychosis.
Drug Name
Generic name: Aripiprazole Tablets
English name: Aripiprazole Tablets
Hanyu Pinyin: Alipaizuo Pian
Ingredients
The main ingredient of this product is aripiprazole.
Chemical name: 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone
Chemical structure formula.
Molecular formula: C23H27Cl2N3O2
Molecular weight: 448.39
Properties
5mg tablet is a pink capsule-shaped biconvex tablet with “5” engraved on one side and “P” engraved on the other side.
10mg tablet is a beige capsule-shaped biconvex tablet with “10” engraved on one side and “P” engraved on the other side.
15mg tablet is a pink round biconvex tablet with “15” engraved on one side and “P” engraved on the other side.
Indications
For the treatment of schizophrenia.
Adults
The efficacy of aripiprazole in the treatment of schizophrenia was established in short-term (4 and 6 weeks) controlled trials in schizophrenic patients. Physicians who choose aripiprazole for long-term treatment should periodically reassess the long-term efficacy of the drug in individual patients.
Adolescents
The efficacy of aripiprazole in treating schizophrenia in adolescent patients (13 to 17 years of age) was established in a 6-week placebo-controlled trial. Physicians who choose aripiprazole for long-term treatment should periodically reevaluate the long-term efficacy of the drug in individual patients.
【Specifications】（1）5mg（2）10mg（3）15mg
【Dosage】.
Take orally, once daily, independent of food intake.
Adults
The recommended starting and therapeutic dose of aripiprazole is 10 or 15 mg/day, independent of food intake. Systematic evaluations have shown that clinically effective doses of aripiprazole range from 10 to 30 mg/day. The efficacy of the higher dose was not superior to the lower dose of 10 mg or 15 mg/day. The dose should not be increased within 2 weeks of dosing (the time required for the drug to reach steady state), after 2 weeks, the dose may be adjusted appropriately based on individual efficacy and tolerance, but the rate of dosing should not be too rapid.
Adolescents
The recommended target dose of aripiprazole is 10 mg/day. The starting daily dose is 2mg, increasing to 5mg after two days, and then to the target dose of 10mg after another two days. Thereafter, the dose is increased in 5 mg increments up to a maximum daily dose of 30 mg. no increase in efficacy is seen at 30 mg/day compared to 10 mg/day.
Dosing for special populations
Dose adjustment based on age, gender, race or renal or hepatic impairment is generally not required.
Dose adjustment for concomitant CYP3A4 inhibitors: When concomitant ketoconazole is administered, the dose of aripiprazole should be reduced to half the usual dose. When CYP3A4 inhibitors are discontinued, the dose of aripiprazole should be increased.
Dose adjustment for concomitant CYP2D6 inhibitors: When taking concomitant CYP2D6 inhibitors (e.g., quinidine, fluoxetine, or paroxetine), reduce the dose of aripiprazole to at least half of its usual dose. The dose of aripiprazole should be increased when CYP2D6 inhibitors are discontinued.
Dose adjustment for concomitant CYP3A4 inducers: The dose of aripiprazole should be doubled (to 20 or 30 mg) when concomitant CYP3A4 inducers (e.g., carbamazepine) are administered. Additional dosing should be based on clinical assessment. When carbamazepine is discontinued, the dose of aripiprazole should be reduced to 10 to 15 mg.
When switching from taking other antipsychotics to this product
Conversion from other antipsychotics to aripiprazole or aripiprazole in combination with other antipsychotics has not been systematically evaluated in patients with schizophrenia. Although immediate discontinuation of the previous medication may be acceptable in some patients, gradual discontinuation may be more appropriate. In all cases, the duration of overlapping antipsychotic doses should be kept as short as possible.
[Adverse reactions].
The safety of aripiprazole was evaluated in a multi-dose, premarketing clinical trial involving 7,951 adult patients with schizophrenia, bipolar disorder manic episodes, and Alzheimer’s dementia; of which the exposure was approximately 5,235 case years. In total, 2,280 aripiprazole users were treated for at least 180 days and 1,558 aripiprazole-treated patients were treated for at least 1 year.
The safety of aripiprazole was evaluated in a multi-dose clinical trial involving 1,686 pediatric patients (6 to 18 years of age) with schizophrenia, bipolar mania, autism, or Tourette’s syndrome; the exposure to oral aripiprazole was approximately 1,342 case years. In total, 959 pediatric patients received oral aripiprazole for at least 180 days, and 556 pediatric patients had at least one year of aripiprazole exposure.
Conditions and courses of aripiprazole treatment included (with overlapping categories) double-blind, controlled and uncontrolled open trials, trials in inpatients and outpatients, trials with fixed and variable doses, and short- and long-term drug trials.
Adverse events during dosing were obtained by spontaneous reporting, as well as by results of physical examination, vital signs, weight, laboratory analysis, and electrocardiogram (ECG).
The incidence of adverse events is the proportion of cases that experienced at least one adverse event of the category to which they belong during treatment. An event was considered to be caused by treatment if it was the first occurrence or if it was worse than the baseline evaluation at the time of treatment. No consideration was given to selecting adverse events by investigator assessment of causality, i.e., all reported adverse events were included in the statistics.
Adults
Adverse outcomes observed in short-term, placebo-controlled clinical trials in patients with schizophrenia
Daily doses of aripiprazole ranged from 2 to 30 mg/kg in five placebo-controlled clinical trials (4 to 6 weeks).
Overall, the incidence of treatment discontinuation due to adverse events did not differ between aripiprazole-treated patients (7%) and placebo-treated patients (9%). The types of adverse events leading to treatment discontinuation were similar between aripiprazole-treated patients and placebo-treated patients.
Adverse outcomes observed in short-term placebo-controlled clinical trials in patients with bipolar disorder manic episodes
The daily dose of aripiprazole in the 3-week placebo-controlled clinical trial was 15 or 30 mg/kg.
Overall, among patients with bipolar disorder manic episodes, the incidence of treatment discontinuation due to adverse events did not differ between aripiprazole-treated patients (11%) and placebo-treated patients (9%). The types of adverse events leading to discontinuation were similar between aripiprazole-treated patients and placebo-treated patients.
Adverse events common in patients with bipolar disorder manic episodes in short-term placebo-controlled clinical trials
The common adverse events associated with the use of aripiprazole in patients with bipolar disorder manic episodes (incidence ≥5%, at least twice the incidence in the aripiprazole group compared with the placebo group) are shown in Table 1. In the short-term clinical trials in schizophrenia, there were no adverse events that met these criteria.
Table 1 Common adverse events in patients with bipolar disorder manic episodes in short-term placebo-controlled clinical trials
Percentage of patients reporting adverse events Aripiprazole placebo adverse events (n=597) (n=436) Accidental injury 63 Constipation 136 Inability to sit still 154
Adverse events occurring at ≥2% and higher than placebo in aripiprazole-treated patients in short-term placebo-controlled clinical trials
Table 2 presents the combined incidence of adverse events occurring during acute treatment (up to 6 weeks for schizophrenia and up to 3 weeks for bipolar disorder manic episodes), modified to the nearest whole number, and includes only adverse events with an incidence ≥2% or higher than placebo in patients treated with aripiprazole (daily dose ≥2 mg/day).
Table 2 Adverse events on treatment in short-term placebo-controlled clinical trials
Percentage of patients reporting adverse eventsa Physical system Aripiprazole placebo adverse events (n=1523) (n=849) Systemic
Headache3126
Weakness87
Accidental injury54
Peripheral edema21 Cardiovascular system
Hypertension21 Gastrointestinal system
Nausea1612
dyspepsia1513 vomiting116 constipation117 musculoskeletal system myalgia43 nervous system agitation2524 anxiety2017 insomnia2015 drowsiness128 inability to sit still125 dizziness118 extrapyramidal syndromeg64 tremor43 polysalivation31 respiratory system pharyngitis43 rhinitis43 cough32 peculiar sensations blurred vision31a: reported by at least 2% of aripiprazole-treated patients adverse events, excluding those with an incidence comparable to or lower than placebo: e.g., abdominal pain, back pain, toothache, diarrhea, dry mouth, loss of appetite, psychosis, hypertonia, upper respiratory tract infection, rash, vaginitisf, dysmenorrheaf. f: percentage based on total gender. g: adverse events associated with extrapyramidal symptoms (e.g., dystonia events, Parkinson’s events, sedentary inability events , dyskinesia events) subpopulation studies did not find any clear evidence of differences in the incidence of adverse events by age, sex, or race.
Pediatric patients (13 to 17 years of age)
The daily dose of aripiprazole in a 6-week placebo-controlled trial ranged from 2 to 30 mg/day. The incidence of treatment discontinuation due to adverse reactions was 5% in aripiprazole-treated patients (13 to 17 years of age) and 2% in placebo-treated patients (13 to 17 years of age). The common adverse reactions associated with the use of aripiprazole (incidence ≥5%, at least twice the incidence in the aripiprazole group compared with the placebo group) were extrapyramidal syndrome, somnolence, and tremor.
Table 3 presents the combined incidence of adverse reactions occurring during acute treatment (up to 6 weeks in patients with schizophrenia, up to 4 weeks in bipolar disorder manic episodes, up to 8 weeks in autism, and up to 10 weeks in patients with tic-tac-toe syndrome), modified to approximately whole percent values, including only those with an incidence ≥2% in pediatric patients treated with aripiprazole (daily dose ≥2 mg) and greater than the placebo-treated patients The incidence of adverse reactions.
Table 3 Adverse reactions in short-term, placebo-controlled trials of oral aripiprazole treatment in pediatric patients (6 to 18 years of age)
Percentage of patients reporting adverse reactions Systemic organ classification Aripiprazole placebo Preferred term (n=732) (n=370) Ophthalmic symptoms Blurred vision30 Gastrointestinal symptoms Abdominal discomfort21 Vomiting87 Nausea84 Diarrhea43 Hypersalivation41 Epigastric pain32 Constipation22 Systemic symptoms and administration site symptoms Fatigue102 Fever41 Irritability21 Weakness21 Infection and invasive nasal Pharyngitis63 ExaminationWeight gain31 Metabolic and nutritional disordersIncreased appetite73 Loss of appetite54 Musculoskeletal tissue and connective tissue symptomsMusculoskeletal stiffness21 Myotonicity21 Neurologic symptomsDrowsiness164 Headache1210 Sedation92 Tremor91 Extrapyramidal syndrome61 Inability to sit still64 Salivation30 Drowsiness30 Dizziness32 Dystonia21 Respiratory, thoracic, and mediastinal symptomsNose bleeds 21 skin and subcutaneous tissue symptoms rash21 dose-related adverse events
Schizophrenia
Dose-effect relationships for the incidence of adverse events occurring at the time of treatment were evaluated in four placebo-controlled clinical trials with adult patients with schizophrenia at different fixed doses (2, 10, 15, 20, and 30 mg/day). Stratified analysis showed that the only adverse event that could have a dose-effect relationship and was most pronounced only at 30 mg was drowsiness (placebo: 7.7%; 15 mg: 8.7%; 20 mg: 7.5%; 30 mg: 15.3%).
In trials in pediatric schizophrenia patients (13 to 17 years of age), three common adverse events may have had dose-effect relationships: extrapyramidal syndrome (placebo: 5.0%; 10 mg: 13.0%; 30 mg: 21.6%); somnolence (placebo: 6.0%; 10 mg: 11.0%; 30 mg: 21.6%) and tremor (placebo: 2.0% ; 10 mg: 2.0%; 30 mg: 11.8%).
Extrapyramidal syndrome
In short-term placebo-controlled trials in adults with schizophrenia, the incidence of extrapyramidal syndrome (EPS) was reported to be 6% in patients in both the aripiprazole and placebo groups. In a short-term placebo-controlled trial of manic episodes in adults with bipolar disorder, the incidence of EPS-related events (other than those related to inability to sit still) was 17% in aripiprazole-treated patients compared with 12% in placebo. In a short-term placebo-controlled trial of manic episodes in adults with bipolar disorder, the incidence of events related to inability to sit still was 15% in aripiprazole-treated patients compared with 4% in placebo. In a short-term placebo-controlled trial in pediatric schizophrenic patients (13 to 17 years of age), the incidence of extrapyramidal syndrome-related events other than sedentary inability-related events was 25% in the aripiprazole group and 7% in the placebo group, and 9% and 6% in the two groups, respectively.
Data were collected objectively on the basis of the Simpson Angus Rating Scale (evaluating EPS), the Barnes Sedentary Inability Scale (evaluating sedentary inability), and the Irregular Motor Assessment Scale (evaluating movement disorders). In the adult schizophrenia trial, the scores did not show a difference between aripiprazole and placebo, except for the Barnes Sedentary Inability Scale (aripiprazole: 0.08, placebo: -0.05). In the Adult Bipolar Disorder Manic Episode Trial, the Simpson-Angus score and Barnes Sedentary Inability score showed significant differences between aripiprazole and placebo (aripiprazole: 0.61, placebo: 0.03; aripiprazole: 0.25, placebo: -0.06). Changes in aripiprazole and placebo involuntary movement scores were similar. In the trial of pediatric schizophrenic patients (13-17 years old), objectively collected data showed no difference in the scores of the other scales between the aripiprazole and placebo groups, except for the Simpson-Angus Rating Scale (aripiprazole: 0.24; placebo: -0.29).
Similarly, in a long-term (26-week) placebo-controlled trial in adults with schizophrenia, the Simpson-Angus score (evaluating EPS), the Barnes Sedentary Inability Score (evaluating sedentary inability), and the Irregular Motor Score (evaluating dyskinesia) did not show differences between aripiprazole and placebo.
Abnormal laboratory tests
Between-group comparisons of the 3- to 6-week placebo-controlled trials showed no significant differences between the aripiprazole and placebo groups in the proportion of subjects with potentially clinically significant changes in blood biochemistry, hematology, and urinalysis parameters. Similarly, there was no difference between aripiprazole and placebo in the rate of discontinuation due to altered blood chemistry, hematology, and urine test parameters.
In the long-term (26-week) placebo-controlled trial, there were no clinically significant mean changes in prolactin, fasting glucose, triglycerides, HDL, LDL, and total cholesterol in aripiprazole-treated patients and placebo-treated patients compared to baseline.
Weight gain
Adults
In a 4-week to 6-week trial of patients with schizophrenia, mean weight gain differed slightly between aripiprazole-treated and placebo-treated patients (+0.7 kg and -0.05 kg, respectively), as did the proportion of patients meeting criteria for weight gain of ≥7% (8% in the aripiprazole group and 3% in the placebo group). In a 3-week trial of patients with manic episodes in bipolar disorder, the mean weight gain was 0.0 kg and -0.2 kg in aripiprazole-treated patients and placebo-treated patients, respectively. the proportion of patients with ≥7% weight gain was 3% and 2% in the aripiprazole and placebo groups, respectively.
Table 4 shows the results of weight change by baseline body mass index (BMI) in the long-term (26-week) placebo-controlled trial of aripiprazole, including the mean change in weight based on baseline and the proportion of patients who gained ≥7% of their baseline weight.
Table 4 Results of weight change by baseline body mass index: placebo-controlled study in schizophrenia, safety sample
BMI<23BMI 23 to 27BMI>27 Placebo Aripiprazole Placebo Aripiprazole Placebo Aripiprazole Mean change in weight based on baseline (kg) -0.5-0.5-0.6-1.3-1.5-2.1 Percentage of patients with ≥7% weight gain 3.7% 6.8% 4.2% 5.1% 4.1% 5.7% Table 5 shows that aripiprazole results of weight change by baseline BMI in the long-term (52-week) clinical study of prazole administration, including mean change in weight based on baseline and the percentage of patients who gained ≥7% of their baseline weight.
Table 5 Results of weight change by baseline BMI: Schizophrenia Active Medication Controlled Study, Safety Sample
BMI<23BMI 23 to 27BMI>27 Mean change in weight based on baseline (kg) 2.61.4-1.2 Percentage of patients with ≥7% weight gain 30% 19% 8% Pediatric patients and adolescents
In the analysis of two placebo-controlled trials (median exposure cycle of 42-43 days) with adolescents with schizophrenia (13-17 years) and pediatric patients with bipolar disorder (10-17 years), the mean change in body weight was +1.6 kg (N=381) in the aripiprazole-treated group and +0.3 kg in the placebo-treated group ( N=187). At week 24, the mean change from baseline in weight was +5.8 kg for patients in the aripiprazole treatment group (n=62) and +1.4 kg for patients in the placebo treatment group (n=13).
Table 6 shows the proportion of pediatric and adolescent patients with ≥7% weight gain by indication.
Table 6: Proportion of pediatric and adolescent patients with ≥7% weight gain in placebo-controlled monotherapy trials
Weight gain ≥7% indication treatment group N patients n (%) Summary of schizophrenia and bipolar maniaa Aripiprazole 38120 (5.2) Placebo 1873 (1.6)a 4-6 week duration
In an open trial enrolling patients from two placebo-controlled trials of adolescents with schizophrenia (13-17 years) and pediatric patients with bipolar disorder (10-17 years), 73.2% (238/325) completed 26 weeks of aripiprazole treatment. after 26 weeks, 32.8% of patients gained ≥7% body weight, uncorrected for normal growth. After correction for normal growth, z-scores (expressed as standard deviation [SD]) were obtained, corrected for normal growth in pediatric patients and adolescents by comparison with age- and sex-matched populations. z-score change<0.5 SD was considered not clinically significant. after 26 weeks, the mean change in z-score was 0.09 SD.
When treating pediatric patients for any indication, weight gain should be monitored and evaluated according to expected normal growth.
Electrocardiographic changes
A mixed group comparison of placebo-controlled trials in patients with schizophrenia or bipolar disorder manic episodes showed no significant difference in the proportion of patients presenting with potentially important changes in electrocardiographic (ECG) parameters between the aripiprazole and placebo groups. The median value of the increase in heart rate was 5 beats per minute in the aripiprazole group and 1 beat per minute in the placebo group.
Other results observed in clinical trials
Adverse events reported in a 26-week double-blind clinical trial comparing aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in short-term placebo-controlled clinical trials, except for a somewhat higher incidence of tremor [9% (13/153) with aripiprazole and 1% (2/153) with placebo]. In that study, most tremor cases were mild in severity (9/13 mild, 4/13 moderate), occurred early in treatment (9/13 ≤ 49 days), and were of limited duration (9/13 ≤ 10 days). Tremor rarely led to aripiprazole discontinuation (<1%). In addition, the incidence of tremor in the aripiprazole group was 4% (34/859) in the long-term (52-week) active drug-controlled study. A similar situation could be observed in long-term bipolar disorder studies.
Other adverse events observed during the premarketing evaluation of aripiprazole
Adverse events that occurred during treatment are listed below using the revised COSTART terminology. These adverse events, as previously mentioned, were derived from a database of 7,951 patients and were reported by patients during their participation in phase I clinical trials of aripiprazole ≥2 mg/day at multiple doses. All reported adverse events were included (excluding the following: those already listed in Table 2 or other paragraphs, those considered in [Precautions], those for which the event terminology was too common to provide much information, those with an incidence of ≤0.05% and no immediate life-threatening potential at all, others as common as background events, and those considered unlikely to be drug-related). It is important to emphasize that although the reported events occurred during treatment with aripiprazole, they were not necessarily caused by aripiprazole.
Adverse events are listed by organism system and in decreasing order of frequency as defined below: common adverse events are those occurring in at least 1 in 100 patients (listed here are only those in placebo-controlled trials not included in the outcome tables); rare adverse events are those occurring in 1 in 100 to 1 in 1,000 patients; and rare adverse events are those occurring in less than 1 in 1, 000 patients.
Adult
Systemic: common – influenza syndrome, fever, chest pain, tonicity (including neck and extremities), neck pain, pelvic pain; rare – facial edema, suicidal ideation, malaise, migraine, chills, photosensitivity, tightness (including abdomen, back, extremities, head, jaw, neck and tongue), jaw pain, gastric distention, bloating, tightness in the chest sore throat; rare – candidiasis, head heaviness, tightness in the throat, Mendelssohn syndrome, heat stroke.
Cardiovascular system: common – tachycardia (both ventricular and supraventricular), hypotension, bradycardia; rare – palpitations, hemorrhage, heart failure, myocardial infarction, cardiac arrest, atrial fibrillation, AV block, prolonged QT interval, extrasystole, myocardial ischemia, deep venous thrombosis, angina pectoris, pallor, cardiopulmonary dysfunction , phlebitis; rare-bundle branch block, atrial flutter, vasovagal response, cardiac hypertrophy, thrombophlebitis, cardiopulmonary failure
Digestive system: common – nausea and vomiting; rare – increased appetite, dysphagia, gastroenteritis, gastrointestinal gas, dental caries, gastritis, gingivitis, gastrointestinal bleeding, hemorrhoids, gastroesophageal reflux, periodontal abscess, fecal incontinence, rectal bleeding, gastritis, colitis, tongue edema, cholecystitis, oral ulcers, oral candidiasis, belching fecal impaction, cholelithiasis; rare-esophagitis, vomiting blood, intestinal obstruction, bleeding gums, hepatitis, peptic ulcer, tongue inflammation, black stool, duodenal ulcer, labyrinthitis, hepatomegaly, pancreatitis.
Endocrine system: rare – hypothyroidism; rare – goiter, hyperthyroidism.
Hematologic/lymphatic system: common – bruising, anemia; rare – hypochromic anemia, leukocytosis, leukopenia (including neutropenia), lymphadenopathy, eosinophilia, macrocytic anemia; rare – thrombocytosis, thrombocytopenia, petechiae.
Metabolic and nutritional disorders: common – weight loss, elevated creatine phosphokinase, dehydration; rare – edema, hyperglycemia, hypercholesterolemia, hypokalemia, diabetes mellitus, hypoglycemia, hyperlipidemia, elevated serum glutamate transaminase, thirst, increased blood urea nitrogen, hyponatremia, elevated serum glutamic oxalacetic transaminase, increased creatinine, cyanosis increased alkaline phosphatase, bilirubinemia, iron deficiency anemia, hyperkalemia, hyperuricemia, obesity; rare- increased lactate dehydrogenase, hypernatremia, gout, hypoglycemic reaction.
Musculoskeletal system: common – painful muscle spasms; rare – arthralgia, muscle weakness, arthrosis, bone pain, arthritis, muscle weakness, spasticity, bursitis, myopathy; rare – rheumatoid arthritis, rhabdomyolysis, tendinitis, tenosynovitis.
Neurological: common – depression, hypersensitivity, schizophrenic reactions, hallucinations, hostility, confusion, paranoid reactions, suicidal thoughts, abnormal gait, manic reactions, delusions, strange dreams; rare – emotional instability, tremors, cogwheel-like tonicity, concentration deficits, dystonia, vasodilation, sensory abnormalities, impotence, extremities tremor, dullness of sensation, vertigo, xylopsia, bradykinesia, apathy, panic attacks, hypoactive sexual desire, hypersomnia, dyskinesia, manic-depressive reactions, ataxia, hallucinations, cerebrovascular accidents, hypokinesia, depersonalization, memory deficits, delirium, dysarthria, tardive dyskinesia, amnesia, hyperactivity, increased libido, myoclonus, hyperactive legs, neuropathy, irritability hyperkinesia, cerebral ischemia, enhanced reflexes, motor inability, decreased consciousness, sensory hypersensitivity, slow thinking; rare- emotional retardation, euphoria, movement disorders, motoneurotic crisis, obsessive-compulsive thinking, hypotonia, buccolingual syndrome, diminished reflexes, reality dissociation, intracranial hemorrhage.
Respiratory system: common – sinusitis, dyspnea, pneumonia, asthma; rare – rhinorrhea, eruption, laryngitis, aspiration pneumonia; rare – pulmonary edema, sputum, pulmonary embolism, hypoxia, respiratory failure, apnea, nasal dryness, hemoptysis.
Skin and adnexa: common – skin ulcers, sweating, dry skin; rare – pruritus, blistering maculopapular rash, acne, eczema, skin discoloration, hair loss, seborrheic dermatitis, psoriasis; rare – maculopapular rash, exfoliative dermatitis, rubella.
Special sensory system: common – conjunctivitis; rare – otalgia, dry eyes, ocular pain, tinnitus, cataract, otitis media, altered taste, blepharitis, ocular hemorrhage, deafness; rare – diplopia, frequent blinking, ptosis otitis externa, amblyopia, photophobia.
Genitourinary system: common – interrupted urine flow; rare – frequent urination, leukorrhea, urinary retention, cystitis, hematuria, dyspareunia, amenorrhea, vaginal bleeding, abnormal ejaculation, renal failure, vaginal candidiasis, urinary urgency, gynecomastia, renal calculi, proteinuria, breast pain, burning urethra; rare -Nocturia, polyuria, menorrhagia, sexual pleasure deficiency, diabetes, cervicitis, uterine bleeding, female lactation, urolithiasis, abnormal penile erection.
Pediatric patients
The majority of adverse events observed in a pooled database of 1,686 pediatric patients aged 6 to 18 years were also seen in the adult patient population. Additional adverse reactions observed in the pediatric population are listed below.
Ophthalmic symptoms.
Rare – oculomotor crisis
Gastrointestinal Symptoms.
Rare – dry tongue, tongue cramps
Examination.
Common – Elevated blood insulin
Neurological symptoms.
Rare – sleep talking disorder
Renal and urinary symptoms
Common – Enuresis
Skin and subcutaneous tissue symptoms.
Rare – hirsutism
Other adverse events observed during post-marketing evaluation of aripiprazole
Adverse events spontaneously reported by patients taking aripiprazole since its launch and not listed above include rare allergic reactions (e.g., anaphylaxis, angioedema, laryngospasm, pruritus, or urticaria), elevated gamma-glutamyl transferase, and abnormalities in thermoregulation (e.g., fever, hypothermia) that may not be causally related to the drug. Post-marketing adverse events observed also include: agitation, pathological gambling, increased glycated hemoglobin, excessive sweating, musculoskeletal stiffness, hiccups, jaundice, hypersalivation, speech disorders, suicidal ideation, suicidal death, hypersexuality, and impulse control disorders.
[Contraindication].
Contraindicated in patients with known hypersensitivity to this product.
Precautions】
General Precautions
Postural hypotension
Aripiprazole has an a1-adrenergic receptor antagonistic effect and may cause postural hypotension. In five short-term placebo-controlled trials of aripiprazole in adults with schizophrenia (n=926), the incidence of events associated with postural hypotension included postural hypotension (placebo 1%, aripiprazole 1.9%), postural dizziness (placebo 1%, aripiprazole 0.9%), and syncope (placebo 1%, aripiprazole 0.6%). The incidence in pediatric patients aged 6 to 18 years (n=732) taking oral aripiprazole included (incidence in the aripiprazole group, incidence in the placebo group) postural hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%). In a short-term placebo-controlled trial of aripiprazole for manic episodes in adults with bipolar disorder (n=597), the incidence of events associated with postural hypotension included postural hypotension (placebo 0%, aripiprazole 0.7%), postural dizziness (placebo 0.5%, aripiprazole 0.5%), and syncope (placebo 0.9%, aripiprazole 0.5%).
The incidence of significant postural blood pressure changes (defined as a decrease in systolic blood pressure of at least 30 mmHg from supine to upright) was not statistically different between aripiprazole and placebo (adults with schizophrenia: 14% in aripiprazole-treated patients versus 12% in placebo-treated patients; adults with bipolar disorder manic episodes: 3% in aripiprazole-treated patients versus 2% in placebo-treated patients).
Aripiprazole should be used with caution in patients with known cardiovascular disease (myocardial infarction or ischemic heart disease, heart failure, or history of conduction abnormalities), in patients with cerebrovascular disease, or in conditions that induce hypotension (dehydration, hypovolemia, and antihypertensive drug therapy).
Seizures
In short-term placebo-controlled clinical trials, seizures occurred in 0.1% (1/926) of adult patients treated with aripiprazole and in 0.1% (1/732) of pediatric patients (6 to 18 years of age) treated with aripiprazole. In short-term placebo-controlled clinical trials for the treatment of adult patients with bipolar disorder manic episodes, seizures occurred in 0.3% (2/597) of aripiprazole-treated patients and 0.2% of placebo-treated patients. As with other antipsychotics, aripiprazole should be used with caution in patients with a history of seizures or in patients with conditions with a low seizure threshold (e.g., Alzheimer’s disease dementia). Low seizure thresholds are more common in people over 65 years of age.
Potential cognitive and motor impairment
In short-term placebo-controlled trials in schizophrenia, 11% of aripiprazole-treated adult patients reported drowsiness compared with 8% of placebo-treated adult patients; 24% of pediatric patients aged 6 to 17 years (n=611) were in the aripiprazole group compared with 6% in the placebo group. In short-term placebo-controlled clinical trials, drowsiness led to discontinuation in 0.1% (1/926) of aripiprazole-treated adult patients with schizophrenia; and in 3% (20/732) of aripiprazole-treated pediatric patients (6 to 18 years of age). In a short-term placebo-controlled trial of bipolar disorder manic episodes in adults, 14% of aripiprazole-treated patients had drowsiness compared with 7% of placebo-treated patients; however, drowsiness did not lead to discontinuation in patients with bipolar disorder manic episodes. Despite the relatively higher incidence of drowsiness in aripiprazole-treated patients compared with placebo, aripiprazole, like other antipsychotics, may impair judgment, thinking, or motor skills. Patients should be warned to operate machines with some risk, including automobiles, with caution until they are confident that aripiprazole treatment will not adversely affect them.
Thermoregulation
Interference with the body’s thermoregulatory mechanisms is a characteristic of antipsychotics. Appropriate care is recommended when aripiprazole is prescribed to patients who are at risk of elevated body temperature (e.g., strenuous exercise, overheating, concomitant administration of anticholinergic active drugs, or dehydration).
Swallowing disorders
Esophageal motor dysfunction and aspiration are associated with the use of antipsychotics. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, especially in elderly patients with progressive Alzheimer’s dementia. Aripiprazole and other antipsychotics should be used with caution in patients at risk for aspiration pneumonia.
Suicide
Suicidal ideation is inherent to psychosis and bipolar disorders, and patients at risk should be closely monitored during pharmacotherapy. To reduce the risk of overdose, the dose of aripiprazole should be kept to a minimum and the patient should be well managed.
Dosing in patients with other comorbidities
There is a lack of clinical experience with the use of aripiprazole in patients with certain comorbid systemic diseases.
Aripiprazole has not been evaluated or used in patients with a history of recent myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarket clinical studies.
Safety experience in elderly psychiatric patients with Alzheimer’s disease: In three 10-week placebo-controlled trials of aripiprazole in elderly psychiatric patients with Alzheimer’s disease (n=938, mean age: 82.4 years; age range: 56 to 99 years), the incidence of ≥3% on treatment and at least twice the incidence in the aripiprazole group compared with the placebo group Adverse events included debilitation (placebo 3%, aripiprazole 8%), drowsiness (placebo 3%, aripiprazole 9%) and urinary incontinence (placebo 1%, aripiprazole 5%), excessive salivation (placebo 0%, aripiprazole 4%), and dizziness (placebo 1%, aripiprazole 4%).
The safety and efficacy of aripiprazole in the treatment of patients with dementia-related psychosis have not been established. Particular caution should be exercised if physicians choose to treat these patients with aripiprazole, especially in those patients who present with dysphagia or excessive drowsiness that may induce accidental injury or accidental aspiration.
Antipsychotic malignant syndrome (NMS)
A potentially fatal syndrome has been reported in association with the administration of antipsychotics, including aripiprazole, and is known as antipsychotic malignant syndrome (NMS). There were 2 cases of suspected NMS in the pre-marketing global clinical database for aripiprazole. clinical signs of NMS are hyperthermia, myoclonus, altered mental status and signs of autonomic instability (irregular pulse or blood pressure fluctuations, tachycardia, sweating and arrhythmias). Other signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
Diagnostic evaluation of patients with this syndrome is complex. In order to obtain this diagnosis, it is important to exclude clinical manifestations that are accompanied by severe medical disease (e.g., pneumonia, systemic infections, etc.) and untreated or inappropriately treated extrapyramidal signs and symptoms (EPS). Another important consideration in the differential diagnosis includes central anticholinergic toxicity, heat stroke, pharmacogenic fever, and primary CNS disease.
Management of NMS should include 1) immediate discontinuation of antipsychotics and other current nonessential therapeutic medications, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of concomitant serious medical problems for which specific treatments are available. For uncomplicated NMS, there is no universally agreed upon specific medication regimen.
If a patient still requires antipsychotic treatment after recovery from NMS, the possibility of retriggering NMS with pharmacotherapy should be carefully considered. Patients should be monitored closely, as relapse of NMS has been reported.
Delayed-onset movement disorders
Irreversible unconscious dyskinesia syndrome may occur in patients treated with antipsychotics. Although the syndrome has the highest incidence in older adults (especially older women), it is not possible to predict which patients are likely to develop the syndrome at the beginning of antipsychotic treatment based solely on epidemiologic estimates. It is not clear whether there are differences in the role of antipsychotics in causing delayed-onset dyskinesia.
It has been established that the risk of developing tardive dyskinesia and the likelihood of it becoming irreversible increases with longer treatment courses and as the total cumulative dose of antipsychotics taken by the patient increases. However, the syndrome may also occur after brief treatment with low-dose antipsychotics, but is generally rare.
Although the syndrome remits partially or completely after discontinuation of antipsychotic treatment, there is no known treatment option for cases diagnosed with tardive dyskinesia. However, antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of this syndrome, which may mask the progression of the disease course. It is not clear whether symptom suppression has an impact on the long-term course of the syndrome.
Based on these considerations, aripiprazole should be administered in a manner that minimizes the occurrence of delayed dyskinesia. Long-term antipsychotic treatment should be reserved for patients who develop chronic disease and who are (1) known to be effectively treated with antipsychotics and (2) for whom alternative equivalent, but potentially less harmful, treatments are not available or appropriate. In patients requiring long-term treatment, the lowest therapeutic dose and shortest duration of treatment that achieves satisfactory efficacy should be sought. The need for continuous therapy should be reassessed periodically.
If aripiprazole-treated patients develop signs and symptoms of delayed dyskinesia, discontinuation of the drug should be considered. These symptoms may worsen temporarily or may even appear after treatment discontinuation. However, some patients may require treatment with aripiprazole despite the presence of this syndrome.
Cerebrovascular adverse events, including stroke, in patients with dementia-related Alzheimer’s psychosis
In placebo-controlled clinical trials in dementia-related psychosis, aripiprazole-treated elderly patients (mean age: 84 years; age range: 78 to 88 years) had an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including death. The results of the fixed-dose trial showed a statistically significant dose-response relationship between cerebrovascular adverse events and the drug in aripiprazole-treated patients. Aripiprazole should not be used in the treatment of patients with dementia-related psychosis.
Hyperglycemia and diabetes mellitus
Hyperglycemia has been reported to be very severe and accompanied by ketoacidosis or hyperosmolar coma or death in some cases in patients treated with atypical antipsychotics. Little hyperglycemia has been reported in aripiprazole-treated patients, although few patients have been treated with aripiprazole, but it is not clear whether these very limited experiences are the only reason for the paucity of such reports. Assessing the relationship between atypical antipsychotic use and dysglycemia is complex because of the possible increased risk of a diabetic background in patients with schizophrenia and the elevated incidence of diabetes in the general population. With the interference of these confounding factors, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is even more completely elusive. However, epidemiological studies that did not include aripiprazole suggested that patients treated with atypical antipsychotics in these studies were at increased risk for hyperglycemia-related adverse events during treatment. Because aripiprazole was not available at the time these studies were conducted, it is not clear whether aripiprazole was associated with this increased risk. In patients treated with atypical antipsychotics, there are no clear values for assessing the risk of hyperglycemia-related adverse events that can be utilized.
Patients with a definite diagnosis of diabetes at the time of initiation of atypical antipsychotic therapy should be monitored regularly for deterioration in glycemic control. Patients with risk factors for diabetes (e.g., obesity, family history of diabetes) should receive fasting glucose testing before and periodically during initiation of atypical antipsychotic therapy. Any patient on atypical antipsychotic therapy should be monitored for symptoms of hyperglycemia, including thirst, polyuria, polyphagia, and malaise. Patients who develop symptoms of hyperglycemia during atypical antipsychotic therapy should receive a fasting blood glucose test. In some cases, hyperglycemia resolves on its own when atypical antipsychotic therapy is discontinued; however, some patients require continued glucose-lowering therapy despite discontinuation of the suspected medication.
12. Pathological Gambling and Other Impulse Control Disorders
Post-marketing reports suggest that patients may experience increased impulsivity, particularly gambling, and inability to control these impulses while taking aripiprazole. Other reports from very rare sources include increased sexual urges, compulsive spending, binge or compulsive eating, and other impulsive or compulsive behaviors. Because patients may not perceive these behaviors as abnormal, prescribers should specifically ask patients or their caregivers about new or increased gambling urges, sexual urges, compulsive spending, overeating or compulsive eating, and other impulsive behaviors. If patients experience these urges while taking aripiprazole, consider reducing the dose or discontinuing the drug.
[Pregnant and lactating women use].
Appropriate and well-controlled studies have not been conducted in pregnant women. It is not known whether aripiprazole can cause fetal damage or affect fertility when administered to pregnant women. In pregnant women, it should be used only if the potential benefit to the fetus outweighs the potential risk. Patients should be advised to notify their internist if they become pregnant or intend to become pregnant while taking aripiprazole. Neonatal exposure to antipsychotics (including aripiprazole) in late gestation carries a risk of developing symptoms including extrapyramidal and/or withdrawal symptoms after delivery.
The effects of aripiprazole on paroxysm and delivery in humans are unknown.
Aripiprazole can be secreted into the milk of lactating rats. It is not known whether aripiprazole and its metabolites are secreted into human breast milk. Women taking aripiprazole are advised to stop breastfeeding.
[Pediatric Dosage].
The safety and efficacy of aripiprazole in pediatric patients with schizophrenia have been established in a 6-week placebo-controlled clinical trial involving 202 pediatric patients aged 13 to 17 years. Although the effectiveness of aripiprazole in the maintenance treatment of pediatric patients has not been systematically evaluated, the effectiveness of aripiprazole in the maintenance treatment of pediatric patients can be determined by comparing the pharmacokinetic parameters of aripiprazole in adult patients with those of pediatric patients and extrapolating the data from adult patients.
Geriatric Use]
Of the 7,951 patients treated with aripiprazole in pre-marketing clinical trials, 991 (12%) were ≥65 years of age and 789 (10%) were ≥75 years of age. the majority of the 991 patients (88%) were diagnosed with Alzheimer’s dementia.
Not enough cases aged 65 years or older were enrolled in placebo-controlled trials of aripiprazole for schizophrenia and bipolar disorder manic episodes to determine whether older patients responded differently to treatment than younger subjects. Age had no effect on the pharmacokinetics of a single dose of 15 mg aripiprazole. Aripiprazole clearance was 20% lower in older subjects (≥65 years) compared to younger adult (18-64 years) subjects, but no effect of age was shown in the population pharmacokinetic analysis of schizophrenia patients.
Studies in older patients with Alzheimer’s disease-related psychosis suggest that this population may have different tolerability compared to younger patients with schizophrenia. The safety and efficacy of aripiprazole in patients with Alzheimer’s disease-associated psychosis have not been established. Caution should be exercised if physicians choose to treat such patients with aripiprazole.
[Drug Interactions].
Since this product acts primarily on the central nervous system, caution should be exercised when combining it with other drugs that act on the central nervous system and ethanol. Because it antagonizes a1-adrenergic receptors, aripiprazole may potentiate the effects of certain antihypertensive drugs.
The possibility of other drugs affecting aripiprazole
Aripiprazole is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2E1 enzymes. Direct glucuronidation is also not performed. This suggests that interactions between aripiprazole and inhibitors or inducers of these enzymes, or other factors (e.g., smoking) are unlikely.
CYP3A4 and CYP2D6 are involved in the metabolism of aripiprazole.CYP3A4 inducers (e.g., carbamazepine) can cause increased clearance and decreased blood levels of aripiprazole.CYP3A4 inhibitors (e.g., ketoconazole) or CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) can inhibit aripiprazole elimination and increase blood levels.
Ketoconazole: Concomitant administration of ketoconazole (200 mg/day for 14 days) and 15 mg single-dose aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. Higher doses (400 mg/day) of ketoconazole were not studied. When ketoconazole and aripiprazole are taken together, the dose of aripiprazole should be reduced to half the usual dose. Other strong inhibitors of CYP3A4 (itraconazole, etc.) are expected to have similar effects and the dose needs to be reduced accordingly; weak inhibitors of CYP3A4 (erythromycin, grapefruit juice, etc.) have not been studied. When discontinuing CYP3A4 inhibitors in combination therapy, the dose of aripiprazole should be increased.
Quinidine: Concomitant administration of 10 mg single-dose aripiprazole and a potent CYP2D6 inhibitor-quinidine (166 mg/day for 13 days) increased the AUC of aripiprazole by 112%, while its active metabolite, dehydroaripiprazole, decreased the AUC by 35%. When taking both quinidine and aripiprazole, the dose of aripiprazole should be reduced to half the usual dose. It is expected that other strong CYP2D6 inhibitors (e.g., fusidine or paroxetine) have similar effects and, therefore, the dose needs to be reduced accordingly. When discontinuing CYP2D6 inhibitors in combination therapy, the dose of aripiprazole should be increased.
Carbamazepine: Concomitant administration of carbamazepine (200 mg twice daily, a strong CYP3A4 inducer) and aripiprazole (30 mg once daily) resulted in an approximately 70% reduction in both Cmax and AUC of aripiprazole and its active metabolite, dehydroaripipiprazole, respectively. When carbamazepine is used concomitantly with aripiprazole, the dose of aripiprazole should be doubled. The additional dose should be based on clinical evaluation. When carbamazepine in combination therapy is discontinued, the dose of aripiprazole should be reduced.
Potential for aripiprazole to affect other drugs
Important pharmacokinetic interactions between aripiprazole and drugs metabolized by cytochrome P450 enzymes are unlikely to occur. In in vivo studies, daily doses of 10-30 mg of aripiprazole had no significant effect on the metabolism of CYP2D6 substrates (dextromethorphan), CYP2C9 substrates (warfarin), CYP2C19 substrates (omeprazole, warfarin), and CYP3A4 substrates (dextromethorphan). In addition, in vitro studies showed that aripiprazole and dehydroaripiprazole did not affect the metabolism of CYP1A2 involved.
Ethanol: When aripiprazole was combined with ethanol in healthy volunteers and placebo was combined with ethanol in the control group, there were no significant differences in gross motor skills or stimulus responses between the two groups of subjects. As with most psychostimulant drugs, patients should be advised to avoid alcohol while taking aripiprazole.
There were no clinically important interactions between aripiprazole and the following drugs
Famotidine: Concomitant administration of aripiprazole (single dose 15 mg) and a single dose of the H2 receptor antagonist famotidine 40 mg (strong acid-suppressive formulation) decreased the solubility of aripiprazole and consequently the absorption of aripiprazole, with a 37% and 21% decrease in Cmax and 13% and 15% decrease in absorption (AUC) of aripiprazole and dehydroaripiprazole, respectively. When coadministered with famotidine, no dose adjustment of aripiprazole is required.
Valproate: When valproate (500-1500 mg/day) and aripiprazole (30 mg/day) were administered concomitantly, the Cmax and AUC of aripiprazole were reduced by 25% at steady state. When co-administered with valproate, no dose adjustment of aripiprazole is required.
Lithium salts: Because lithium is not bound to plasma proteins, is not metabolized, and is excreted almost exclusively in the urine as a prodrug, pharmacokinetic interactions between aripiprazole and lithium salts are unlikely to occur. Concomitant administration of therapeutic doses of lithium salts (1200-1800 mg/day) and aripiprazole (30 mg/day) for 21 consecutive days did not result in clinically significant changes in the pharmacokinetics of aripiprazole or its active metabolite, dehydroaripipiprazole (less than 20% increase in Cmax and AUC). When co-administered with lithium salts, no dose adjustment of aripiprazole is required.
Dextromethorphan: Aripiprazole administered for 14 consecutive days at 10-30 mg/day does not affect the O-dealkylation of dextromethorphan to produce its major metabolite, dextromorphan, a metabolic pathway known to be dependent on CYP2D6 activity. Aripiprazole also had no effect on the N-demethylation of dextromethorphan to produce the metabolite 3-methoxymorphinane, a metabolic pathway known to be dependent on CYP3A4 activity. When co-administered with aripiprazole, no dose adjustment of dextromethorphan is required.
Warfarin: Aripiprazole, 10 mg/day, administered for 14 consecutive days had no effect on the pharmacokinetics of R and S-type warfarin or on the pharmacodynamic endpoints of the international normalized ratio, suggesting that aripiprazole has little effect on CYP2C9 and CYP2C19 metabolism and the binding of highly protein-bound warfarin. When co-administered with aripiprazole, no warfarin dose adjustment is required.
Omeprazole: Aripiprazole, 15 mg/day, administered for 14 consecutive days had no effect on the pharmacokinetics of a single dose of 20 mg omeprazole (CYP2C19 substrate) in healthy volunteers. When co-administered with aripiprazole, no dose adjustment of omeprazole is required.
[Drug overdose].
Use MedDRA terminology to classify adverse events.
Clinical experience
A total of 76 intentional or accidental aripiprazole overdoses have been reported worldwide, including overdoses with aripiprazole alone and in combination with other drugs, with no deaths. 33 of 44 cases with known outcomes recovered with no sequelae and 1 recovered with sequelae (pupillary dilation and sensory abnormalities). The patient recovered completely from a known maximum acute intake of aripiprazole of 1,080 mg (36 times the maximum recommended daily dose). 76 cases included 10 pediatric cases (age 12 years or younger) with intentional or accidental aripiprazole overdose, with a maximum intake of 195 mg of aripiprazole and no deaths. Potentially serious symptoms reported included drowsiness and transient loss of consciousness.
With respect to aripiprazole overdose (alone or in combination), common (at least 5% of all overdose cases) adverse events reported included vomiting, drowsiness and tremors, increased blood pressure, and tachycardia. Other clinically significant signs and symptoms observed in one or more patients with aripiprazole overdose (alone or in combination) included acidosis, aggressive behavior, elevated aspartate aminotransferase, atrial fibrillation, bradycardia, coma, confusion, convulsions, elevated blood creatine phosphokinase, depressed mental alertness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS prolonged duration of complex wave groups, prolonged QT interval, aspiration pneumonia, persistent epilepsy, and tachycardia.
Overdose management
There is no specific way to rescue an aripiprazole overdose. Once an overdose occurs, an electrocardiogram should be checked: if a prolonged QTc interval is present, close cardiac monitoring should be performed. At the same time, supportive therapy, keeping the airway open, oxygenation and ventilation, and symptomatic treatment should be used. Close monitoring should be continued until the patient recovers.
Activated charcoal: If aripiprazole overdose occurs, early use of activated charcoal may help prevent absorption of aripiprazole to some extent. One hour after a single dose of 15 mg of oral aripiprazole, 50 g of activated charcoal reduced the mean AUC and Cmax of aripiprazole by 50% and 41%, respectively.
Hemodialysis: Although there is no information on the management of aripiprazole overdose by hemodialysis, hemodialysis may have no significant effect on overdose management because of the high plasma protein binding of aripiprazole.
[Clinical trials].
Adults
The effectiveness of aripiprazole in the treatment of schizophrenia was evaluated in 4 short-term (4-6 weeks) placebo-controlled clinical trials with inpatients with acute relapsing schizophrenia who primarily met DSM-III/IV criteria. Three of the active-controlled trials showed significant differences between aripiprazole and placebo, and the active control drugs were risperidone and haloperidol. However, a comparison between aripiprazole and the active control drug was not considered in the study design.
In the three aripiprazole positive control trials, four main measures were used to evaluate psychiatric signs and symptoms. The Positive and Negative Symptom Scale (PANSS) is a multi-item scale used in general psychopathology to evaluate the efficacy of medications in schizophrenia.The Positive Symptom Scale of the PANSS is a subset of symptom scales assessing 7 positive symptoms of schizophrenia (delusions, conceptual disorganization, hallucinatory behavior, euphoria, exaggeration, suspicion/hypochondriasis, and hostility), and the Negative Symptom Scale of the PANSS is a subset of symptom scales assessing 7 symptom scale subsets of the negative symptoms of schizophrenia (affective retardation, emotional withdrawal, affective communication disorder, passive-emotional indifference avoidance of social interaction, difficulty with abstract thinking, lack of spontaneity and fluency in conversation, and stereotyped thinking). The Clinical Composite Impression (CGI) assessment reflects the impression of the patient’s overall clinical status by a skilled observer who is very familiar with the manifestations of schizophrenia.
The effectiveness of daily doses of aripiprazole 15 mg, 20 mg, and 30 mg was established in two studies, and in one study the effectiveness of aripiprazole 10 mg dose was established. There was no evidence of superiority of the high-dose group over the lowest-dose group in any of the studies.
Population subgroup analyses did not show any differences in age, sex, or race factors.
In a long-term trial enrolling 310 inpatients or outpatients who met DSM-IV criteria for schizophrenia, patients were treated with other antipsychotics for 3 months or more to stabilize symptoms, discontinued the antipsychotic these patients were using, randomized them to receive aripiprazole 15 mg or placebo, and observed for relapse over a period of up to 26 weeks. Relapse during double-blind treatment was defined as a CGI improvement score ≥5 (minimal exacerbation), a PANSS hostility or noncooperation score ≥5 (moderate to severe), or a ≥20% increase in total PANSS score. Aripiprazole 15 mg resulted in a significantly longer time to relapse compared with placebo over 26 weeks.
Pediatric patients
The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in a 6-week placebo-controlled clinical trial in outpatients who met DSM-IV criteria for schizophrenia and had a baseline PANSS score ≥70. In this trial comparing two fixed doses of aripiprazole (10 or 30 mg/day) with placebo (n=302), aripiprazole was adjusted from a starting dose of 2 mg/day to the target dose over 5 days in the 10 mg/day dose group and from a starting dose of 2 mg/day to the target dose over 11 days in the 30 mg/day treatment group. Both doses of aripiprazole were superior to placebo in terms of PANSS total scores (Table 7), the primary outcome indicator for this trial. the 30 mg/day dose was not shown to be more effective than the 10 mg/day dose.
Table 7 Study of schizophrenia in pediatric patients
Main efficacy indicators in the treatment group: mean baseline PANSS score
(SD) Difference in LS mean (SE) minus placebo change from baselinea (95% CI) Aripiprazole (10 mg/day)* 93.6 (15.7) -26.7 (1.91) -5.5 (-10.7, -0.21) Aripiprazole (30 mg/day)* 94.0 (16.1) -28.6 (1.92) -7.4 (- 12.7, -2.13) placebo 94.6 (15.6) -21.2 (1.93) – SD: standard deviation; SE: standard error; LS Mean: least squares mean; CI confidence interval
a Least squares mean difference in change from baseline (drug minus placebo)
* statistically significantly better in the dose group than in the placebo group.
[Pharmacological Toxicology].
Pharmacological effects
Aripiprazole has high affinity for D2, D3, 5-HT1A, 5-HT2A receptors and moderate affinity for D4, 5-HT2C, 5-HT7, a1, H1 receptors and 5-HT reuptake sites. Aripiprazole is a partial agonist of D2 receptors and 5-HT1A receptors and an antagonist of 5-HT2A receptors.
As with other drugs with anti-schizophrenic properties, the mechanism of action of aripiprazole is not known. However, it is currently thought to be mediated through partial agonism at D2 and 5-HT1A receptors and antagonism at 5-HT2A receptors. Interaction with other receptors may produce some other clinical effects of aripiprazole, such as antagonism of a1 receptors that may explain its postural hypotension.
Toxicological studies
Genotoxicity
In an in vitro chromosomal aberration assay in CHL cells, aripiprazole and its metabolite (2,3-DCPP) caused chromosome breakage in the presence or absence of metabolic activation, and the metabolite 2,3-DCPP increased the number of aberrations in the absence of metabolic activation. In vivo micronucleus test results were positive in mice, but the results are thought to be produced by mechanisms unrelated to humans. Aripiprazole had negative results in the in vitro bacterial reversion mutation assay, bacterial DNA repair assay, mouse lymphoma cell assay, and rat programmed in vitro DNA synthesis assay.
Reproductive toxicity
Aripiprazole was given orally to female rats at 2, 6, and 20 mg/kg/day [0.6, 2, and 6 times the maximum recommended human dose (MRHD) in mg/m2] from 2 weeks before mating to day 7 of gestation, and disturbed motile cycles and increased luteal bodies were observed in all dose groups, but no impairment of fertility was observed; increased pre-labour loss in the 6 and 20 mg/kg dose groups, and decreased fetal weight in the 20 mg/kg group. In the 6 and 20 mg/kg dose groups, the preimplantation loss was increased and the fetal weight was decreased in the 20 mg/kg group. In male rats, aripiprazole was administered orally at 20, 40 and 60 mg/kg/day (6, 13 and 19 times the MRHD in mg/m2) from the 9th week before mating to the entire mating period, and impaired spermatogenesis was observed at the 60 mg/kg dose, and prostate atrophy was observed at the 40 and 60 mg/kg doses, but no impairment of fertility was observed.
Aripiprazole showed developmental toxicity in animal studies, including possible teratogenic effects in rats and rabbits.
In pregnant rats given aripiprazole orally at 3, 10, and 30 mg/kg/day (1, 3, and 10 times MRHD in mg/m2) during the organogenesis period, there was a mild prolongation of gestation, a slight delay in litter development (reduced litter weight), and an increased incidence of undescended testes in the 30 mg/kg dose group, and a delay in skeletal ossification in the 10 and 30 mg/kg dose groups; for embryo- No effect was seen on embryo-fetus or pup survival; reduced birth weight in the 10 and 30 mg/kg dose groups, increased incidence of lateral hepatodiaphragmatic nodules and diaphragmatic hernia in the 30 mg/kg dose group (other dose groups were not examined); delayed vaginal opening in the 10 and 30 mg/kg dose groups, impaired reproductive function of the offspring in the 30 mg/kg dose group (reduced fertility, corpus luteum count, number of implantations and live births, and increased post-implantation loss, probably due to a decrease in the number of fetuses born. The 30 mg/kg dose group showed maternal toxicity, but there was no evidence of developmental effects of aripiprazole secondary to maternal toxicity. In pregnant rats given intravenous aripiprazole at 3, 9, and 27 mg/kg/day during the organogenesis period, reduced fetal litter weight and delayed skeletal ossification were observed at high doses, and maternal toxicity was observed.
In pregnant rabbits given aripiprazole 10, 30, and 100 mg/kg/day orally during the organogenesis period (2, 3, and 11 times the MRHD in terms of AUC; 6, 19, and 65 times the MRHD in terms of mg/m2, respectively), maternal feeding decreased, abortion rate increased, and fetal mortality increased in the 100 mg/kg dose group, and fetal weight decreased and skeletal abnormalities increased in the 30 and 100 mg/kg dose groups. The incidence of fetal weight reduction and skeletal abnormalities (fusion of sternal segments) increased in the 30 and 100 mg/kg doses. The highest doses of intravenous aripiprazole 3, 10, and 30 mg/kg/day in pregnant rabbits during the organogenesis period produced significant maternal toxicity, decreased fetal weight, increased fetal abnormalities (mainly skeletal), and increased delayed skeletal ossification in fetuses at a no-effect dose of 10 mg/kg (equivalent to 5 times the MRHD in terms of AUC and 6 times the MRHD in terms of mg/m2 (6 times the MRHD in mg/m2).
Mild maternal toxicity and mild prolongation of gestation, increased stillbirths, decreased pup weights (lasting into adulthood) and decreased survival were observed in the 30 mg/kg dose group in rats given orally aripiprazole 3, 10 and 30 mg/kg/day (1, 3 and 10 times MRHD in mg/m2, respectively) during the perinatal period (from day 17 of gestation to day 21 postpartum). In rats, aripiprazole was administered intravenously at 3, 8, and 20 mg/kg/day from day 6 of gestation to day 20 postpartum, with increased stillbirths in the 8 and 20 mg/kg/day dose groups and decreased pup weights and survival in the early postnatal period in the 8 and 20 mg/kg/day dose groups. These responses occurred in the absence of maternal toxicity, and no effects on postnatal behavior or reproductive function were observed in the offspring.
Carcinogenicity
Lifetime carcinogenicity tests were conducted on ICR mice, SD rats and F344 rats. Aripiprazole was administered by adulteration for 2 years at doses of 1, 3, 10, and 30 mg/kg/day in ICR mice, 1, 3, and 10 mg/kg/day in F344 rats, and 10, 20, 40, and 60 mg in SD rats. in addition, aripiprazole was administered orally for 2 years in SD rats at doses of 10, 20, 40, and 60 mg/kg/day (in mg /m2, equivalent to 3 to 19 times the MRHD). In male mice and rats, no tumor production was seen. In female mice, the incidence of pituitary adenomas, mammary adenocarcinomas and adenosquamous tumors was increased in the 3 to 30 mg/kg dose group (0.1 to 0.9 times MRHD as AUC; 0.5 to 5 times MRHD as mg/m2). In female rats, the incidence of mammary fibroadenoma was increased at an adulteration dose of 10 mg/kg/day (0.1 times MRHD at AUC and 3 times MRHD at mg/m2), and at an oral administration dose of 60 mg/kg/day (14 times MRHD at AUC and 19 times MRHD at mg/m2), adrenocortical carcinoma and combined The incidence of adrenocortical adenoma/carcinoma was increased.
Proliferative alterations of the pituitary and mammary glands in rodents have been found after long-term administration of other anti-schizophrenic drugs and are thought to be prolactin-mediated. Serum prolactin levels were not measured in the aripiprazole carcinogenicity test. However, elevated serum prolactin levels were observed in female mice at doses administered in association with mammary and pituitary tumors in the 13-week repeated feeding assay. No increase in serum prolactin levels was observed in female rats at the doses associated with mammary and pituitary tumors in the 4-week and 13-week repeated feeding trials. The relevance of prolactin-mediated endocrine tumors in rodents to human risk is unknown.
Toxicity in young animals
Aripiprazole caused death, CNS symptoms, impaired memory and learning ability, and delayed sexual maturation in young rats given orally at 10, 20, and 40 mg/kg/day from the time of lactation (21 days of age) until maturity (80 days of age). death, reduced activity, hind limb flare, arching of the back, ataxia, tremor, and other In addition, delayed sexual maturation was observed in male rats. Dose-dependent impairment of memory and learning ability, increased spontaneous activity, and histopathological changes in pituitary (atrophy), adrenal (adrenocortical hypertrophy), mammary (hyperplasia and increased secretion), and female reproductive organs (mucinization of vaginal mucosa, endometrial atrophy, and decreased ovarian corpus luteum count) were observed in all dose groups. The lesions in the female reproductive organs are thought to be secondary to elevated serum prolactin levels. No no apparent adverse effect dose (NOAEL) could be determined and, at the lowest dose examined, 10 mg/kg/day, there was no safe range of systemic exposure (AUC0-24) to aripiprazole or its major active metabolite relative to the maximum recommended dose for children (15 mg/day) used in adolescents. after a 2-month recovery period, all drug-related effects were reversed and in young rats and most of the drug responses observed in young rats were also observed in previously conducted tests in adult rats.
In young dogs (2 months of age) given aripiprazole 3, 10, and 30 mg/kg/day orally for 6 months, central nervous system signs such as tremor, reduced activity, ataxia, slouching, and limited hind limb movement were observed. Mean body weight and weight gain were reduced by up to 18% in female dogs of all dosing groups compared to controls. The NOAEL could not be determined and there was no safe range of systemic exposure (AUC0-24) to aripiprazole or its major active metabolite at the lowest dose of the trial, 3 mg/kg/day, relative to the maximum recommended dose for children (15 mg/day) used in adolescents. all drug-related effects were reversible after a 2-month recovery period.
Other toxicity
Aripiprazole caused retinal degeneration in albino rats in a 26-week repeated administration toxicity test at doses up to 60 mg/kg and in a 2-year carcinogenicity test at doses of 40 and 60 mg/kg (equivalent to 13 and 19 times the MRHD in mg/m2 and 7 to 14 times the MRHD in AUC, respectively). No retinal degeneration was induced in albino mice and monkeys. Additional studies to further evaluate its mechanism of action have not been conducted. The relevance of the results to human risk is unknown.
Drug Abuse and Dependence
Systematic studies of aripiprazole abuse, tolerance, or somatic dependence have not been conducted in humans. In monkey somatic dependence trials, withdrawal symptoms were observed after abrupt discontinuation of the drug. A tendency to develop drug craving behavior was not seen in clinical trials, but these studies are not systematic and it is not possible to predict on the basis of this limited experience that a CNS active drug will be misused, diverted, and/or abused once it becomes available. Therefore, a patient’s history of drug abuse should be carefully evaluated and such patients should be closely monitored for signs of misuse or abuse (e.g., development of drug resistance, increased dosing, drug craving behavior).
[Pharmacokinetics].
I. As reported in foreign literature.
It is hypothesized that the activity of aripiprazole originates primarily from the parent drug, aripiprazole, and to a lesser extent from its major metabolite, dehydroaripipiprazole, which shows a similar affinity for D2 receptors as the parent drug, with plasma levels 40% of the parent drug exposure. The mean elimination half-lives of aripiprazole and dehydroaripipiprazole were approximately 75 and 94 hours, respectively. Steady-state concentrations of both active ingredients were reached within 14 days of administration. The accumulation of aripiprazole can be predicted from its single-dose pharmacokinetics. At steady state, the pharmacokinetics of aripiprazole are proportional to the dose. Aripiprazole is eliminated primarily through hepatic metabolism, and the two P450 enzymes involved in metabolism are CYP2D6 and CYP3A4.
Absorption
Aripiprazole tablets are well absorbed after oral administration, with plasma concentrations peaking within 3 to 5 hours, and the absolute oral bioavailability of the tablets is 87%. Aripiprazole can be taken alone or with food. Administration of aripiprazole 15 mg tablets with a standard high-fat diet did not significantly affect the Cmax and AUC of aripiprazole and its active metabolite, dehydroaripipiprazole, but delayed the Tmax of aripiprazole and dehydroariprazole by 3 and 12 hours, respectively.
Distribution
After intravenous administration, the steady-state volume of distribution of aripiprazole was high (404 L or 4.9 L/kg), indicating a wide distribution in the body. At therapeutic concentrations, more than 99% of aripiprazole and its major metabolites are bound to serum proteins, primarily serum albumin. Dose-dependent D2 receptor binding of aripiprazole 0.5 to 30 mg/day for 14 consecutive days in healthy male volunteers indicates that aripiprazole can cross the blood-brain barrier.
Metabolism and elimination
Aripiprazole is metabolized by three main biotransformation pathways: dehydrogenation, hydroxylation and N-dealkylation. Based on the results of in vitro assays, CYP3A4 and CYP2D6 are involved in dehydrogenation and hydroxylation, and CYP3A4 is involved in N-dealkylation. Aripiprazole is the main drug component in the body circulation. At steady state, its active metabolite, dehydroaripipiprazole, accounts for about 40% of the AUC of aripiprazole in plasma.
About 8% of Caucasians lack the ability to metabolize CYP2D6 substrates and are classified as hypometabolizers (PM) and the others as adequate metabolizers (EM). Compared to EM, PM had approximately 80% more aripiprazole exposure and approximately 30% less active metabolite exposure. This resulted in approximately 60% higher aripiprazole total active pharmaceutical ingredient exposure in PM than in EM. Combining aripiprazole and CYP2D6 inhibitors, such as quinidine, in EM resulted in a 112% increase in aripiprazole plasma exposure and therefore required dose adjustment. The mean elimination half-life of aripiprazole in EM and PM is approximately 75 hours and 146 hours, respectively. Aripiprazole does not inhibit or induce the CYP2D6 metabolic pathway.
Following oral administration of a single dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the radioactivity was recovered in the urine and feces, respectively. 1% was excreted as prodrug in the urine and 18% was excreted as prodrug in the feces.
Special Populations
Dosage adjustments of aripiprazole based on patient age, gender, race, smoking status, hepatic or renal function are not usually required. When aripiprazole (20-30 mg) is given to pediatric patients (10-17 years of age), the weight-corrected clearance of aripiprazole is similar to that of adults. The pharmacokinetics of aripiprazole in special populations are as follows.
Hepatic hypofunction
In a single-dose trial (aripiprazole 15 mg) in patients with varying degrees of cirrhosis (Child-Pugh classification A, B, C), the AUC of aripiprazole increased by 31% in subjects with mild hepatic impairment (HI), increased by 8% in subjects with moderate HI, and decreased by 20% in subjects with severe HI compared with healthy subjects. None of these changes required dose adjustment.
Renal hypofunction
In patients with severe renal hypofunction (creatinine clearance <30 mL/min), Cmax increased by 36% for aripiprazole (single dose 15 mg) and 53% for dehydroaripiprazole, but AUC decreased by 15% for aripiprazole and increased by 7% for dehydroariprazole. Renal excretion of aripiprazole prodrug and dehydroaripiprazole was less than 1% of the administered dose. No dose adjustment is required in subjects with low renal function.
Geriatric patients
In formal single-dose (aripiprazole 15 mg) pharmacokinetic studies, aripiprazole clearance was 20% lower in elderly (≥65 years) subjects than in subjects of lower age (18 to 64 years). However, no age differences were found in the population pharmacokinetic analysis of patients with schizophrenia. Similarly, the pharmacokinetics of older patients following multiple dose administration were similar to those of young healthy subjects. Dose adjustment in elderly patients is not recommended.
Gender
The Cmax and AUC of aripiprazole and its active metabolite, dehydroaripipiprazole, were 30% to 40% higher in female subjects than in male subjects, and the apparent oral clearance of aripiprazole was relatively lower in female subjects. However, these differences can be largely explained by differences in body weight between men and women (25%). Dose adjustment for gender differences is not recommended.
Race
Although no specific pharmacokinetic studies have been conducted on racial factors, the population pharmacokinetic evaluation of aripiprazole did not show clinically meaningful racial differences. Dose adjustment for racial differences is not required.
Smoking status
Aripiprazole is not a substrate for CYP1A2 and does not participate in direct glucuronidation based on the results of in vitro tests using human liver enzymes. Therefore, smoking does not affect the pharmacokinetics of aripiprazole. Consistent with the results of these in vitro trials, population pharmacokinetic evaluation did not show significant pharmacokinetic differences between smokers and nonsmokers. No dose adjustment for smoking status is required.
Second, it was reported from domestic research data that
The results of single and multiple pharmacokinetic studies in healthy Chinese subjects showed that Aripiprazole showed a linear proportional relationship between AUC0-t and Cmax with dose in the dose range of 10 mg to 30 mg. Tablets are rapidly absorbed after oral administration, with blood concentrations peaking within 2 to 5 hours and elimination half-lives of 63 to 75 hours. Aripiprazole and its metabolites accumulate in subjects, and it takes about 14 days to reach steady-state blood concentration under continuous dosing, and the blood concentration after reaching steady-state is about 5-6 times of the peak blood concentration after a single dose.
Storage
Store in a dry place under shade and seal.
Package
Packed in plastic bottles, 30 tablets per bottle.
Expiration date
24 months
Execution Standard
Approval number】
【Marketing license holder
Company Name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal code: 317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Web
Address: www.huahaipharm.com
Manufacturer
Company name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal Code: 317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Web
Address: www.huahaipharm.com