It is forbidden for those who are allergic to risperidone and paliperidone, including allergic reaction and angioneurotic edema.
Sandostatin 0 will be converted into paliperidone, a metabolite of risperidone, so sandostatin 0 is prohibited for patients who are known to be allergic to paliperidone or risperidone, and for patients who are allergic to any auxiliary materials of sandostatin 0.
Shansida manual
Trade name shansida
General name papaverine palmitate injection
Chinese Pinyin Palmae
Paliperidone palmitate injection
raw material
The main component is papaverine palmitate,
Accessories: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, disodium hydrogen phosphate (anhydrous), sodium dihydrogen phosphate monohydrate, sodium hydroxide and water for injection.
Molecular formula C39H57FN4O4
The molecular weight is 664.8.
The character of Shansida 0 is white to grayish white suspension.
Indications: Sandostatin 0 is used for the treatment of schizophrenia in acute stage and maintenance stage.
dosage
Recommended dose:
For patients who have never used paliperidone oral preparation, risperidone oral preparation or risperidone injection, it is suggested that patients' tolerance to paliperidone should be determined by taking paliperidone sustained-release tablets or risperidone orally before starting sandostatin 0 treatment.
It is suggested that patients should be injected with 0 150mg sandostatin on the first day of initial treatment, and then injected with 100mg again one week later. The first two doses of the initial therapeutic drug are injected into the deltoid muscle.
It is suggested that the therapeutic dose should be maintained at 75mg per month, and the monthly injection dose can be increased or decreased within the range of 25- 150mg according to the patient's tolerance and/or curative effect. After the second dose, the injection site can be deltoid muscle or gluteus muscle every month/kloc-0 times.
The dose of maintenance treatment can be adjusted every month. When adjusting the dose, the long-term release characteristics of Sunstar 0 should be taken into account, and all the effects produced by dose adjustment may take several months to be reflected.
Management mode:
Sunstar 0 is only used for intramuscular injection. When injecting, slowly inject into the deep muscle. Be careful not to inject drugs into blood vessels. Every injection must be operated by a professional health technician.
Each dose of medicine should be injected once, not in multiple injections. Do not inject drugs into blood vessels or under the skin.
counteraction
The following will be discussed in detail in other parts of the manual (see notes):
Increase the mortality rate of patients with Alzheimer's disease-related psychosis
Adverse cerebrovascular events (including stroke) in patients with senile dementia-related psychosis
Malignant syndrome of antipsychotic drugs
QT interval prolongation
Delayed dyskinesia
Hyperglycemia and diabetes
put on weight
Hyperprolactinemia
Postural hypotension and syncope
Leukopenia, neutropenia and agranulocytosis
For potential cognitive and motor dysfunction, please refer to the precautions.
epilepsy
dysphagia
commit suicide
penile persistent erection
Thrombotic thrombocytopenic purpura
Thermoregulation disorder
Avoid accidental injection into blood vessels.
Antiemetic effect
Increase the sensitivity of patients with Parkinson's disease or Lewy body dementia
Diseases or disease states can affect metabolic or hemodynamic responses.
The following adverse reactions have been confirmed by drugs used after marketing. Because these adverse reactions are reported spontaneously, it is impossible to evaluate their incidence, including angioneurotic edema, abnormal erection of penis, tongue swelling, urinary incontinence and urinary retention.
To report the adverse reactions related to risperidone: Paparisperidone is the main active metabolite of risperidone. Adverse reactions related to oral risperidone tablets and risperidone long-acting injection can be found in the adverse reactions section of the packaging instructions of these products.
Contraindications
It is forbidden for those who are allergic to risperidone and paliperidone, including allergic reaction and angioneurotic edema.
Sandostatin 0 will be converted into paliperidone, a metabolite of risperidone, so sandostatin 0 is prohibited for patients who are known to be allergic to paliperidone or risperidone, and for patients who are allergic to any auxiliary materials of sandostatin 0.
warn
Atypical antipsychotics can increase the mortality of patients with senile dementia-related psychosis;
When atypical antipsychotics are used to treat patients with Alzheimer's disease-related psychosis, the risk of death will increase.
The analysis of 17 placebo-controlled clinical trials of senile dementia-related mental patients (the average mode of treatment was 10 week) showed that the death risk of drug treatment group was 1.6- 1.7 times that of placebo control group.
In the typical controlled trial of 10 week, the mortality rate of drug treatment group was 4.5%, and that of placebo control group was 2.6%. Although the causes of death are different, most of them die from cardiovascular diseases (such as heart failure and sudden death) or infections (such as pneumonia).
Observational studies show that, similar to atypical antipsychotics, traditional antipsychotics may also increase mortality. At present, it is not clear how much of the increase in death rate found in observational studies is caused by antipsychotics, rather than the patient's physical illness.
Palipedone palmitate injection is not approved for the treatment of dementia-related mental patients.
Matters needing attention
1, the mortality rate of senile dementia-related mental patients increased;
The death risk of senile dementia-related mental patients treated with antipsychotics is higher than that of placebo. Sandostatin 0 has not been approved for the treatment of senile dementia-related mental patients.
Adverse cerebrovascular events (including stroke) in patients with senile dementia-related psychosis;
In placebo-controlled clinical trials of Alzheimer's patients, the incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) and death in patients treated with atypical antipsychotics (including risperidone, aripiprazole and olanzapine) is higher than that in placebo group.
2, antipsychotic malignant syndrome:
Sometimes the potentially life-threatening malignant syndrome of antipsychotics (NMS) is mentioned, which has been reported in some antipsychotics, including paliperidone.
The clinical manifestations of NMS are high fever, muscular rigidity, mental instability and voluntary movement instability (irregular pulse and blood pressure, tachycardia, sweating and arrhythmia). Other signs may include elevated serum creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
The diagnosis of this symptom is complicated. In order to ensure the correct diagnosis, it is important to identify those patients with the following clinical manifestations, including serious diseases (such as pneumonia, systemic infection, etc.). ) and untreated or incomplete extrapyramidal symptoms. Other special diagnoses that need to be considered include central anticholinergic poisoning, heatstroke, drug-induced fever and central nervous system diseases.
The control of NMS includes: (1) immediately stop taking antipsychotic drugs and other drugs at the same time; (2) treatment and medical monitoring of key symptoms; (3) Treating any serious medical problems. At present, there is no consistent specific drug treatment plan.
If patients need antipsychotic drugs after NMS rehabilitation, it is necessary to closely monitor the retreatment, because NMS recurrence has been reported.
3.QT interval prolongation:
Palipedone can cause moderate prolongation of corrected QT(QTc) interval. Palipedone and other drugs known to prolong QTc interval (including class IA drugs (such as quinidine and procainamide) or class III drugs (such as amiodarone and sotalol), antiarrhythmic drugs (such as chlorpromazine and sulindazine), antibiotics (such as gatifloxacin and moxifloxacin hydrochloride),
Or any other drug known to prolong QTc interval. Patients with congenital long QT interval syndrome and patients with a history of arrhythmia should also avoid using paliperidone.
Some cases may increase the risk of torsade de pointes and/or sudden death, which are related to the use of drugs that can prolong QT interval, including: (1) bradycardia; (2) Hypokalemia or hypomagnesemia; (3) At the same time, use other drugs that can prolong QTc interval; (4) Congenital prolongation of QT interval.
4, tardive dyskinesia:
Subjects receiving antipsychotic drugs may have potential irreversible and involuntary dyskinesia. Although the prevalence of this syndrome is the highest among elderly patients, especially elderly women, it is impossible to predict which patients will develop this syndrome.
With the increase of treatment time and the cumulative dose of antipsychotic drugs given to patients, the risk of tardive dyskinesia and the possibility of irreversible syndrome seem to increase, but the syndrome will also appear after a relatively short low-dose treatment period, although this is not common.
At present, there is no way to treat the diagnosed tardive dyskinesia, but if antipsychotics are stopped, the syndrome can be partially or completely relieved.
Antipsychotic drug treatment itself will inhibit (or partially inhibit) the signs and symptoms of syndrome, so it will cover up the potential progress of the disease. The effect of inhibiting this symptom on the long-term course of this syndrome is not clear.
If patients receiving sandostatin have signs and symptoms of tardive dyskinesia, they should consider stopping taking the drug. However, although some patients have this syndrome, they may still need treatment with good results.
5, hyperglycemia and diabetes:
Hyperglycemia has been reported in patients receiving all atypical antipsychotics. In some extreme cases, hyperglycemia is related to ketoacidosis or hyperosmolar coma or death.
At present, the relationship between the use of atypical antipsychotics and adverse events related to hyperglycemia has not been fully clarified. However, epidemiological studies show that patients receiving atypical antipsychotics are at increased risk of hyperglycemia-related adverse events during treatment.
When patients diagnosed with diabetes begin to receive atypical antipsychotic drugs, their blood sugar control should be monitored regularly. Patients with diabetes risk factors (for example, obesity, family history of diabetes) should be tested for fasting blood glucose at the beginning of treatment with atypical antipsychotics and regularly during treatment.
In some cases, when atypical antipsychotics are stopped, hyperglycemia will disappear; However, some patients still need to continue to use antidiabetic drugs after stopping using suspected drugs.
6. Weight gain:
Weight gain was observed in patients treated with sandostatin and other atypical antipsychotics.
7, hyperprolactinemia:
Like other drugs that antagonize dopamine D2 receptor, paliperidone can also increase prolactin level, which will last for a long time. Palipedone has a prolactin-increasing effect similar to risperidone, and risperidone has a prolactin-increasing effect higher than other antipsychotics.
8, postural hypotension and syncope:
Palipedone can cause postural hypotension and syncope in some patients because of its α receptor blocking effect.
Patients who are known to have cardiovascular diseases (such as heart failure, myocardial infarction or ischemic history, abnormal conduction), cerebrovascular diseases, or conditions that are prone to hypotension (such as dehydration, hypovolemia, and being treated with antihypertensive drugs) should be cautious in using Sandostatin 0. Monitoring the body position and vital signs of patients prone to hypotension should be considered.
9, leukopenia, neutropenia and agranulocytosis:
Clinical trials and/or post-marketing experience show that leukopenia/neutropenia is reported to be related to antipsychotic drugs, including the oral dosage form of Inverga-paliperidone. Agranulocytosis was also reported.
For patients with significant low white blood cell count (WBC) or clinical history of drug-induced leukopenia/neutropenia, their whole blood count (CBC) should be monitored frequently in the first few months of treatment. In the absence of other pathogenic factors, when there are clinically significant signs of WBC decline, Sinostar 0 should be considered to be discontinued.
10, potential cognitive and motor disorders:
Subjects who received sandostatin 0 reported adverse events such as drowsiness, sedation and dizziness [see Adverse Events]. Antipsychotic drugs, including sandostatin, may impair judgment, thinking or motor function.
. Patients should be warned not to engage in vigilance activities, such as operating dangerous machines or motor vehicles, until there is reason to believe that paliperidone treatment will not adversely affect them.
1 1, seized:
In four fixed-dose, double-blind, placebo-controlled studies, within the recommended dose range of 25- 150 mg, the proportion of subjects with adverse convulsions in Sandostatin 0 treatment group was <1%(11293), and the proportion of subjects with severe convulsions in placebo group was <.
Like other antipsychotics, patients with a history of epilepsy or other diseases that may lower the threshold of seizures should be treated with caution. Conditions that may lower the seizure threshold may be more common in patients aged 65 and over.
12, dysphagia:
Esophageal motor dysfunction and respiratory diseases are related to the use of antipsychotics. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease and dementia. Patients at risk of aspiration pneumonia should be cautious in using sandostatin 0 and other antipsychotics.
13, suicidal tendency:
The possibility of attempted suicide is an inherent feature of mental illness, and high-risk patients should be closely monitored while receiving drug treatment.
14, abnormal erection of penis:
It is reported that drugs with α -adrenergic blocking effect can cause abnormal erection of penis. Although no cases of priapism were reported in the clinical trial of Sandostatin 0, priapism caused by oral paliperidone was reported during the post-marketing monitoring. Severe priapism may require surgery.
15, thrombocytopenic purpura (TTP):
TTP was not observed in the clinical study of oral paliperidone tablets or sandostatin 0. Although there are reports that TTP cases are related to the use of risperidone, the relationship between TTP cases and risperidone treatment is still unclear.
16, temperature adjustment:
Antipsychotics can damage the body's ability to lower the central body temperature. Special care should be taken when prescribing sandostatin for patients who may lead to elevated central body temperature (such as strenuous exercise, exposure to extreme high temperature, combined use of anticholinergic drugs or dehydration).
17, antiemetic effect:
The antiemetic effect was observed in the preclinical study of paliperidone. If this effect occurs in human body, it will cover up some signs and symptoms of drug overdose or some diseases, such as intestinal obstruction, Ryle syndrome, brain tumor and so on.
18, medication for patients with diseases:
To report the increased sensitivity of patients with Parkinson's disease or Lewy body dementia to antipsychotic drugs. The manifestations of increased sensitivity include confusion, dullness, unstable posture with frequent falls, extrapyramidal symptoms and the same clinical manifestations as the malignant syndrome of antipsychotics.
Sandostatin 0 has not been evaluated in patients with a history of myocardial infarction or unstable heart disease or used for any evaluation. Patients with these diagnosis results were excluded from the post-marketing clinical trials. Because of the risk of orthostatic hypotension, patients with known cardiovascular diseases should use it with caution.
Monitoring: Laboratory tests-no specific laboratory tests are recommended.
The safety and efficacy of sandostatin 0 in children under 18 years old have not been studied.
Medication for elderly patients
The clinical study of Sandstar 0 did not include a sufficient number of subjects aged 65 and over to determine whether their responses were different from those of young subjects. Other reported clinical studies have not determined the difference of drug reactions between elderly patients and young patients.
Pregnant women and lactating women are forbidden to take drugs.
excessive
Human experience:
No overdose cases were reported in the pre-marketing study of Sunstar 0. Because sandostatin is administered by health care professionals, patients are unlikely to overdose.
Although the experience of paliperidone overdose is limited, the highest intake of paliperidone tablets is estimated to be 405mg in several cases of overdose reported in pre-marketing trials. The observed signs and symptoms include extrapyramidal symptoms and gait instability.
Other potential signs and symptoms include those caused by the known pharmacological effects of paliperidone, namely drowsiness and sedation, tachycardia and hypotension, and prolonged QT interval. 1 patient reported torsade de pointes after oral paliperidone overdose.
Palipedone is the main active metabolite of risperidone. Reports of risperidone overdose can be found in the drug overdose section of the risperidone instructions.
Disposal of drug overdose:
There is no specific antidote for paliperidone overdose, so appropriate support measures can be taken and strict medical monitoring and surveillance can be carried out until the patient recovers.
The long-term characteristics of sandostatin 0 and the significantly longer half-life of paliperidone should be considered when evaluating the treatment demand and recovery. The interaction of multiple drugs should also be considered.
In case of acute drug overdose, establish and maintain airway patency to ensure adequate oxygen content and ventilation. Muscle tension in the head and neck, seizure or unconsciousness after drug overdose may cause vomiting of stomach contents to be inhaled into the respiratory system by mistake.
For possible arrhythmia, cardiovascular monitoring should be started immediately, including continuous ECG monitoring. If antiarrhythmic treatment is carried out, procainamide and quinidine will theoretically have cumulative QT interval prolongation when used in patients with acute overdose of paliperidone.
Similarly, the α -blocking effect of bromobenzylamine tosylate will also accumulate with this effect of paliperidone, which will lead to clinically significant hypotension.
Hypotension and circulatory failure should be treated with appropriate measures, such as intravenous injection and/or sympathomimetic drugs (adrenaline and dopamine should not be used, because β stimulation will aggravate hypotension in the case of α -block induced by paliperidone). If it is a serious extrapyramidal symptom, anticholinergic drugs should be used for treatment.
pharmacological action
Paliperidone palmitate is hydrolyzed into paliperidone in vivo, which is the main metabolite of risperidone.
Like other anti-schizophrenia drugs, the mechanism of paliperidone is unclear, but it is thought to be mediated by the combined action of antagonizing central dopamine 2 (D2) receptor and serotonin 2(5HT2A) receptor.
Palipedone is also an antagonist of α 1 and α2 adrenergic receptors and H 1 histamine receptors, which may be the reason for some other effects of the drug.
Palipedone has no affinity for cholinergic muscarinic receptors or β 1- and β2- adrenergic receptors. In vitro, the pharmacological effects of (+)-and (-)-paliperidone enantiomers are similar.
Toxicological effect
Genotoxicity:
The results of Ames test of paliperidone palmitate and mouse lymphoma test were all negative, and the results of Ames test of paliperidone palmitate, mouse lymphoma test and rat micronucleus test were all negative.
Reproductive toxicity:
In a fertility test, the pregnancy rate of female rats was not affected by oral dose of paliperidone as high as 2.5mg/kg/ day. However, at this dose, the loss rate increased before and after implantation, the number of live births decreased slightly, and the maternal toxicity was also slight. When the dose is 0.63mg/kg, these indexes are not affected, which is equivalent to half of the maximum recommended dose 12mg/ day (inviga).
Male rats were given paliperidone orally at a dose as high as 2.5 mg/kg/day, but sperm count and sperm motility were not studied. Risperidone is widely converted into paliperidone in dogs and humans.
In the long-term toxicity test of Beagle dogs, the decrease of serum testosterone, sperm motility and concentration was observed at all test doses (0.3 1-5.0mg/kg). Two months after drug withdrawal, serum testosterone and sperm-related indexes partially recovered, but they were still at a declining level.
Risperidone is widely converted into paliperidone in rats and humans. In the reproductive toxicity test of risperidone on rats, when the dose calculated by mg/m2 is lower than the maximum recommended dose of human beings, it can be seen that the infant mortality rate increases.
Carcinogenicity:
The carcinogenicity test of intramuscular injection of papaverine palmitate was carried out in rats. At the doses of 16, 47 and 94 mg/kg/month, the incidence of breast cancer in female rats increased. Calculated by mg/m2, the above doses are equivalent to 0.6, 2 and 4 times of the maximum recommended dose of 234mg (Sunstar 0) respectively.
In male rats with doses of 47 and 94 mg/kg/month, the incidence of breast adenoma, fibroma and breast cancer increased. The carcinogenicity of paliperidone palmitate in mice has not been tested.
The carcinogenicity of risperidone in mice and rats was studied. The drug will be widely converted into paliperidone in rats, mice and humans. The daily dose of risperidone was 0.63 mg/kg, 2.5 mg/kg and 10mg/kg respectively. Mice took risperidone for 65,438+08 months, and rats took risperidone for 25 months.
The results showed that the incidence of pituitary adenoma, endocrine pancreatic tumor and breast cancer in animals increased significantly. Calculated by mg/m2, the dose that has no effect on these tumors is less than or equal to the maximum recommended dose of risperidone (see the instructions of risperidone).
In the experiment of long-term administration of other antipsychotic drugs in rodents, the incidence of breast, pituitary and pancreatic tumors has also increased, which is considered to be caused by long-term antagonism of dopamine D2 receptor and increased prolactin level. The correlation between these results observed in rodents and humans is not clear.
pharmacokinetics
Absorption and distribution:
Because of its extremely low water solubility, sandostatin 0 will slowly dissolve after intramuscular injection until it is decomposed into paliperidone and absorbed into the whole body circulation.
After a single intramuscular injection, the plasma concentration of paliperidone gradually increased, and the median time for plasma concentration to reach the peak (Tmax) was 13 days. The drug in the preparation began to release at the earliest 1 day after administration, and the longest sustained release time was 126 days.
The average Cmax of a single injection of sandostatin 0(25- 150mg) into deltoid muscle was 28% higher than that of gluteal muscle. Injecting 1 50 mg and 100mg sandostatin 0 into deltoid muscle on the first1and the eighth day, respectively, is helpful to make the drug concentration in the body reach the required concentration quickly.
The release characteristics and administration scheme of sandostatin 0 keep the drug concentration in patients within the therapeutic concentration range. In the dose range of 25- 100mg, the dose of sandostatin 0 is directly proportional to the total exposure of paliperidone.
After the dose exceeded 50mg, the increase of Cmax value was lower than that of dose. After deltoid muscle injection 100mg sandostatin 0, the steady-state peak-valley concentration ratio was 1.8, and when gluteal muscle injection, the steady-state peak-valley concentration ratio was 2.2. The median apparent half-life of paliperidone was 25 to 49 days after sandostatin 0 was administered in the dosage range of 25- 150mg.
Metabolism and clearance:
After a single oral dose of 1mg 14C- paliperidone preparation 1 week, the original drug excreted from urine accounted for 59% of the original dose, suggesting that paliperidone is not widely metabolized in the liver.
The radioactivity recovered in urine accounts for about 80% of the total dose, and the radioactivity recovered in feces accounts for about 1 1% of the total dose.
Comparison of sandostatin 0 and paliperidone oral sustained-release preparations;
Compared with taking paliperidone daily, sandostatin 0 can be taken every month. Without taking oral auxiliary drugs, the initial administration regimen (1 deltoid muscle administration on day 8 and day 8 150 and 100mg) can make the concentration of papaverine quickly reach a steady state.
Generally speaking, the total plasma concentration of sandostatin 0 in the initial treatment stage is within the drug exposure range after oral administration of 6- 12mg paliperidone sustained-release preparation.
After oral administration of 6- 12mg paliperidone sustained-release preparation according to the initial drug regimen, the patient's drug exposure can be kept within the exposure range, even the concentration on the day before administration (day 8 and day 36) can be kept within this range.
Compared with the situation after taking paliperidone sustained-release tablets, the pharmacokinetics of paliperidone after taking sandostatin 0 has lower variability among subjects. Because the plasma concentration-time curves of the two products are different, we should be cautious when comparing their pharmacokinetic characteristics directly.
standard
0.25ml:25mg/ tablet;
0.5ml:50m g/ tablet;
0.75ml: 75mg/tablet;
1.0 ml: 100 mg/cigarette;
1.5ml: 150mg/ tablet.
Store at room temperature 30 c. Please don't freeze.