Date of approval.
Date of revision.
Sodium Valproate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
[Drug Name].
Generic name: Sodium Valproate Tablets
English name: Sodium Valproate Tablets
Hanyu Pinyin：Bingwusuanna Pian
Ingredients
The main ingredient of this product is sodium valproate. Its chemical name is sodium 2-propyl valproate.
Its chemical structure formula is
Molecular formula: C8H15NaO2
Molecular weight: 166.20
Properties】This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
It is used for generalized, partial or other types of epilepsy.
Specification】0.2g
Dosage and Administration
Monotherapy.
Adults.
Generally start with 600mg/day and may increase by 200mg every 3 days until symptoms are controlled. The usual dose range is 1000mg to 2000mg per day; i.e. 20-30mg/kg body weight. If still not controlled, the dose can be increased to 2500mg/day.
Children weighing more than 20kg.
Generally start with 400mg/day (independent of body weight) and increase the dose at intervals until symptoms are controlled; the general dose range is 20-30mg/kg/day. If not controlled, the dose may be increased to 35mg/kg/day.
Children weighing less than 20kg.
Generally 20mg/kg/day; dose may be increased in severe cases, but only in those patients in whom valproic acid blood levels can be monitored. Doses above 40 mg/kg/day require monitoring of clinical biochemical and hematological parameters.
Patients with renal insufficiency.
Dose reduction may be required. Because plasma concentration monitoring may be misleading, dose should be adjusted based on clinical monitoring.
Patients with hepatic impairment.
Because salicylates share the same metabolic pathway as valproic acid, they should not be administered concurrently. (See [Precautions] and [Adverse Reactions]).
Hepatic impairment, including death due to liver failure, has occurred in patients treated with valproic acid. (See [Contraindications] and [Precautions]).
Salicylates should not be used in children under 16 years of age (see product description for aspirin/salicylate Reye syndrome). In addition combination with sodium valproate syrup increases the risk of hepatotoxicity in children under 3 years of age (see [Precautions]).
Combination therapy
If the patient is already on other antiepileptic drugs when sodium valproate is started, slow withdrawal of the drug is required. The dose of sodium valproate should also be increased gradually, usually after 2 weeks, to the target dose. If combined with an antiepileptic drug that induces hepatic enzyme activity (e.g., phenytoin, phenobarbital, carbamazepine), the rate of dosing should be 5-10 mg/kg/day. Once the hepatic enzyme inducer is withdrawn, the dose of sodium valproate should also be reduced. If barbiturates are co-administered, especially if sedation is present (especially in children), the barbiturate should be reduced.
Note: If the dose exceeds 40 mg/kg/day in children, care should be taken to monitor clinical biochemical and hematological indices.
The determination of the appropriate dose depends mainly on the control of the disease and routine monitoring of blood levels is not necessary. However, if control is poor or side effects are suspected, blood level monitoring may be helpful.
Adverse reactions]
The incidence of adverse reactions was graded using CIOMS frequency.
Very common ≥ 10%; common ≥ 1 and <10%; rare ≥ 0.1 and <1%; rare ≥ 0.01 and <0.1%; very rare <0.01%, unknown (cannot be estimated from available data).
Congenital, familial and hereditary disorders (see section “[Medication for Pregnant and Lactating Women]”).
Blood and lymphatic system abnormalities
Common: anemia, thrombocytopenia (see [Precautions]).
Rare: complete blood cytopenia, leukopenia.
Rare: bone marrow failure, including simple red blood cell aplastic anemia, granulocyte deficiency, megaloblastic anemia, macrocytosis.
Tests
Rare: decreased coagulation factors (at least one), abnormal coagulation tests, (e.g., prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged prothrombin time, prolonged INR). (See [Precautions] and [Use in Pregnant and Lactating Women]). Biotin deficiency/biotin amidase deficiency.
Neurological abnormalities
Very common: tremor.
Common: extrapyramidal disorder, lucidity, drowsiness, convulsions*, memory impairment, headache, nystagmus, dizziness may occur a few minutes after intravenous administration (for intravenous administration, dizziness may occur within a few minutes and the reaction will resolve spontaneously after a few minutes).
Rare: coma*, encephalopathy*, somnolence* (see below), reversible Parkinson’s disease, ataxia, sensory abnormalities, increased convulsions (see [Precautions]).
Rare: reversible dementia with reversible brain atrophy, cognitive dysfunction.
* Some patients on valproate treatment have been reported to develop lignation or lethargy, sometimes resulting in transient coma (encephalopathy). The above symptoms are isolated or associated with an increased incidence of convulsions during treatment and are reduced upon discontinuation of treatment or dose reduction. These symptoms have been reported more frequently when combined therapy (especially with phenobarbital or topiramate) or when dosing is too rapid.
Ear and vagus abnormalities
Common: Deafness.
Respiratory, thoracic and mediastinal system abnormalities
Rare: pleural effusion.
Abnormalities of the gastrointestinal system
Very common: nausea.
Common: vomiting, gum abnormalities (mainly gum enlargement), oral mucositis, epigastric pain, diarrhea, mostly occurring at the beginning of treatment. These abnormalities usually disappear after a few days of continued medication.
Rarely: pancreatitis, sometimes resulting in death. (See [Precautions])
Kidney and urinary system abnormalities
Rare: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi’s syndrome, but the mechanism of action is unclear
Skin and subcutaneous tissue abnormalities
Common: hypersensitivity reactions, transient and/or dose-related alopecia, disorders of the nail and nail bed
Rare: angioneurotic edema, rash, hair abnormalities (e.g., abnormal hair structure, hair color changes, abnormal hair growth)
Rare: toxic epidermolysis bullosa, Stevens-Johnson syndrome, erythema multiforme, drug-derived rash with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue abnormalities
Rare: Decreased bone mineral density, osteomalacia, osteoporosis, and fractures in patients treated with this product over a long period of time. The mechanism by which this product affects bone metabolism has not been determined.
Rare: Systemic lupus erythematosus, rhabdomyolysis (see [Precautions]).
Endocrine abnormalities
Rare: syndrome of abnormal secretion of antidiuretic hormone (SIADH), andropause (hirsutism, masculinization, acne, male pattern baldness, and/or andropause).
Rare: Hypothyroidism (see [Pregnancy and Lactation Medication]).
Metabolic and nutritional abnormalities
Common: hyponatremia, weight gain*
*Since weight gain is a factor in polycystic ovary syndrome, it should be carefully monitored (see [Precautions]).
Rare: hyperammonemia* (see [Precautions]), obesity.
* Isolated and moderate hyperammonemia without changes in liver function tests may occur and should not result in discontinuation of the drug. Hyperammonemia with neurological symptoms has also been reported. In such cases, further investigations should be considered (see [Precautions]).
Benign, malignant and unspecified tumors (including cysts and polyps)
Rare: myelodysplastic syndromes.
Vascular abnormalities
Common: bleeding (see [Precautions] and [Use in Pregnant and Lactating Women])
Rare: vasculitis.
Systemic abnormalities and administration site conditions
Rare: hypothermia, non-severe peripheral edema.
Hepatobiliary system abnormalities
Common: liver injury (see [Precautions]).
Reproductive system and breast abnormalities
Common: dysmenorrhea.
Rare: amenorrhea.
Rare: male infertility, polycystic ovaries.
Mental disorders
Common: confusion, hallucinations, aggressive behavior*, agitation*, attention deficit disorder*.
Rare: abnormal behavior*, psychomotor hyperactivity*, learning disabilities*.
*These adverse reactions occur mainly in the pediatric dosing population.
Contraindications]
– Acute hepatitis
– Chronic hepatitis
– History or family history of severe hepatitis, especially drug-related
– Hypersensitivity to sodium valproate, bivalproate, valproamide or any other component of this product
– Hepatic porphyria
– Patients with known mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase gamma (POLG, e.g., Alpers-Huttenlocher syndrome) and children under 2 years of age with suspected POLG-related disorders
– Patients with known urea cycle disorders
Note]
Special Notes.
In rare cases, the adoption of an antiepileptic drug therapy may result in an increase in the number of seizures or the type of seizures that occur and are different from those observed in certain types of epilepsy. When valproate is used, the reasons for these phenomena are mainly related to combined antiepileptic drug therapy or pharmacokinetic interactions (see [Drug Interactions]), toxic reactions (liver disease or encephalopathy) (see content in [Precautions] and [Adverse Reactions]), or drug overdose.
Because the drug is converted to valproic acid in the body after administration, other drugs containing active ingredients that can be converted to the same compound should not be taken in combination with this product to prevent an overdose of valproic acid in the body (e.g., bispropionate, valproamide, etc.).
*For women of childbearing age, this product is an appropriate choice for women of childbearing age in some cases if, after careful evaluation of all relevant factors, the patient and her treating physician make an informed choice (see [Precautions] and [Use in Pregnant and Lactating Women]).
Warnings
Girls, female adolescents, women of childbearing age and pregnant women
Due to the high potential risk of teratogenicity and developmental disorders in fetuses with a history of intrauterine exposure to sodium valproate, valproate should not be prescribed to girls, female adolescents, women of childbearing age, and pregnant women unless other treatments are ineffective or intolerable. For adolescent patients with potential pregnancy who are treated with valproate, are planning to become pregnant or are pregnant, the risks and benefits should be carefully weighed at routine follow-up visits.
During treatment, women with potential pregnancy must use effective contraception during treatment and be informed of the risks associated with treatment with valproate during pregnancy (see [Use in Pregnant and Lactating Women]) .
Prescribers must ensure that comprehensive risk information is provided to the patient so that the patient fully understands the risks.
In particular, prescribers must ensure that all female patients are informed of and understand the
– The nature and extent of the risks of exposure during pregnancy, in particular the risk of teratogenicity and the risk of delayed developmental disorders
– The need for effective contraceptive measures.
– The need for regular assessment of treatment.
– The need to consult a physician immediately if a pregnancy is planned or has occurred.
If a woman plans to become pregnant, she should be switched to other appropriate treatment, if possible, prior to pregnancy (see [Medications for Pregnant and Lactating Women]).
Valproate therapy should be continued only after reassessment of the risks and benefits for patients treated with valproate by an experienced expert in the treatment of epilepsy and bipolar disorder.
Severe liver damage
Conditions for occurrence.
Very rare cases of severe liver damage resulting in death have been reported. Experience has shown that the patients at greatest risk are infants, especially when treated with a combination of multiple anticonvulsants, and that infants and children under 3 years of age and those with severe seizures are at high risk, especially those with concomitant brain damage, mental deficits, and/or congenital metabolic or degenerative disorders.
The occurrence of the above conditions decreases significantly after the age of 3 years and gradually decreases with age.
In most cases, this liver damage occurs in the first 6 months of treatment.
Precursory symptoms.
Clinical signs are essential for early diagnosis. In particular, the following conditions should be considered prior to the onset of jaundice, especially in patients at risk for these conditions (see “Conditions of Occurrence”).
– Non-specific symptoms: usually sudden onset, such as malaise, anorexia, weakness and lethargy, sometimes accompanied by recurrent vomiting and abdominal pain.
– Recurrence of symptoms in patients with epilepsy.
The patient (or the child’s family) should be informed to report the above to the physician as soon as it occurs. A clinical physical examination and laboratory tests for liver function should be performed immediately.
Tests.
Liver function should be measured prior to treatment and monitored regularly for the first 6 months of starting treatment.
Of the routine tests, those reflecting protein synthesis, particularly the prothrombin ratio, are the most important.
If an abnormally low prothrombin ratio is identified, especially in combination with other biological abnormalities (significantly lower fibrinogen and coagulation factor levels; increased bilirubin concentrations and elevated transaminases), treatment with this product should be discontinued.
As a precaution, if salicylic acid is used in combination, it should also be discontinued because it shares the same metabolic pathway as this product.
Pancreatitis
There have been very rare reports of severe pancreatitis, even fatal. This risk of fatalities is highest in children, but the risk decreases with age. Severe seizures, neurological damage, or antiepileptic therapy may be risk factors for severe pancreatitis. The morbidity and mortality rate is increased when liver failure is complicated by pancreatitis.
Patients with acute abdominal pain should be given a rapid medical examination. If the diagnosis of pancreatitis is established, sodium valproate should be discontinued immediately.
Suicidal intent and behavior
Suicidal intent and behavior have been reported in patients receiving antiepileptic therapy according to treatment indications. A meta-analysis of a randomized placebo-controlled trial of antiepileptic drugs also showed a mildly increased risk of suicidal intent and behavior. The mechanism of this effect is unclear.
Therefore, patients should be monitored for signs of suicidal intent and behavior and considered for appropriate treatment. If signs of suicidal intent and behavior are detected, the patient (patient’s caregiver) should be advised to seek immediate medical help.
Carbapenems
Concomitant use of sodium valproate and carbapenems is not recommended (see [Drug Interactions]).
Patients with known or suspected mitochondrial disease
Valproic acid may trigger or exacerbate clinical signs of mitochondrial disease caused by variants in the mitochondrial DNA and nuclear-encoded POLG genes. In particular, acute liver failure and liver-related death accompanying valproate treatment are higher in patients with hereditary neurometabolic syndrome (POLG; e.g., Alpers-Huttenlocher syndrome) caused by mitochondrial enzyme polymerase gamma gene variants. Patients with a family history or symptoms suspected of POLG-related disorders should be suspected of having a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), manifestations of persistent epilepsy, developmental delay, psychomotor degeneration, sensorimotor axonal neuropathy, myopathic cerebellar ataxia, oculomotor palsy, or complex migraine with occipital aura. POLG variant testing should be performed according to the current operational criteria for clinical diagnostic evaluation of this disorder (see [Contraindications].)
Exacerbation of convulsions
As with other antiepileptic drugs, some patients may experience reversible exacerbations in seizure frequency and severity (including status epilepticus) or new types of convulsive seizures with the use of sodium valproate. Patients should be advised to seek immediate medical attention in the event of an exacerbation of convulsions. (See [Adverse Reactions])
Precautions
– Liver function should be measured prior to treatment (see [Contraindications]) and monitored regularly for the first 6 months of treatment initiation, especially in patients at risk.
-As with most antiepileptic drugs, slight elevations in liver enzyme levels should be noted, especially at the start of treatment, but are usually transient and independent, without clinical signs.
-More in-depth biological investigations (including prothrombin ratios) are recommended in these patients; and dose adjustments should be considered when appropriate and reviewed as necessary.
– Routine blood tests (blood count, including platelet count, bleeding time, and coagulation test) should be performed prior to treatment, prior to surgery, or in the event of spontaneous bruising or bleeding. (See [Adverse Reactions])
– Although immunologic abnormalities are rarely observed during dosing, patients with SLE should weigh the possible benefits against the risks.
-Because of the risk of hyperammonemia associated with valproic acid, metabolic testing should be performed prior to treatment when patients are suspected of having urea cycle enzyme deficiencies.
-Patients should be warned of the risk of weight gain that may occur at the start of treatment with valproate and appropriate measures should be taken to reduce its occurrence. (See [Adverse Reactions]).
– Patients with type II carnitine palmitoyltransferase deficiency should be warned of the increased risk of rhabdomyolysis due to the administration of sodium valproate.
-Alcohol intake during treatment with sodium valproate is not recommended.
– Children: Single-dose therapy with this product is recommended in children under 3 years of age, but the potential benefit should be weighed against the risk of hepatic damage or pancreatitis before initiating therapy in such patients.
Due to the risk of hepatotoxicity, the combination of salicylates should be avoided in children under 3 years of age.
– Patients with renal insufficiency: dose reduction may be required. Dose adjustments should be made based on clinical monitoring as plasma concentration monitoring may lead to misleading results.
Effects on the ability to drive and operate machinery
Patients should be warned of the risk of possible drowsiness, especially in combination with antiepileptic drugs or in combination with benzodiazepines (see [Drug Interactions]).
Pregnant women and nursing mothers
Women of childbearing age
This product should not be used in women of childbearing age unless clearly needed (i.e., when other treatments are ineffective or not tolerated). This assessment should be done before the first prescription of this product or when a woman of childbearing age treated with this product is planning to become pregnant. Women of childbearing potential must use an effective method of contraception during treatment.
Pregnancy
– Risks associated with epilepsy and antiepileptic drugs
Studies have shown that the incidence of malformations in the offspring of mothers treated with any antiepileptic drug is 2-3 times higher than that reported in the general population (approximately 3%). An increased number of malformations were reported with multiple medications, with the most common malformations being cleft lip and cardiovascular malformations.
Very few children born to mothers with epilepsy have reported developmental delays. It is not possible to distinguish between the above conditions due to genetic, social, or environmental factors, the mother’s epilepsy, or antiepileptic drug therapy.
Despite the above potential risks, antiepileptic treatment cannot be abruptly terminated because it may lead to seizures, and the latter can have serious consequences for both the mother and the fetus.
During pregnancy, maternal tonic-clonic seizures and hypoxia due to continuous status epilepticus may increase the risk of death of the mother and the unborn child.
– Risks associated with this product
In animals: teratogenic effects have been demonstrated in mice, rats and rabbits.
Congenital malformations
In humans: There are data showing an increased incidence of mild or severe malformations, particularly neural tube malformations, craniofacial defects, limb malformations, cardiovascular malformations, hypospadias, and multiple anomalies including multisystem malformations, in infants born to mothers treated with valproic acid compared to other antiepileptic drugs. Data from a comprehensive analysis (including registries and cohort studies) showed that the incidence of congenital malformations in children of women with epilepsy who were treated with valproic acid monotherapy during pregnancy was 10.73%. (95% CI: 8.16 -13.29). The risk of major malformations is greater than in the general population (risk of approximately 2-3%). This risk is dose-related, but below what dose threshold there is no risk, and this dose threshold cannot be determined.
There are data showing an increased rate of infant malformations when combined with other drugs for multidrug antiepileptic therapy compared to monotherapy with valproic acid.
Developmental delay
There are data suggesting that in utero exposure to valproate produces adverse effects on mental and physical development in exposed children. This risk may be dose-related, but based on the available data, the dose threshold below which no risk exists cannot be determined. It is not possible to determine precisely in which trimester the risk of these adverse reactions occurs, and the possibility that the risk persists throughout pregnancy cannot be ruled out.
Studies of preschool children who have been exposed to valproic acid in utero have shown that up to 30-40% have developmental delays in early development, such as later speaking and walking, lower IQ, poor expressive language skills (speech and comprehension) and memory problems.
School-age children (age 6) who had in utero exposure to valproic acid were measured to have IQs 7-10 points lower than those exposed to other antiepileptic drugs. Although the role of confounding factors cannot be ruled out, this remains evidence that the risk of intellectual deficits in children exposed to valproic acid is independent of maternal IQ.
Data on the results of long-term studies are limited.
There are data showing an increased risk (approximately 3-5 fold increased risk) of autism spectrum disorders, including childhood autism, in children exposed to valproic acid in utero.
Limited data suggest that children exposed to valproic acid in utero may be more likely to develop symptoms of attention-deficit/hyperactivity disorder (ADHD).
There are data suggesting that prenatal exposure to this product is associated with developmental delays, particularly delayed verbal IQ development, in infants born to mothers treated with valproic acid for epilepsy. Developmental delays are often accompanied by dysmorphic and/or deformed features. However, a causal relationship is difficult to establish because there are other possible confounding factors such as low maternal or paternal IQ, other genetic, social, and environmental factors, and poor maternal seizure control during pregnancy.
Spectrum disorders of autism have been reported in children exposed to valproic acid in utero.
-In summary
The following recommendations should be considered.
This product should not be used in women of childbearing age unless clearly needed (i.e., when other treatments are ineffective or not tolerated). This assessment should be done prior to the first prescription of this product or when a woman of childbearing age treated with this product is planning to become pregnant. Women of childbearing potential must use an effective method of contraception during treatment.
Women of childbearing age should be informed in detail of the risks and benefits of using valproic acid during pregnancy.
If a woman is planning to become pregnant or is pregnant, treatment with this product should be re-evaluated regardless of the indication.
Discontinuation of treatment with this product should be considered when applied to bipolar disorder indications.
Treatment with valproate should not be discontinued without reassessment of benefit/risk in the treatment of epilepsy. If the product is continued after further risk benefit assessment, the minimum effective daily dose should be used in divided doses.
In addition, if appropriate, folic acid supplementation should be initiated prior to pregnancy at the appropriate dose (5 mg daily) as it may reduce the risk of neural tube abnormalities. However, the available evidence does not suggest that it can prevent birth defects or malformations due to exposure to valproic acid.
Special prenatal monitoring should be performed to detect possible neural tube abnormalities or other malformations.
– Neonatal risks
Hemorrhagic syndrome has occasionally been reported in neonates whose mothers used valproate during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, fibrinogen deficiency, and/or a decrease in other coagulation factors; fibrinogen deficiency has also been reported and can be fatal. However, this syndrome must be differentiated from phenobarbital- and enzyme-inducing agent-induced reductions in vitamin K factor.
Therefore, platelet counts, plasma fibrinogen concentrations, coagulation tests, and coagulation factors should be measured in newborns.
Cases of neonatal hypoglycemia have been reported in newborns whose mothers took valproate during the last trimester of pregnancy.
Cases of neonatal hypothyroidism have been reported in mothers who took valproate during pregnancy.
Withdrawal syndromes (e.g., specifically, agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, dystonia, tremors, convulsions, and feeding disorders) may occur in newborns whose mothers took valproate during the last trimester of pregnancy.
– Fertility
Amenorrhea, polycystic ovaries, and increased testosterone levels have been reported in women using valproic acid sodium. Valproic acid administration may also impair fertility in men (see [Adverse Reactions]). Case reports suggest that reproductive dysfunction can be reversibly restored after discontinuation of the drug.
Lactation.
The concentration of valproic acid in breast milk is very low, only 1% to 10% of the maternal serum concentration. To date, based on information from the literature and clinical experience, breastfeeding may be considered when considering the safety of this product, especially in the case of hematologic disorders. (See [Adverse Reactions]).
Pediatric Use]
Monotherapy is recommended for the use of valproate in children, but the possible benefits of valproate should be weighed against the risk of liver damage or pancreatitis before initiating therapy in such patients (see [Precautions]).
Avoid coadministration of acetylsalicylic acid in children due to the risk of hepatotoxicity and the risk of bleeding.
Children with liver and GI dysfunction of unknown etiology (e.g., anorexia, vomiting, cytolytic phenomena), signs of depression or coma, mental retardation, or a family history of neonatal or infant death must be tested for metabolic markers, particularly fasting and postprandial blood ammonia levels, prior to receiving any valproate therapy.
[Geriatric Use].
Compared to younger adult patients, older patients (age > 68 years) show a decreased ability to clear valproate and may have an increased incidence, so the starting dose administered should be decreased in these patients. Also, the dose should be increased more slowly and fluid and nutrient intake, dehydration, drowsiness, and other adverse events should be monitored regularly. When the patient’s food and fluid intake decreases, or if the patient becomes excessively drowsy, then a downward adjustment in the dose of valproate or discontinuation of valproate therapy should be considered. The final therapeutic dose should be determined based on tolerability and clinical response.
See other sections of this leaflet or as directed by your doctor.
Drug Interactions]
Careful consideration should be given to the use of seizure-inducing drugs, or drugs that reduce the threshold for seizures, in conjunction with this product, and may be withheld or contraindicated depending on the severity of the potential risk. Such drugs mainly include most antidepressants (promethazine, SSRI), tranquilizers (phenothiazines and phenylbutazones), melphalan, bupropion, tramadol, etc.
Prohibited combination applications.
In combination with melquinine.
When combined with melquinine, patients with epilepsy may be at risk of seizures due to the increased metabolism of valproic acid and its own seizure-inducing effects
In combination with St. John’s Wort.
There is a risk of reduced blood levels and reduced anticonvulsant efficacy.
Combinations to be aware of.
Amantadine.
There is a risk of spasticity due to reduced blood levels of valproic acid. Clinical monitoring, blood concentration measurements and timely dose adjustment of anticonvulsants should be performed during treatment with anti-infective drugs and monitoring should remain necessary after discontinuation.
Carbapenems (panipenem, menopenem, imipenem …… ).
It has been reported that when coadministered with carbapenems, it can lead to a decrease in valproic acid levels in the blood, by 60-100% within two days, which may sometimes trigger convulsions. Due to the rapid occurrence and the extent of the decrease, co-administration of carbapenems should be avoided in patients with stable valproic acid levels (see [Precautions] section). If treatment with these antibiotics cannot be avoided, the blood levels of this product should be closely monitored.
Carbamazepine.
Blood concentrations of the active metabolites of carbamazepine can be increased, leading to the development of drug overdose reactions. Also, due to the induction of hepatic metabolism by carbamazepine, blood concentrations of valproic acid can be decreased. Thus, clinical drug monitoring is recommended to determine the blood concentrations of both anticonvulsant drugs and adjust their doses.
Lamotrigine.
There is an increased risk of developing severe skin reactions (Lyell’s syndrome).
Valproic acid may increase blood levels of lamotrigine by inhibiting its hepatic metabolism. If coadministration is necessary, close clinical monitoring is warranted.
This product decreases the metabolism of lamotrigine and increases the mean half-life of lamotrigine by nearly twofold. This interaction may lead to increased toxicity of lamotrigine, especially severe rash. Therefore, clinical monitoring is recommended and dose adjustments (dose reduction of lamotrigine) should be made when appropriate.
Felbamate.
Valproic acid reduces the mean clearance of felbamate by up to 16%.
On the other hand, felbamate in combination with valproate reduces the clearance of valproic acid by 22% to 50% and consequently increases the blood levels of valproic acid, creating a risk of overdose.
Clinical and biochemical monitoring should be performed during treatment with felbamate, and the dose of valproate should be adjusted. These observations should be taken even after discontinuation of the drug.
Phenobarbital, paromidone.
Due to the inhibitory effect of valproate on hepatic metabolism, it can lead to increased blood levels of phenobarbital or paromidone and drug overdose, which occurs more often in children. Also, the induction of hepatic metabolism by phenobarbital or paromidone can lead to a decrease in the blood concentration of valproic acid.
Clinical monitoring should be performed during the first 15 days of combination therapy, and the dose of phenobarbital or paromidone should be rapidly reduced at the onset of any symptoms of sedation. In particular, blood concentrations of both anticonvulsants should be monitored.
Phenytoin (and may be extrapolated to fosphenytoin).
It can lead to changes in phenytoin blood concentrations. There is also a risk of reduced blood levels of valproic acid due to the induction of hepatic metabolism by phenytoin.
Clinical monitoring and blood concentration measurements should be performed and the doses of both anticonvulsants should be adjusted appropriately.
Topiramate, acetazolamide.
Concomitant administration of valproate and topiramate or acetazolamide is associated with encephalopathy and or hyperammonemia. Signs and symptoms of hyperammonemic encephalopathy in patients receiving both drugs should be monitored closely.
Cimetidine and erythromycin.
Concomitant administration may increase serum valproic acid concentrations.
Acetylsalicylic acid.
Infants and young children with temperature dysfunction should not take medicines containing valproic acid and acetylsalicylic acid at the same time. They should only be taken by adolescents with temperature dysfunction under medical supervision.
Benzodiazepines, barbiturates and tranquilizers, monoamine oxidase inhibitors, antidepressants and nerve blockers.
When combined, valproic acid can increase the central depressant effect of these drugs. Patients should be monitored closely when combining the above drugs, and dose adjustments should be made to the drugs if necessary.
Zidovudine.
Valproic acid may increase the blood levels of zidovudine and may lead to an increase in zidovudine toxicity.
Olanzapine.
Valproic acid may decrease the blood levels of olanzapine.
Lufimide.
Sodium valproate may increase blood concentrations of lufenamide. The extent of the increase depends on the concentration of valproic acid. Caution should be exercised, especially in children, as the effect is more pronounced in this population.
Propofol.
Sodium valproate may cause an increase in the blood concentration of propofol. When co-administered with valproate, a reduction in the dose of propofol should be considered.
Nimodipine.
Combination therapy with valproic acid and nimodipine may increase the blood concentration of nimodipine by 50%.
Anticoagulants and antiplatelet aggregating agents.
Concomitant administration with valproic acid-containing drugs may result in an increased bleeding tendency. Therefore, routine monitoring of coagulation during coadministration is recommended.
With the combination of phenytoin or phenobarbital, valproic acid metabolism levels may be increased. Therefore, patients receiving these two drugs should be carefully monitored for signs and symptoms of hyperammonemia.
Valium.
Results of studies in healthy subjects have shown that valproic acid displaces diazepam from its binding site in plasma proteins and inhibits its metabolism. The blood concentration of free Valium in the body may increase, and the plasma clearance and volume of distribution of free diazepam may decrease (by 25% and 20%, respectively). However, the half-life remains unchanged.
Results of studies in healthy subjects have shown that valproate and lorazepam can reduce lorazepam blood concentrations by up to 40% when taken together.
In children, serum phenytoin levels may be elevated after concomitant administration of clonidine and valproate.
Nimodipine (administered by oral and intravenous routes).
Due to the inhibitory effect of valproic acid on metabolism, the blood levels of nimodipine may be elevated, contributing to the hypotensive response to nimodipine.
Rifampicin.
Rifampin may decrease the blood concentration of valproate, resulting in reduced efficacy. Therefore, when used in combination with rifampin, it is necessary to adjust the dose of valproate administered.
Protease inhibitors.
Protease inhibitors such as lopinavir, ritonavir reduce the blood concentration of valproate when used in combination.
Desipramine.
When co-administered, abciximide may cause a decrease in valproic acid blood levels.
Other forms of interactions.
Lithium.
This product has no effect on serum lithium levels.
Quetiapine.
The combination of valproate and quetiapine can cause neutropenia and leukopenia.
Oral contraceptives.
Because valproic acid has no enzyme-inducing activity, it does not diminish the estrogen-progestin effect of hormonal contraceptives taken by women.
[Drug overdose].
When an acute overdose is administered, the usual symptoms include coma with hypotonia, hyporeflexia, pupillary constriction, respiratory dysfunction, metabolic acidosis, hypotension, and circulatory collapse/shock. Clinical symptoms can be variable, and seizures have been reported with high blood levels. Cases of intracranial hypertension associated with cerebral edema have also been reported.
Management of overdose should be symptomatic: gastric lavage therapy is effective for 10-12 hours after drug ingestion, maintenance of urinary secretion, and cardiopulmonary monitoring. In very severe cases, hemodialysis may be used for treatment if necessary. Naloxone has been reported to reverse the CNS depressant effects of sodium valproate overdose. Since naloxone also theoretically reverses the antiepileptic effect of sodium bivalate, more care should be taken when applying naloxone in patients with epilepsy.
The prognosis is usually good. However, sporadic cases of death have been reported.
When overdosed, hypernatremia can result due to the presence of the sodium component in the sodium valproate preparation.
Pharmacology and Toxicology]
Pharmacological effects.
Sodium valproate is a broad-spectrum antiepileptic drug.
The most likely mechanism of action of sodium valproate is to enhance the inhibitory effect of GABA by enhancing the synthesis of γ-aminobutyric acid (GABA) or its metabolism.
Valproic acid has been reported to stimulate HIV replication in in vitro assays, but studies on peripheral blood mononuclear cells from HIV-infected patients have shown that sodium valproate does not possess a mitogenic effect that induces HIV replication. In fact, the results of the effect of sodium valproate on HIV replication are variable and the number of changes is small, seemingly independent of the dose, and no studies in humans have been documented.
Pharmacokinetics]
The half-life of sodium valproate is generally 8-20 hours. It may be shorter in children.
In patients with severe renal insufficiency, the dose should be adjusted according to the free valproic acid blood concentration.
The range of blood concentrations reported for effective treatment with valproic acid is 40-100 mg/L (278-694 μmol/L). The size of this range varies depending on the timing of blood sampling and whether or not the drug is coadministered. Free (unbound) drug concentrations usually account for 6%-15% of the total blood concentration. When blood concentrations are higher than the therapeutic range, the chance of adverse side effects increases.
The pharmacological effect (or therapeutic effect) of sodium valproate is not entirely related to the total or free (unbound) form of valproic acid.
Storage】Seal and store in a dry place, avoid moisture after opening.
Package】 Inside is pharmaceutical aluminum foil and polyvinyl chloride/polyvinylidene chloride solid pharmaceutical compound hard sheet (PVC/PVDC), outside is polyester/aluminum/polyethylene pharmaceutical compound bag (double aluminum bag). 10 tablets/plate x 2 plates/bag/box.
Expiration date】24 months
【Execution standard
【Approval number】
【Drug marketing license holder
Name: Shanghai Qingping Pharmaceutical Co.
Registered address: No. 397 Zhaojiang Road, Baihe Town, Qingpu District, Shanghai
Postal Code: 201711
Contact：021-59211577
Fax: 021-59210266
【Manufacturer
Company name: Shanghai Qingping Pharmaceutical Co.
Address: No. 397 Zhaojiang Road, Baihe Town, Qingpu District, Shanghai
Postal code：201711
Contact：021-59211577
Fax: 021-59210266