Amisulpride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name
Generic Name: Amisulpride Tablets
English name: Amisulpride Tablets
Hanyu Pinyin: Anhuangbili Pian
Ingredients
Chemical Name: 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-ethylsulfonyl-2-methoxybenzamide
Chemical structure formula.
Molecular formula: C17H27N3O4S
Molecular weight: 369.48
Characteristic]
This product is white or off-white tablet.
【Indications】.
Treatment of schizophrenia.
Specification
(1) 50mg (2) 0.2g
Dosage]
Usually, if the daily dose is less than or equal to 400mg, it should be taken in one dose; if the daily dose is greater than 400mg, it should be divided into two doses.
Acute phase
The recommended dose is 400 to 800 mg/day orally, with a maximum dose of 1200 mg/day. The safety of doses above 1200 mg/day has not been evaluated. No specific dose titration is required to initiate treatment. Dose adjustment should be based on individual response.
Phase with predominantly negative symptoms
The recommended dose is 50 to 300 mg/day. The optimal dose is approximately 100 mg/day. Dose should be adjusted according to individual response.
Maintenance therapy
In all cases, the maintenance dose should be adjusted to the minimum effective dose depending on the patient’s condition.
Renal damage
Amisulpride is excreted through the kidneys. The dose should be reduced by half in patients with renal insufficiency with a creatinine clearance of 30-60 ml/min and by one-third in patients with renal insufficiency with a creatinine clearance of 10-30 ml/min.
Amisulpride is not recommended for patients with severe renal insufficiency (creatinine clearance <10 ml/min) due to lack of study data (see [Contraindications]).
Liver damage
Hepatic metabolism of amisulpride is low and no dose adjustment is required in patients with hepatic impairment.
[Adverse Reactions].
The incidence of adverse reactions was graded using CIOMS criteria: very common ≥ 10 %; common ≥ 1 and < 10 %; occasional ≥ 0.1 and < 1 %; rare ≥ 0.01 and < 0.1 %; very rare < 0.01 %, unknown (assessment cannot be made from known data).
Blood and lymphatic system disorders.
Occasional: leukopenia, neutropenia (see [Precautions] section).
Rare: Granulocyte deficiency (see [Precautions] section).
Immune system disorders.
Occasionally: allergic reactions.
Endocrine system disorders.
Common: Amisulpride causes elevated blood prolactin levels, which may cause the following clinical symptoms: breast overflow, amenorrhea, mastopathy in men, breast swelling, breast pain, impotence, and sexual frigidity in women. It may recover after stopping treatment.
Rare: Benign pituitary tumors such as prolactinomas (see [Contraindications] and [Precautions]).
Metabolic and nutritional disorders.
Occasionally: hyperglycemia (see [Precautions]), hypertriglyceridemia, and hypercholesterolemia.
Rare: hyponatremia, syndrome of abnormal secretion of antidiuretic hormone (SIADH).
Psychiatric disorders.
Common: insomnia, anxiety, agitation, orgasmic disorder.
Occasionally: blurred consciousness.
Neurological disorders.
Very common: Extrapyramidal symptoms (tremor, hypertonia, salivation, inability to sit still, hypokinesia, dyskinesia) may occur. With maintenance doses, these symptoms are usually moderate and do not require discontinuation; treatment with anticholinergic antitremorine paralytic drugs provides partial relief. The incidence of dose-related extrapyramidal symptoms is low when treating schizophrenic patients with predominantly negative symptoms at doses of 50-300 mg/day.
Common: Acute dystonia (spastic slanting neck, eye rolling crisis, teeth clenching, etc.) may occur without discontinuation of medication and may be recovered with anticholinergic anticonvulsant paralytic medication. Drowsiness.
Occasionally: delayed dyskinesia. Delayed dyskinesia has been reported with amisulpride, especially after prolonged dosing, with involuntary tongue or face movements as the main symptom. Anticholinergic anticonvulsant paralytic drugs have no therapeutic effect on this symptom and may also aggravate it. Seizures.
Rare/malignant syndrome of antipsychotics (see [Precautions]), a potentially fatal complication.
Eye disorders.
Common: Blurred vision.
Cardiac disorders.
Common/Prolonged QT interval.
Occasional: Bradycardia.
Rare: Ventricular arrhythmias, such as tip-twist ventricular tachycardia and ventricular tachycardia, which can lead to ventricular fibrillation or cardiac arrest and sudden death (see [Precautions]).
Vascular and lymphatic vascular disorders.
Common: hypotension.
Occasionally: elevated blood pressure.
Rare: venous thromboembolism, including pulmonary embolism, sometimes fatal, and deep vein thrombosis (see [Precautions] section).
Respiratory, thoracic and mediastinal disorders.
Occasionally: nasal congestion, aspiration pneumonia (mainly in combination with other antipsychotics and CNS depressants).
Gastrointestinal disorders.
Common: constipation, nausea, vomiting, dry mouth.
Skin and subcutaneous tissue disorders.
Rare/angioedema, urticaria.
Musculoskeletal and connective tissue disorders
Occasional: osteopenia, osteoporosis.
Renal and urinary disorders.
Occasionally: urinary retention.
Diseases of pregnancy, puerperium and perinatal period.
Incidence unknown: Neonatal drug withdrawal syndrome (see section [Medication in Pregnant and Lactating Women]).
Screening.
Common: Weight gain.
Occasionally: Elevated liver enzymes, primarily transaminases.
[Contraindications].
This product is contraindicated in the following conditions.
Persons with known hypersensitivity to an ingredient in the drug.
Severe hypertension has been reported in patients with pheochromocytoma treated with anti-dopaminergic drugs (including amphetamides). Therefore, this product is contraindicated in patients with pheochromocytoma.
Patients with prolactin-dependent tumors, such as pituitary prolactin adenoma and breast cancer (see [WARNINGS] and [ADVERSE REACTIONS]).
Pediatric patients under 15 years of age.
Lactating women.
Patients with severe renal insufficiency (creatinine clearance <10 ml/min).
The combination of this product with the following drugs is prohibited.
-Except for the treatment of Parkinson’s disease, the combination of this product with dopaminergic drugs (cartegolide, quinagolide) is prohibited.
-Citalopram, escitalopram, domperidone, hydroxyzine, piperaquine (see [Drug Interactions]).
[Precautions].
Malignant syndrome
As with other antipsychotics, a malignant syndrome (potentially fatal complication) may occur, manifested by hyperthermia, myotonia, vegetative dysfunction, impaired consciousness, and elevated phosphocreatine kinase levels. All antipsychotic therapy, including this product, should be discontinued in the presence of hyperthermia, especially in those patients taking high doses of the drug.
Prolongation of QT interval
Amisulpride prolongs the QT interval in a dose-related manner. This effect may increase the risk of severe ventricular arrhythmias, such as tip-twist ventricular tachycardia, if there is bradycardia, hypokalemia, congenital or acquired QT interval prolongation (combined dosing may also prolong the QT interval), and an increased risk of severe ventricular arrhythmias.
If the clinical situation permits, it should be determined before administration that the patient does not have the following arrhythmogenic factors present.
-Bradycardia, with a heart rate <55 beats/min.
-Electrolyte imbalance, especially hypokalemia.
-Congenital prolongation of the QT interval.
-The current medication being administered can result in significant bradycardia (<55 beats/min), hypokalemia, slowed intracardiac conduction or prolonged QT interval.
An electrocardiogram (ECG) should be performed as part of the early evaluation in patients preparing for long-term psychosedation medication.
Stroke
A 3-fold increased risk of cerebrovascular events has been observed in placebo-controlled, randomized clinical trials in elderly patients with dementia and on certain atypical antipsychotic medications. The mechanism for this elevated risk is unknown. The possibility of an increased risk in combination with other antipsychotics or in other patient populations cannot be ruled out. Amisulpride should be used with caution in patients with risk factors for stroke.
Alzheimer’s patients
Elderly patients with dementia-related psychosis treated with antipsychotics are at increased risk of death. Although the causes of death in clinical trials of atypical antipsychotic therapy are varied, most deaths appear to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that similar to atypical antipsychotics, conventional antipsychotic treatment may also cause death. The extent to which increased mortality in observational studies is attributable to antipsychotics is uncertain because the characteristics of a subset of patients are unknown.
Venous thromboembolism
Cases of venous thromboembolism, sometimes fatal, have been reported with antipsychotic treatment. Therefore, this product should be used with caution in patients with risk factors for thromboembolism (see [Adverse Reactions]).
Hyperglycemia/metabolic syndrome
Hyperglycemia has been reported in patients treated with certain atypical antipsychotics, including amisulpride; therefore, patients with a clear diagnosis of diabetes mellitus or with risk factors for diabetes mellitus should be monitored appropriately if amisulpride is initiated.
Convulsions
Psychotropic sedative drugs can lower the threshold for seizures. Therefore, administration of amisulpride should be carefully monitored in patients with a history of seizures.
Special Populations
Because the drug is excreted primarily through the kidneys, the dose should be reduced in patients with renal insufficiency (see [DOSAGE AND ADMINISTRATION]). No clinical data are available for patients with severe renal insufficiency (see [Contraindications]).
Special care should be taken in the elderly due to their hypersensitivity to the drug (which can produce symptoms of sedation or hypotension).
As with other antidopaminergic drugs, amisulpride should be prescribed with caution to patients with Parkinson’s disease because of the potential to cause worsening of the disease. Amisulpride should be used only if psychosedation cannot be avoided.
Withdrawal syndrome
Withdrawal symptoms have occurred with abrupt discontinuation of high doses of antipsychotics. Involuntary movement abnormalities (e.g., inability to sit still, dystonia, and dyskinesia) have been reported with amisulpride. Therefore, gradual discontinuation of amisulpride is recommended.
Breast Cancer
Amisulpride may increase prolactin levels. Therefore, amisulpride should be used with caution and patients with a history or family history of breast cancer should be closely monitored during amisulpride therapy.
Benign pituitary tumors
Amisulpride may raise the level of prolactin. Benign pituitary tumors such as lactinomas have been observed with amisulpride treatment (see [Adverse Reactions]). Pituitary imaging should be performed if prolactin levels are high or if there are clinical signs of a benign pituitary tumor (e.g., visual field defects and headaches). If a diagnosis of pituitary tumor is confirmed, amisulpride therapy should be discontinued (see [Contraindications]).
Other
Leukopenia, neutropenia, and granulocyte deficiency have been reported with antipsychotics, including amisulpride. Unexplained infection or fever may be a sign of the development of a hematologic disorder (see [ADVERSE REACTIONS]) and require immediate hematologic testing.
Related to excipients
Due to the presence of lactose, this product is contraindicated in patients with congenital galactosemia, glucose or galactose malabsorption syndrome, or lactase deficiency.
Effects on Drivers and Machine Operators
Even when used as recommended, amisulpride may cause drowsiness and blurred vision that may impair the ability to drive a motor vehicle or operate machinery (see [ADVERSE REACTIONS]).
Pregnant women and nursing mothers
Pregnant women
In animals, amisulpride has not shown reproductive toxicity. A decrease in fertility associated with the pharmacological effects of the drug (modulation of prolactin action) was observed. No teratogenic effects of amisulpride were observed.
Clinical data on exposure to amisulpride in women during pregnancy are very limited; therefore, the safety of amisulpride use during pregnancy is uncertain. It is not recommended for use during pregnancy unless the benefits outweigh the potential risks.
Neonates born to women taking antipsychotic medications (including amisulpride) during the last trimester of pregnancy are at risk for adverse reactions, including extrapyramidal and/or withdrawal symptoms, which may vary in severity and duration after birth (see [ADVERSE REACTIONS] section).
Agitation, hypertonia, hypotonia, tremor, drowsiness, respiratory distress, or feeding disorders have been reported. Therefore, close monitoring of the newborn is required.
Lactation
Since there is no information on whether this drug can pass through breast milk, this drug should be prohibited during breastfeeding.
Pediatric Use]
Because the safety and efficacy of amisulpride in adolescents between the ages of adolescence and 18 years have not been established, and because there are limited data on the use of amisulpride in adolescent schizophrenia, amisulpride is not recommended for use in adolescents between the ages of adolescence and 18 years; amisulpride is contraindicated in children under 15 years of age.
[Geriatric Use].
Because of hypersensitivity to the drug (which can produce symptoms of sedation or hypotension) in the elderly, special care should be taken when taking the drug in the elderly.
Data from pharmacokinetic studies have shown that Cmax, T1/2 and AUC values can be increased by 10-30% for a single dose of 50 mg in elderly people aged above 65 years.
Drug Interactions]
+psychostatic drugs
Can enhance the depressant effect of many drugs or substances on the central nervous system and reduce alertness. Examples include morphine derivatives (analgesics, cough suppressants, and replacement therapy), tranquilizers, barbiturates, benzodiazepines (e.g., tranylcypromine), anxiolytics such as Ambien, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimethoprim), sedative antihistamines H1, central antihypertensives, baclofen, and thalidomide.
+ Drugs that may cause tip-twisting ventricular tachycardia
This severe rhythm disturbance may be caused by some antiarrhythmic drugs. Hypokalemia (see potassiumuric drugs) is a very important factor, as well as bradycardia (see bradycardic drugs), or congenital or acquired prolongation of the QT interval. Class Ia and Class III antiarrhythmic drugs, and certain psychosedative drugs. Other drugs. Examples include intravenous dolasetron, erythromycin, spiramycin, and vincristine. Generally, there are contraindications to the use of one tip-twist type drug with another tip-twist type drug. There are, of course, some exceptions, but concomitant use of tip-twisting drugs is not recommended. Examples include methadone, hydroxychloroquine, antiparasitics (chloroquine, halofantrine, benflunomide, pantamidine), and psychotropic drugs. However, there are no exceptions for the following drugs, citalopram, edipram, domperidone, hydroxyzine and piperaquine are contraindicated with all tip-twister drugs.
Contraindications for Compounding
+ except in the treatment of patients with Parkinson’s disease, the combination of this product with dopaminergic agonists other than levodopa (amantadine, anhydromorphine, bromocriptine, cartegolide, entacapone, lisuride, pergolide, piribedil, pramipexole, quinagolide, ropinirole) is contraindicated.
Dopaminergic agonists have a reciprocal antagonistic effect with psychotropic drugs. In the presence of psychostatic drug-induced extrapyramidal symptoms, do not treat with dopaminergic agonists and use anticholinergic drugs.
+ citalopram, escitalopram, domperidone, hydroxyzine, piperaquine.
Higher risk of ventricular arrhythmias, especially tip-twist ventricular tachycardia.
Combination drugs are not recommended
+ Antiparasitic drugs (chloroquine, halofantrine, benfotiol, pantamidine) may increase the risk of ventricular arrhythmias, especially in tip-twisting ventricular tachycardia.
If possible, interrupt one of the therapeutic drugs. If unavoidable, prior QT examination and electrocardiogram (ECG) monitoring should be performed.
+ Anti-Parkinson’s dopaminergic agonists (amantadine, anhydrous morphine, bromocriptine, entacapone, ergocalciferol, pegolide, piribedil, pramipexole, resagiline, ropinirole, rotigotine, sellegran, tolcapone).
Dopaminergic agonists can cause or exacerbate psychiatric disorders. In cases where dopaminergic agonists are needed to treat Parkinson’s disease, their dose should be gradually reduced until they are completely discontinued (effectively reducing the high risk of “antipsychotic malignant syndrome”).
+Drugs that may cause ventricular tachycardia in the form of tip-twisting: Class Ia antiarrhythmic drugs, such as quinidine, hydroquinidine, and propyzamide; and Class III antiarrhythmic drugs, such as amiodarone, dronedarone, sotalol, dofetilide, and ibrit; and other drugs, such as arsenicals, bepridil, cisapride, sultopride, thioridazine, methadone, dibenflunomide, dolasetron IV Erythromycin IV, levofloxacin, methaqualazine, imipramine, procapride, vincristine IV, halofantrine, pentoxifylline, sulforaphane, moxifloxacin, spiramycin IV, toremifene, vandetanib.
Higher risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia.
+ Other psychotropic drugs that can cause tip-turn ventricular tachycardia, such as chlorpromazine, cyromazine, haloperidol, flurbixicol, fluphenazine, haloperidol, levomepromazine, pimozide, perphenazine, perphenazine, sulpiride, sutropril, tebrile, and zuclopenthixol.
Higher risk of ventricular arrhythmias, especially tip-twist ventricular tachycardia.
+Alcohol (drink or excipient)
Amisulpride may potentiate the central effects of alcohol. Decreased alertness can be dangerous for driving and mechanical operations. Avoid alcoholic beverages and medications.
+ Levodopa
There are reciprocal antagonistic effects between levodopa and psychotropic drugs. For the treatment of patients with Parkinson’s disease, use the lowest effective dose of both drugs.
+Methadone
Higher risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia.
+ sodium oxybutyrate
Increases central nervous depression. Decreased alertness can be dangerous for driving and machine operation.
+hydroxychloroquine
Higher risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia.
Precautions for use in combination with other drugs
+Anagrelide
Higher risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia. Pay attention to clinical and ECG monitoring during use.
+ Azithromycin, ciprofloxacin, clarithromycin, levofloxacin, norfloxacin, roxithromycin
Higher risk of ventricular arrhythmias, especially tip-twist ventricular tachycardia. Pay attention to clinical and electrocardiographic monitoring during use.
+ beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol)
Higher risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia. In addition, there is a risk of vasodilatory effects and hypotension, especially upright (additive effects). Clinical and electrocardiographic monitoring.
+ drugs that cause bradycardia, such as beta-blockers, calcium channel blockers that cause bradycardia, such as diltiazem and verapamil, colistin, guanfacine, digitalis, anticholinesterase).
Higher risk of ventricular arrhythmias, especially tip-twist ventricular tachycardia. Clinical and electrocardiographic monitoring.
+ Drugs causing hypokalemia: potassium-lowering diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, ticlopidine. Hypokalemia, eicosanoic acid and amphotericin B IV should be corrected.
Higher risk of ventricular arrhythmias, especially tip-twist ventricular tachycardia. Treatment of hypokalemia is required prior to use of this product and clinical monitoring, electrolyte and ECG monitoring are required.
+ Lithium
Patients with neuropsychiatric symptoms are at risk for neuroleptic malignant syndrome or lithium toxicity. Regular clinical and biological monitoring, especially at the start of the combination.
+ ondansetron
Higher risk of ventricular arrhythmias, especially tip-twist ventricular tachycardia. Clinical and electrocardiographic monitoring during coadministration. Combination effects to consider.
+ Can potentiate the depressant effect of sedative drugs on the central nervous system.
Decreased alertness can be dangerous for driving and mechanical operations.
+orlistat
There is a risk of therapeutic failure when used in combination with orlistat.
[Drug overdose].
Signs and symptoms.
To date, data on acute overdose with amisulpride are limited. Overdose has been reported, primarily as an exacerbation of the known pharmacological effects of the product. These include sleepiness, sedation, hypotension and extrapyramidal symptoms and coma. Overdose fatalities have been reported primarily when this product is used in combination with other psychotropic drugs.
Treatment.
If an acute overdose occurs, the possibility of using multiple drugs should be considered.
Because dialysis has little effect on amisulpride, hemodialysis may not be effective in clearing the drug.
There is no specific antidote for amisulpride. Therefore, appropriate supportive management should be given; close monitoring of vital functions and continuous cardiac monitoring (due to the risk of QT interval prolongation) until the patient recovers.
If extrapyramidal symptoms occur, anticholinergic drugs should be given.
[Pharmacology and Toxicology
Pharmacodynamic characteristics
Amisulpride is an aniline substitute psychostimulant that selectively binds to D2 and D3 dopaminergic receptors in the limbic system. It does not bind to 5-hydroxytryptaminergic receptors or other histaminergic receptors, cholinergic receptors, or adrenergic receptors.
In animal studies, high doses of amisulpride mainly blocked dopaminergic neurons in the middle of the limbic system compared to the striatum. This affinity may account for the greater psycho-inhibitory effect of amisulpride than its extrapyramidal effect.
Low doses of amisulpride mainly block presynaptic D2/D3 dopaminergic receptors, which could explain its effect on negative symptoms.
A total of 191 patients with acute schizophrenia were enrolled in a double-blind trial for comparison with haloperidol. Compared to haloperidol, amisulpride significantly improved secondary negative symptoms in patients.
Preclinical Safety Study Results
The toxicological profile of amisulpride is primarily related to the pharmacological effects of this compound. No target organs associated with toxicity were identified by repeated dosing. The compound was not teratogenic or mutagenic. Animal carcinogenicity tests showed that hormone-dependent tumors could be produced in rodents. However, no clinical relevance in humans.
Pharmacokinetics]
In humans, amisulpride has two absorption peaks: the first peak is reached quickly, 1 hour after dosing, and the second peak is reached 3 to 4 hours after dosing.
After taking 50 mg of the drug, the blood concentrations relative to the two absorption peaks were 39±3 and 54±4 ng/ml, respectively.
The volume of distribution was 5.8 L/kg. plasma protein binding was low (16%) and there were no drug interactions in terms of protein binding. Absolute bioavailability was 48%.
Amisulpride is poorly metabolized: two inactive metabolites were detectable, accounting for 4% of the excretion.
With repeated administration, amisulpride does not accumulate in the body and the pharmacokinetic parameters are not altered.
The oral elimination half-life is approximately 12 hours.
Amisulpride is mostly excreted in its original form in the urine. When administered by intravenous injection, 50% of the drug is excreted in the urine in its original form, mostly within 24 hours of administration (90% of the urinary excretion).
Renal clearance is approximately 330 ml/min.
A high-carbohydrate diet significantly reduced the AUC, Tmax and Cmax values of amisulpride; a high-fat diet did not alter these parameters. The effect of alterations in these parameters during treatment is unclear.
Hepatic insufficiency
Due to the small metabolism of amisulpride, no dose adjustment is required in patients with hepatic insufficiency.
Renal insufficiency
The elimination half-life is not altered in patients with renal insufficiency, although the total clearance is reduced by 2.5 to 3-fold.
The AUC of amisulpride is doubled in patients with mild renal insufficiency and is increased approximately 10-fold in patients with moderate renal insufficiency.
The data available to us are limited to this point, and no data are available for studies above 50 mg.
Amisulpride is rarely eliminated by dialysis.
Geriatric patients
Data from pharmacokinetic studies indicate that Cmax, T1/2, and AUC values are increased by 10-30% for a single dose of 50 mg in elderly patients older than 65 years of age.
Storage
Seal and store below 30℃.
Package
Aluminum-plastic packaging.
(1) 50mg: 10 tablets/plate, 10 tablets/box, 20 tablets/box, 50 tablets/box.
(2) 0.2g: 10 tablets/board, 10 tablets/box, 20 tablets/box, 50 tablets/box.
[Expiration date
24 months
【Execution standard
Approval number】
50mg：State Drug Administration H20113230
0.2g：GuoYaoZhenZi H20113231
Manufacturer
Company Name: Qilu Pharmaceutical Co.
Production Address: No. 8888, Tourism Road, High-tech Zone, Jinan City
Postal Code: 250100
Telephone number: 0531-83126000, 83126111, 83126333, 83126548
Fax number: 0531-83126288, 83126545
Website: http://www.qilu-pharma.com