Valproic acid is a colorless liquid.The molecular formula is C8H16O2, the molecular weight is 144.21100, the boiling point is 221 ℃, the relative density is 1.1 (24.5/4 ℃), the refractive index is 1.4250, and the flash point is 111 ℃.Insoluble in water.It is extremely harmful to water and toxic to fish. Do not let the product enter the water.[1]Store in a cool and ventilated warehouse.Keep away from kindling and heat sources.Packing and sealing.It shall be stored separately from oxidants and alkalis, and mixed storage is strictly prohibited.
It is extremely harmful to water and toxic to fish. Do not let the product enter the water.[1]
Molecular structure data
1. Molar refractive index: 40.63
2. Molar volume (m3/mol): 155.5
3. Isotonic specific volume (90.2K): 369.6
4. Surface tension (dyne/cm): 31.8
5. Dielectric constant:
6. Dipole distance (10-24cm3):
7. Polarization rate: 16.10[1]
Calculate chemical data
1. Reference value for drainage parameter calculation (XlogP): None
2. Number of hydrogen bond donors: 1
3. Number of hydrogen bond receptors: 2
4. Number of rotatable chemical bonds: 5
5. Number of tautomers: none
6. Topological molecular polar surface area 37.3
7. Number of heavy atoms: 10
8. Surface charge: 0
9. Complexity: 93.4
10. Number of isotope atoms: 0
11. Determine the number of atomic structure centers: 0
12. Number of uncertain atomic structure centers: 0
13. Determine the number of chemical bond structural centers: 0
14. Number of indeterminate chemical bond structure centers: 0
15. Number of covalent bond units: 1[1]
Storage method
Store in a cool and ventilated warehouse.Keep away from kindling and heat sources.Packing and sealing.It shall be stored separately from oxidants and alkalis, and mixed storage is strictly prohibited.Explosion proof lighting and ventilation facilities shall be adopted.It is prohibited to use mechanical equipment and tools that are easy to generate sparks.The storage area shall be equipped with appropriate materials to contain leakage.[1]
Production method
Announce
edit
1. It is obtained from the elimination and decarboxylation of dipropylmalonic acid.Dipropylmalonic acid is put into the reaction pot and heated to 180 ℃. The reactant gradually melts and a large amount of carbon dioxide gas escapes.After elimination reaction is completed, vacuum distillation is carried out to collect 112-114 ℃ (0.93-1.06kPa) fraction, namely 2-propylvaleric acid, with a yield of 86%.[1]
2. Preparation method:
Dipropylmalonic acid: add 122g (0.5mol) of diethyl dipropylmalonate, 220mL of ethanol, and 400g of 4% potassium hydroxide into the reaction bottle equipped with agitator and reflux condenser, and reflux reaction for 4h under stirring.Distill ethanol under reduced pressure.Cool to room temperature, slowly add concentrated hydrochloric acid, adjust to PH1, and precipitate solids.After cooling, suction filtration, water washing and drying, 75.0g of dipropylmalonic acid yellow crystal was obtained with a yield of 80% at mp.155-158 ℃.2-propylvaleric acid: add 75.0g (0.4mol) of dipropylmalonic acid into the reaction bottle, slowly heat the oil bath to 180 ℃, gradually melt the reactant, and release a large amount of carbon dioxide gas until no carbon dioxide gas escapes.Distillation under reduced pressure, collect the fraction of 120 ～ 123 ℃/1.86kPa to obtain light yellow 2-n-propyl acid ① 49.5, with a yield of 86%, nD141.4252. Note: ① It can also be prepared by reacting ethyl acetoacetate with n-bromopropane, followed by alkaline hydrolysis.[1]
purpose
Used as pharmaceutical intermediates, organic synthesis.[1]
security information
Dangerous transport code: UN 1230 3/PG 2
Dangerous goods sign: T toxic Xn harmful
Safety sign: S26
Hazard sign: R22 R36/37/38
Pharmacology and toxicology
Announce
edit
Valproate exerts its pharmacological effects mainly through the central nervous system.Animal studies have shown that it can resist various types of convulsions.
Laboratory and clinical studies have shown that valproate has anticonvulsant effects in two ways.The first mode of action is the direct pharmacological action related to the concentration of valproic acid in plasma and brain.The second mode of action is indirect, which may be related to the metabolism of valproate in the brain, or the change of neurotransmitters or direct membrane action.At present, the widely accepted hypothesis is that taking valproate can lead to the increase of γ - aminobutyric acid (GABA) level in the body.
Valproate can reduce the cycle of the middle period of sleep and increase the slow wave sleep period.[3]
Pharmacokinetics
Announce
edit
Several pharmacokinetic studies of valproate were carried out, and the results showed that:
*The bioavailability of oral drug was close to 100% by using the blood concentration as an indicator;
*Most drugs are distributed in the blood, and there is a rapid exchange process with extracellular fluid.At the same time, drugs can also be distributed in cerebrospinal fluid (CSF) and brain.The concentration of valproate in CSF was close to that of free drug in plasma.The half-life of the drug is 15-17 hours.Children are usually shorter.
*The lower limit of serum drug concentration for therapeutic effect is generally 40-50mg/L, and the range can be widened to 40-100mg/L.If it is necessary to make the blood concentration higher, it is necessary to balance the efficacy and possible adverse reactions, especially those related to the blood concentration.However, if the blood concentration level remains above 150mg/L, the dose needs to be reduced.
*The blood concentration of the drug reached steady state after 3-4 days of continuous administration.
*Valproate is excreted in urine through glucuronization and β - oxidation in vivo.
*Valproate can be dialyzed out, but hemodialysis only affects the blood concentration of free drugs (about 10% of the blood concentration).Valproate did not induce the enzymes involved in the CYP450 metabolic system.Compared with most other antiepileptic drugs, it will not accelerate the degradation of itself and other drugs, such as estrogen progesterone and oral anticoagulants.Compared with the enteric coated preparation of valproate, the pharmacokinetics of the drug in vivo after taking this product at the same dose has the following characteristics:
*No absorption delay phase;
*Absorption phase prolongation;
*Same bioavailability;
*The peak values of total blood drug concentration and free blood drug concentration decreased (Cmax decreased by about 25%, and showed a relatively stable plateau between 4 and 14 hours after administration);During the 24-hour period, the blood concentration time curve of valproic acid presents a "smooth peak" phenomenon. The blood concentration of valproic acid is relatively stable and lasts for 24 hours. After taking the same dose twice a day, the change range of the blood concentration of valproate is reduced by half.
*The linear relationship between the total blood concentration and free blood concentration and the dosage is better.[3]
indication
Announce
edit
epilepsy
It can be used as a single drug treatment or as an addition treatment.
*It is used to treat generalized epilepsy, including absence seizure, myoclonic seizure, tonic clonic seizure, dystonic seizure, mixed seizure, and special type syndrome (West, Lennox Gastaut syndrome).
*For the treatment of partial epilepsy: local seizures, with or without general seizures.
Mania
It is used to treat manic episodes related to bipolar disorder.[3]
Specifications:
Announce
edit
Each tablet contains 0.333g sodium valproate and 0.145g valproate (equivalent to 0.5g sodium valproate).[3]
Usage and dosage:
Announce
edit
epilepsy
This product is a sustained-release preparation. After taking this drug, the peak blood concentration in the body can be reduced, and the blood concentration can be maintained at a normal level within 24 hours.
This dose is applicable to adults and children weighing more than 17 kg.
This dosage form is not suitable for children younger than 6 years old.(There is danger of entering the air pipe by mistake)
This product can control seizures.In those patients who use drugs to prevent the occurrence of grand mal, the antiepileptic drugs should not be stopped suddenly, because if the drugs are stopped suddenly, there is a great possibility of the status epilepticus with hypoxia and life threat.
dose
The initial dose is usually 10~15mg/kg per day, and then increases until the curative effect is satisfactory (see initial treatment).The general dose is 20-30mg/kg per day.However, if the paroxysmal state cannot be controlled within this dose range, it may be considered to increase the dose, but the patient must be closely monitored.
When children take this product, the routine dose is 30mg/kg per day.
When adults take this product, the routine dose is 20-30mg/kg per day.
When elderly patients take this product, the dosage should be determined according to the control of seizure state.
The daily dose should be determined according to the patient's age and weight.At the same time, it should be considered that there are obvious individual differences in clinical sensitivity to valproate.
So far, the correlation between daily dose, blood concentration level and efficacy is still unclear, and the dosage is mainly determined based on clinical efficacy.When the attack cannot be controlled or adverse reactions are suspected, in addition to clinical monitoring, the plasma concentration of sodium valproate should be measured. It has been reported that the effective range is 40~100mg/L (300~700 μ mol/L).[3]
Method of administration
Oral.The daily dose should be taken 1-2 times.
Once a day may be considered when epilepsy has been well controlled.
This product should be swallowed in whole, and can be taken in half, but cannot be crushed or chewed.
Initial treatment
*For patients newly diagnosed with epilepsy or who have not used other antiepileptic drugs, the drug dose shall be increased every 2-3 days to reach the optimal dose within one week.
*For patients who take other quick acting preparations of sodium valproate and whose condition has been well controlled, the recommended daily dose of this product is still maintained.
*For patients who have previously received other antiepileptic drugs, the use of sodium valproate sustained-release tablets should be gradually carried out, reaching the optimal dose within 2 weeks, and other treatments should be gradually reduced to discontinuation.If other antiepileptic drugs need to be added, they should be gradually added.(See the content in Drug Interaction)
Mania
Oral administration.In patients who do not receive other psychotropic drugs, increase the drug dose every 2-3 days to reach the optimal dose within one week.For patients with other psychotropic drugs, the dosage will be adjusted according to the characteristics of drug action and individual clinical response.
dose
Antimania should start from a small dosage. The recommended initial dosage is 500 mg/day, which should be taken twice, once in the morning and once in the evening. The dosage should be increased as soon as possible, reaching 1000 mg/day on the third day and 1500 mg/day on the first weekend. After that, the dosage can be adjusted according to the condition and the blood concentration of Debakin. The maintained dosage range is 1000-2000 mg/day, and the maximum dose does not exceed 3000 mg/day,The therapeutic blood concentration is in the range of 50-125ug/mL.
For children and young people under 18 years old, the safety and effectiveness of Debakin in the treatment of mania related to bipolar disorder have not been studied.The elderly patients should reduce the dosage as appropriate.[3]
Adverse reactions
Announce
edit
The incidence of adverse reactions was graded by OOMS frequency.
Very common ≥ 10%, common ≥ 1 and ≤ 10%, rare ≥ 0.1 and<1%, rare ≥ 0.01 and<0.1%, extremely rare<0.01%, unknown (cannot be estimated from existing data).
Gastrointestinal system:
·Very common: nausea.
·Common: epigastric pain and diarrhea often occur at the beginning of treatment.These abnormalities usually disappear after a few days of continued medication
·Rare: pancreatitis, sometimes fatal cases are reported.(See the contents in [Precautions])
Hepatobiliary system:
·Common: liver injury.(See [Precautions])
Congenital and familial/hereditary abnormalities:
·Teratogenic risk (see the content in [Medication for pregnant and lactating women]).
Central nervous system:
·Rare: cases of cognitive dysfunction and secret and progressive attack of vague consciousness can develop to complete dementia, and can be reversed weeks to months after stopping treatment.
·Very common: tremor
Common: Extravertebral system disorders, stupor *, lethargy, convulsions *, memory disorders, headache, nystagmus, dizziness may occur a few minutes after intravenous injection, and the reaction will disappear automatically in a few minutes.
Rare: coma *, encephalopathy *, lethargy *, reversible Parkinson's disease, ataxia, and paresthesia.
·Blurred consciousness: It is reported that some patients have numbness or lethargy, sometimes leading to transient coma (encephalopathy).The above symptoms are isolated or related to the increased incidence of convulsions during treatment, and will be alleviated after termination of valproate treatment or reduction of dose.When combined treatment (especially with phenobarbital) or the dosage of valproate suddenly increased, the above symptoms were reported more frequently.
*These adverse reactions mainly occur in pediatric drug users.
Metabolic/nutritional system:
·Common cases of hyponatremia.
·Rare: Hyperazotemia * (see "Precautions").
*Individual and moderate hyperazoemia may not cause changes in liver function tests, which should not cause drug withdrawal. Hyperazoemia related to neurological symptoms has also been reported, in which case, further research should be considered (see "Precautions").
·There are few reports of non serious peripheral edema.
·There have been reports about Fanconi syndrome (metabolic acidosis, hyperphosphatemia, aminoaciduria, diabetes) in the literature, and the above reactions can be reversed after stopping taking valproic acid containing drugs.However, the mechanism of these reactions is still unclear.
·Common: weight gain.Weight gain is a risk factor for polycystic ovary syndrome, and the weight of patients should be closely monitored.(See the contents in [Precautions])
Benign, malignant and unspecified tumors (including cysts and polyps)
Rare: myelodysplastic syndrome
Urogenital system:
·Rare enuresis and urinary incontinence were reported.Kidney injury was reported in some cases.
·Common: dysmenorrhea
·Rare: menopause
·Rare: male infertility, polycystic ovary
Hemolymph system:
·Common: anemia, thrombocytopenia (see [Precautions]).
·Rare: pancytopenia, leukopenia.
·Rarely seen: bone marrow failure, including simple red cell aplasia, granulocytopenia, large cell anemia, and megared cell disease.
·Rare: reduction of coagulation factor (at least one), abnormal coagulation test (such as prolongation of coagulation factor time, prolongation of activated partial prothrombin kinase time, prolongation of thrombin time, and prolongation of INR) (see [Precautions] and [Medication for pregnant women and lactating women]).
Skin and subcutaneous tissue:
·Common: hypersensitivity, temporary hair loss, and related to the dosage.
*Rare: angioneurotic edema, rash.
*Rare: toxic epidermal necrosis and lysis, Steven Johnson syndrome and erythema multiforme, drug rash, drug rash with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue
Rare: decreased bone density, osteoporosis, osteoporosis and fracture in patients treated with this product for a long time.The mechanism of this product affecting bone metabolism has not been determined.
Rare: systemic lupus erythematosus (see "Precautions").
Vascular abnormalities
Common: bleeding
Rare: vasculitis
endocrine
Rare: Syndrome of abnormal antidiuretic hormone secretion (SIADH)
Rare: hypothyroidism (see "Medication for pregnant and lactating women")
Special sensory system
Common: deafness.Respiratory, thoracic and mediastinal systems
Rare: pleural effusion[3]
Taboos:
Announce
edit
*Allergic to valproate, dipvalproate, valproamide or any component of this product;
*Patients with acute hepatitis;
*Chronic hepatitis patients;
*Patients with severe hepatitis or family history, especially those with porphyria hepatica related to medication;
*Patients with urea circulation disorders.[3]
matters needing attention:
Announce
edit
Special tips:
In rare cases, the use of an antiepileptic drug may lead to an increase in the number of seizures or the type of seizures that occur, and it is different from the phenomenon observed in some types of epilepsy.When using valproate, the reasons for the above phenomenon are mainly related to the combination of antiepileptic drug treatment or pharmacokinetic interaction (see [Drug interaction]), toxic reaction (liver disease or encephalopathy) (see [Precautions] and [Adverse reactions]) or drug overdose.
Since the drug is converted into valproic acid in the body after taking this product, other drugs containing active ingredients that can be converted into the same compound should not be taken together while taking this product to prevent excessive valproic acid in the body (such as dipvalproate, valproamide, etc.).
*In some cases, if the patient and her therapist make an informed choice after careful evaluation of all relevant factors, TM is the appropriate choice for women of childbearing age (see [Precautions] and [Pregnant women should not use drugs for lactating women]).[3]
warning
1. Hepatotoxicity: Occurrence conditions: there are very rare cases of severe liver function damage, including fatal cases reported.
The experience of epilepsy treatment shows that infants are at the greatest risk, especially children under 3 years of age and those with severe seizures, especially those suffering from brain injury, mental retardation and/or congenital metabolic or degenerative diseases when using multiple anticonvulsant drugs.After 3 years of age, the incidence of the disease decreased significantly, and gradually decreased with age.In most cases, this kind of liver injury occurs in the first 6 months of treatment, usually between the second to the 12th week and during the period of combined antiepileptic treatment with multiple drugs.[3]
Prompt symptoms:
Clinical symptoms are essential for early diagnosis.Especially when jaundice occurs in the following patients at risk:
*Non specific symptoms: usually sudden onset, such as weakness, anorexia, weakness and lethargy, sometimes related to repeated vomiting and abdominal pain.
*Symptoms of epilepsy patients recur.The patient (or the child's family) should be informed, and once the above situation occurs, the doctor should be reported immediately.Clinical physical examination and biological determination of liver function should be carried out immediately.[3]
Inspection:
The measured liver function should be monitored regularly before treatment and within the first 6 months after treatment.
In routine tests, the tests reflecting protein synthesis, especially prothrombin time, are most closely related.If it is confirmed that there is abnormally low prothrombin time, especially with other biological abnormalities (fibrinogen and coagulation factor levels are significantly reduced; when the concentration of bilirubin and transaminase is increased, sodium valproate treatment needs to be stopped.)
(As a precaution, if salicylic acid derivatives are used together, the treatment of this product should also be stopped because this product has the same metabolic pathway as the latter.)
When this product is applied to patients with a history of liver disease, more attention should be paid.This risk is particularly prominent for patients who use a variety of anticonvulsant drugs, children, patients with congenital metabolic diseases, patients with severe convulsions accompanied by mental retardation, and patients with organic brain diseases.
2. Pancreatitis: It has been reported that very few patients have severe or even fatal pancreatitis.This reaction is related to the patient's age and treatment cycle, and there may be some risks for children to react.
Pancreatitis leading to adverse reactions can usually be observed in young children or patients with severe seizures, brain damage or taking multiple antiepileptic drugs.If pancreatitis is accompanied by liver dysfunction, it increases the risk of death.
Patients and their guardians should be warned that abdominal pain, nausea, vomiting and/or loss of appetite may be symptoms of pancreatitis.This requires an immediate medical assessment.If pancreatitis has been diagnosed, this product should be stopped under normal circumstances.According to the clinical indications, other treatments should be carried out for the potential disease status.
3. Teratogenicity: According to published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who used the drug during pregnancy.Sodium valproate may produce teratogenic effects such as neural tube defects (such as spina bifida).Therefore, only when the benefit of treatment is greater than the risk of fetal injury can it be applied in women of childbearing age.(See the content in [Medication for Pregnant and Lactating Women])
This drug should not be used in women of childbearing age unless it is clearly needed (that is, in the case of other treatments that are ineffective or intolerable). This evaluation should be carried out before the first prescription of this product or when a woman of childbearing age who is treated with this product plans to become pregnant. Women of childbearing age must use effective contraceptive methods during treatment.
According to published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who used the drug during pregnancy.Sodium valproate may produce teratogenic effects such as neural tube defects (such as spina bifida).Therefore, only when the benefit of treatment is greater than the risk of fetal injury can it be applied in women of childbearing age.(See the content in [Medication for Pregnant and Lactating Women])
4. Urea circulation disorder disease (UCD): This product is not recommended for patients with urea circulation enzyme deficiency.Urea circulatory disorders are a group of uncommon genetic disorders, especially in the case of ornithine carbamyltransferase deficiency.In these patients, sporadic cases of coma caused by hyperammonemia were reported.
Before starting to use this product, UCD should be evaluated in the following patients: 1) patients with unexplained encephalopathy or coma history, patients with encephalopathy history related to protein load, patients with pregnancy related encephalopathy or postpartum encephalopathy history, patients with a history of increased plasma ammonia or glutamate levels;2) Those patients with periodic vomiting, occasional hyperexcitability, exercise ataxia, low urea nitrogen or protein avoidance;3) Patients with a family history of UCD or with a family history of unexplained infant death (especially boys);4) Patients with other signs and symptoms of UCD.Patients with high blood ammonia encephalopathy of unknown cause should receive treatment immediately (including stopping the treatment of sodium valproate) when receiving this product, and the potential urea circulation disorders should be evaluated.
5. Sleepiness in elderly patients: In elderly patients, the dosage should be increased more slowly, and the intake of liquid and nutrients, dehydration, sleepiness and other adverse events should be monitored regularly.(See [Dosage and usage]).
6. Thrombocytopenia: Thrombocytopenia has been reported in the treatment of dipvalproic acid. Due to the inhibition of the drug on the second stage of platelet aggregation and the abnormality of coagulation parameters (such as low fibrinogen), it is recommended to detect the platelet count and coagulation function before starting the treatment and during the periodic interval.
7. Application in pregnant women: According to published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who use the drug during pregnancy.
The incidence of neural tube defects in their fetuses may increase among mothers who received valproate treatment in the first three months of pregnancy.The National Center for Disease Control (CDC) has determined that the risk of spina bifida in children of women exposed to valproic acid is about 1% to 2%.
Other congenital abnormalities have been reported (such as craniofacial defects, cardiovascular malformations and abnormalities involving multiple body systems), which can or may not coexist with life.There is not enough data to determine the incidence of these congenital anomalies.
The high incidence of fetal congenital abnormalities in women with convulsive diseases who receive antiepileptic drugs cannot be considered as a causal relationship.There are inherent methodological problems in obtaining sufficient data on teratogenicity of drugs from humans;Genetic factors or epilepsy itself may play a more important role than drug therapy in causing fetal congenital malformations.
Patients treated with sodium valproate may have coagulation abnormalities.If sodium valproate is used in pregnant women, the coagulation parameters should be carefully monitored.
In the process of treatment and consultation for women of childbearing age, prescription doctors will hope to balance the benefits and risks of treatment.If the drug is to be used during pregnancy, or if the patient is to become pregnant during the use of the drug, the patient should be informed of the potential danger of the drug treatment to the fetus.
In patients who use antiepileptic drugs to prevent grand mal epilepsy, antiepileptic drugs should not be stopped suddenly, because it may promote the occurrence of status epilepticus accompanied by hypoxia, and it is life threatening.For some patients with epilepsy whose severity and seizure frequency are so low that stopping drug treatment will not pose a serious threat to the patient, drug treatment can be considered to be stopped before and during pregnancy, although it cannot be guaranteed that seizures will not pose some risks to the development of embryos or fetuses.
In pregnant women receiving sodium valproate treatment, it should be considered to use existing acceptable examination procedures to detect neural tube defects and other defects.
8. Suicide intention and behavior
There have been reports of suicidal intention and behavior of patients after receiving antiepileptic treatment according to treatment indications. A meta-analysis of a randomized placebo controlled antiepileptic drug trial also showed a slight increase in suicidal intention and behavior risk.The mechanism of this action is still unclear.
Therefore, we should monitor the suicide intention and signs of behavior of patients, and consider appropriate treatment. If suicide intention and signs of behavior are found, we should advise patients (patient caregivers) to seek medical help immediately.
9. Carbapenems
Simultaneous use of sodium valproate and carbapenems is not recommended (see [Drug interactions]).[3]
Precautions
Announce
edit
The liver function should be measured before treatment (see the contents in [Contraindications]), and monitored regularly within 6 months before starting treatment, especially for dangerous patients (see the contents in [Precautions]).
For most antiepileptic drugs, attention should be paid to the slight increase of transaminase level, especially at the beginning of treatment, but it is usually temporary and moderate, without clinical significance.
More in-depth biological examination (including prothrombin time) is recommended in these patients;If appropriate, consider adjusting the dose and repeat the above tests.
Single drug treatment is recommended when children use sodium valproate, but the possible benefits of sodium valproate should be weighed against the risk of liver damage or pancreatitis before starting treatment for such patients (see [Precautions]).
Blood tests (such as blood cell count, bleeding time and agglutination test) should be carried out before treatment, surgery or in case of spontaneous bruising or bleeding (see [Adverse reactions]).
Due to the risk of liver toxicity and bleeding, children should avoid using acetylsalicylic acid when taking this product to treat epilepsy.
Patients with renal insufficiency may need to reduce the dose.Since plasma concentration monitoring may lead to misleading, the dose should be adjusted according to clinical monitoring.
When acute abdominal pain or gastrointestinal symptoms including nausea, vomiting and/or anorexia occur, the diagnosis of pancreatitis must be considered.For patients with elevated pancreatic enzyme levels, treatment should be stopped and necessary treatment measures should be taken.
This product is not recommended for patients with urea circulating enzyme deficiency.Among these patients, sporadic cases of coma caused by hyperammonemia were reported.
Children with liver and digestive tract dysfunction (such as anorexia, vomiting, cytolysis), depression or coma, and mental retardation of unknown etiology, or children with neonatal or infant death in their families, must be tested for metabolic indicators before receiving any valproate treatment, especially fasting and postprandial blood ammonia levels.
Although few immunologic abnormalities were observed during the course of medication, the possible benefits and risks should be weighed for patients with systemic lupus erythematosus.
All patients should understand the risk of weight gain before receiving sodium valproate treatment, and take appropriate measures to reduce its occurrence.
At the beginning of treatment, if the patient is a woman of childbearing period, it should be confirmed that she is not pregnant, and she has taken effective contraceptive measures before starting treatment (see the content in [Medication for pregnant women and lactating women]).
Since valproic acid can be partially metabolized to ketone bodies, it should be noted that it may have a false positive effect on the results of ketone excretion test of diabetic patients suspected of ketoacidosis.
In the treatment of acute mania with sodium valproate, there is no control test data on the clinical safety and efficacy of this product for long-term use (more than 4 weeks). Therefore, if we choose to extend the treatment time of sodium valproate, we should evaluate the necessity of continuous use of this drug according to the patient's individual conditions.[3]
Hyperammoniaemia:
Hyperammoniaemia has been reported to be related to sodium valproate treatment. Hyperammoniaemia can occur even if the liver function test results are normal.The possibility of hyperammonemia encephalopathy should be considered in patients with unexplained lethargy, vomiting or mental state changes, and the blood ammonia level should be measured.If the blood ammonia is increased, then the sodium valproate treatment should be stopped.Appropriate treatment for hyperammonemia should be started, and such patients should be examined to determine whether they have urea circulation disorders.
Asymptomatic increase in blood ammonia level is more common. When there is an asymptomatic increase in blood ammonia level, the plasma ammonia level needs to be closely monitored.If the blood ammonia continues to increase, then we should consider stopping sodium valproate treatment.In patients with unexplained lethargy, vomiting or mental state changes, the possibility of hyperammonemia encephalopathy should be considered, and the level of blood ammonia should be measured (see [Contraindications]).
Alcohol consumption during treatment with sodium valproate is not recommended.
Impact on driving and mechanical operation ability: patients should pay attention to the danger of drowsiness, especially drivers or mechanical operators.When taking multi drug anticonvulsant treatment or other drugs at the same time, pay special attention to this somnolence reaction.[3]
Drugs for pregnant and lactating women:
Announce
edit
Women of childbearing age
This drug should not be used in women of childbearing age unless it is clearly needed (i.e. when other treatments are ineffective or intolerable).
This evaluation should be carried out before the first prescription of this product or when a woman of childbearing age who is treated with this product plans to become pregnant.Women of childbearing age must use effective contraceptive methods during treatment.[3]
gestation
Based on the data obtained, the use of sodium valproate during pregnancy is not recommended.
The risk of malformation induced by pregnant women taking sodium valproate by taking drugs is 3-4 times higher than that of normal people, which is 3%.
The most common malformations are neural duct closure defects (about 2-3%), craniofacial defects, limb malformations, cardiovascular malformations and multiple malformations, including different human systems.
The obvious risk factors of the above malformations when the dosage is more than 1000mg/day and combined with other anticonvulsant drugs.
The existing epidemiological data do not show that exposure to valproate in utero can reduce the overall IQ of children. However, a slight decline in oral expression ability and/or an increase in the need for speech related adjuvant treatment have been observed in these children.Further results showed that sporadic cases of autism and related disorders were reported among children exposed to sodium valproate in utero.Further clinical studies are needed to confirm these results.
Children exposed to valproic acid in utero also have latent diseases reporting autism.
Both valproate monotherapy and valproate multidrug therapy are associated with abnormal pregnancy.The available data show that the risk of abnormal pregnancy is higher with multi drug therapy containing valproate than with single drug therapy of valproate.
in summary
The following recommendations should be considered: this drug should not be used during pregnancy and in women of childbearing age unless explicitly needed (i.e. in cases where other treatments are ineffective or intolerable).This evaluation should be carried out before the first prescription of this product or when a woman of childbearing age who is treated with this product plans to become pregnant.Women of childbearing age must use effective contraceptive methods during treatment.[3]
Planned pregnancy:
If a woman plans to become pregnant, regardless of the indications, the treatment of this product should be reassessed.Complete steps should be taken to consider whether other treatment measures can be used.
When applied to the indication of bipolar disorder, the treatment of this product should be stopped.For any other indication, if the use of sodium valproate is inevitable (or there is no other choice), it is recommended that the daily dose should be the lowest effective dose, and the sustained-release dosage form should be used as far as possible. If the sustained-release dosage form is not timely, it can be considered to take the ordinary dosage form in batches to avoid the peak concentration of valproic acid in the blood.
So far, there is no evidence to support the effectiveness of folic acid supplementation when women take valproate during pregnancy.However, in consideration of the beneficial effects in other cases, folic acid may be supplemented one month before pregnancy and two months after pregnancy at a dose of 5mg/day.And no matter whether patients take folic acid or not, they should receive the same malformation examination.
During pregnancy:
If there is no alternative (no alternative) to continuous treatment with sodium valproate, the minimum effective dose is recommended.If possible, avoid doses higher than 1000 mg/day.
Before birth:
Patients treated with sodium valproate may have coagulation abnormalities.If sodium valproate is used in pregnant women, the mother should be tested for blood coagulation before birth, including platelet count, fibrinogen level and blood coagulation time (aPTT).[3]
newborn:
This product may cause neonatal bleeding syndrome unrelated to vitamin K deficiency.
This bleeding syndrome is associated with thrombocytopenia, fibrinogen deficiency, and/or other coagulation factors. Fibrinogen deficiency has also been reported and may be fatal.However, this syndrome must be distinguished from vitamin K dependent coagulation factor reduction, which is induced by phenobarbital and enzyme inducers.
Routine hematological examination of mothers cannot fully reflect the possibility of hematological abnormalities in newborns.Platelet count, fibrinogen level, coagulation test and coagulation factors should be checked.
Cases of neonatal hypoglycemia have been reported, and their mothers took valproate during the last three months of pregnancy.
Cases of neonatal hypothyroidism have been reported, and their mothers took valproate during pregnancy.
Breastfeeding:
The concentration of valproic acid in milk is very low, only 1% to 10% of the maternal serum concentration.Although up to now, no clinical abnormalities have been reported in breast fed children monitored during the newborn period, breast feeding is not a contraindication to taking sodium valproate.It should be weighed against various factors.[3]
Children's medication:
Announce
edit
Single drug treatment is recommended when children use sodium valproate, but the possible benefits of sodium valproate should be weighed against the risk of liver damage or pancreatitis before starting treatment for such patients (see [Precautions]).
Due to the risk of liver toxicity and bleeding, children should avoid using acetylsalicylic acid when taking this product.
Children with liver and digestive tract dysfunction (such as anorexia, vomiting, cytolysis), depression or coma, and mental retardation of unknown etiology, or children with neonatal or infant death in their families, must be tested for metabolic indicators before receiving any valproate treatment, especially fasting and postprandial blood ammonia levels.
For children and young people under 18 years of age, the safety and effectiveness of valproate sodium in the treatment of manic disorder related to bipolar disorder have not been studied.[3]
Medication for the elderly:
Announce
edit
Compared with young adult patients, the ability of elderly patients (older than 68 years) to clear sodium valproate has decreased, and the incidence may increase. Therefore, the initial dose should be reduced in these patients.At the same time, the increase rate of dosage should be more slow, and the intake of liquid and nutrients, dehydration, lethargy and other adverse events should be monitored regularly.When the intake of food and liquid of the patient decreases, or the patient has excessive sleepiness, the dosage of sodium valproate should be reduced or the treatment of sodium valproate should be stopped.The final therapeutic dose should be determined based on tolerance and clinical response.Refer to the relevant contents under other items in this manual, or follow the doctor's advice.[3]
Drug interactions:
Announce
edit
When taking this product and taking drugs to induce seizures or drugs to reduce seizure threshold, careful consideration should be taken. According to the severity of potential risks, it can be determined not to use or disable.Such drugs mainly include most antidepressants (imipramine, SSRI), tranquilizers (phenothiazine and phenylbutanone drugs), melquinine (see the following chapter), bucyclospirone, tramadol, etc.
Prohibited syndication
Combined use with melquinine: when patients with epilepsy take it together, because melquinine may lead to an increase in valproic acid metabolism and its own role in inducing seizures, they may be at risk of seizures.
In combination with St. John's wort: there is a risk of reduced blood concentration and anticonvulsant effect.[3]
Joint application needing attention
Combined use with aztreonam, imipenem and meropenem: there is a risk of spastic reaction caused by the reduction of valproic acid blood concentration.During the treatment of anti infective drugs, clinical monitoring, blood drug concentration determination and timely adjustment of the dosage of anti convulsive drugs should be carried out, and monitoring should still be carried out after drug withdrawal.
Carbamazepine: It can increase the blood concentration of the active metabolite of carbamazepine, leading to the reaction of overdose.At the same time, due to the induction of liver metabolism by carbamazepine, the blood concentration of valproic acid can be reduced.Therefore, it is suggested to carry out clinical drug monitoring, measure the blood concentration of the two anti convulsive drugs and adjust their doses.
Lamotrigine: increased risk of serious skin reactions (Lyell's syndrome).Valproic acid can increase the blood concentration of lamotrigine by inhibiting its liver metabolism.If it must be taken in combination, it should be closely monitored in clinical practice.
Felamine ester: It can increase the blood concentration of valproic acid, resulting in the risk of drug overdose.
Clinical and biochemical indicators should be monitored and the dosage of valproate should be adjusted during the treatment with felamate.The above observation measures should still be taken after drug withdrawal.
one
Phenobarbital and acetaminophen: due to the inhibitory effect of valproic acid on liver metabolism, the blood concentration of phenobarbital or acetaminophen may increase, resulting in drug overdose, which occurs frequently in children.At the same time, due to the induction of phenobarbital or promidone on liver metabolism, the blood concentration of valproic acid can be reduced.Clinical monitoring should be carried out within the first 15 days of combined treatment, and the dose of phenobarbital or acetaminophen should be rapidly reduced when any sedative symptoms occur.In particular, the blood concentration of two anticonvulsant drugs should be monitored.
two
Phenytoin (and can be extended to phosphophenytoin): can cause changes in the blood concentration of phenytoin.At the same time, due to the induction of liver metabolism by phenytoin, the plasma concentration of valproic acid may be reduced.Clinical monitoring and blood concentration determination should be carried out, and the dosage of two anticonvulsant drugs should be properly adjusted.
three
Topiramate: There is a risk of hyperammonemia or encephalopathy, which is usually caused by taking valproate while taking Topiramate.Clinical monitoring and laboratory monitoring should be increased at the initial stage of treatment, and attention should be paid to the signs of the reaction.
four
Cimetidine and erythromycin: when taken at the same time, the concentration of valproic acid in serum may increase.
five
Acetylsalicylic acid: infants and young children with temperature regulation disorder should not take drugs containing valproic acid and acetylsalicylic acid at the same time.Only under the guidance of a doctor can teenagers with temperature regulation disorder take it.
six
Benzenediazepines, barbiturates and tranquilizers, monoamine oxidase inhibitors and antidepressants: when combined, valproic acid can increase the central inhibitory effect of these drugs.When the above drugs are used together, the patients should be closely monitored, and the dosage of drugs should be adjusted if necessary.
seven
Zidovudine: Valproic acid can increase the serum drug concentration of Zidovudine, which may lead to increased toxicity of Zidovudine.Anticoagulants and antiplatelet aggregators: Taking them together with drugs containing valproic acid may increase bleeding tendency.Therefore, it is recommended to conduct routine monitoring of blood coagulation during the combination of drugs.
eight
Diazepam: The research results in healthy subjects show that valproic acid can displace diazepam from its plasma protein binding site and inhibit its metabolism.The plasma concentration of free diazepam in the body may increase, and the plasma clearance rate and distribution volume of free diazepam may decrease (by 25% and 20% respectively).However, the half-life remains unchanged.The research results in healthy subjects show that when valproate and lorazepam are taken together, the blood concentration of lorazepam can be reduced by up to 40%.In children, after taking clonazepam and valproic acid at the same time, the level of phenytoin in serum may increase.
nine
Nimodipine (given orally and intravenously): due to the inhibitory effect of valproic acid on metabolism, the blood concentration of nimodipine may rise, which plays a role in promoting the hypotension reaction of nimodipine.
ten
Rifampicin may reduce the blood concentration of valproate, leading to reduced efficacy.Therefore, when combined with rifampicin, it is necessary to adjust the dosage of valproate.[3]
Other forms of interaction:
And lithium: this product has no effect on the serum lithium level.
And oral contraceptives: Since valproic acid has no enzyme inducing activity, it will not reduce the effect of hormonal contraceptives on estrogen and progesterone taken by women.Phenobarbital and acetaminophen: due to the inhibitory effect of valproic acid on liver metabolism, the blood concentration of phenobarbital or acetaminophen may increase, resulting in drug overdose, which occurs frequently in children.At the same time, due to the induction of phenobarbital or promidone on liver metabolism, the blood concentration of valproic acid can be reduced.
Clinical monitoring should be carried out within the first 15 days of combined treatment, and the dose of phenobarbital or acetaminophen should be rapidly reduced when any sedative symptoms occur.In particular, the blood concentration of two anticonvulsant drugs should be monitored.
Phenytoin (and can be extended to phosphophenytoin): can cause changes in the blood concentration of phenytoin.At the same time, due to the induction of liver metabolism by phenytoin, the plasma concentration of valproic acid may be reduced.Clinical monitoring and blood concentration determination should be carried out, and the dosage of two anticonvulsant drugs should be properly adjusted.
Topiramate: There is a risk of hyperammonemia or encephalopathy, which is usually caused by taking valproate while taking Topiramate.Clinical monitoring and laboratory monitoring should be increased at the initial stage of treatment, and attention should be paid to the signs of the reaction.
Cimetidine and erythromycin: when taken at the same time, the concentration of valproic acid in serum may increase.
Acetylsalicylic acid: infants and young children with temperature regulation disorder should not take drugs containing valproic acid and acetylsalicylic acid at the same time.Only under the guidance of a doctor can teenagers with temperature regulation disorder take it.
Benzenediazepines, barbiturates and tranquilizers, monoamine oxidase inhibitors and antidepressants: when combined, valproic acid can increase the central inhibitory effect of these drugs.When the above drugs are used together, the patients should be closely monitored, and the dosage of drugs should be adjusted if necessary.
Zidovudine: Valproic acid can increase the serum drug concentration of Zidovudine, which may lead to increased toxicity of Zidovudine.Anticoagulants and antiplatelet aggregators: Taking them together with drugs containing valproic acid may increase bleeding tendency.Therefore, it is recommended to conduct routine monitoring of blood coagulation during the combination of drugs.
Diazepam: The research results in healthy subjects show that valproic acid can displace diazepam from its plasma protein binding site and inhibit its metabolism.The plasma concentration of free diazepam in the body may increase, and the plasma clearance rate and distribution volume of free diazepam may decrease (by 25% and 20% respectively).However, the half-life remains unchanged.The research results in healthy subjects show that when valproate and lorazepam are taken together, the blood concentration of lorazepam can be reduced by up to 40%.In children, after taking clonazepam and valproic acid at the same time, the level of phenytoin in serum may increase.
Nimodipine (given orally and intravenously): due to the inhibitory effect of valproic acid on metabolism, the blood concentration of nimodipine may rise, which plays a role in promoting the hypotension reaction of nimodipine.[3]
Drug overdose:
Announce
edit
When an acute super dose is taken, the common symptoms include coma with hypotonia, hyporeflexia, miosis, respiratory dysfunction, and metabolic acidosis.The clinical symptoms can vary. It is reported that epilepsy will occur when the blood concentration is too high.Cases of intracranial hypertension related to brain edema have also been reported.
The treatment of overdose should be based on the symptoms: gastric lavage, furuncle treatment, urine secretion and cardiopulmonary monitoring.In very serious cases, hemodialysis can be used if necessary.It has been reported that naloxone can reverse the inhibitory effect of central nervous system caused by sodium valproate overdose.In theory, naloxone also reverses the antiepileptic effect of sodium valproate, so more attention should be paid to the use of naloxone in epileptic patients.Generally, the prognosis is good.However, sporadic deaths were reported.[3]
