XINDONG XIFUZHI Compound Sodium and Valproic Acid Sustained Release Tablets For Epilepsy 0.5g*30

【Drug Name】
Generic Name: Sodium Valproate Sustained-Release Tablets (I)
Brand Name: Xifuzhi
English Name: Compound Sodium and Valproic Acid Sustained Release Tablets
Pinyin: Bingwusuanna Huanshi Pian

【Ingredients】
This product is a compound preparation. Each tablet contains 333mg sodium valproate and 145mg valproic acid (equivalent to 500mg sodium valproate).

【Appearance】
This product is a white, oval-shaped film-coated tablet. After removing the coating, it is white.

【Indications】
Epilepsy can be treated as a monotherapy or as adjunctive therapy: For the treatment of generalized epilepsy, including absence seizures, myoclonic seizures, tonic-clonic seizures, atonic seizures, and mixed seizures, as well as special types of syndromes (West, Lennox-Gastaut syndrome, etc.). For partial epilepsy: suitable for simple partial seizures, complex partial seizures, and partial secondary generalized seizures. For mania: used to treat manic episodes associated with bipolar disorder.

【Dosage and Administration】
Epilepsy: Administration: Oral. The daily dose should be divided into 1-2 doses. If epilepsy is well controlled, once-daily administration may be considered. This product should be swallowed whole, or broken in half, but should not be crushed or chewed. Dosage: The starting dose is usually 10-15 mg/kg daily, then increased until satisfactory efficacy is achieved. The usual dose is 20-30 mg/kg daily. However, if seizure status is not controlled within this dose range, an increase in dose may be considered, but the patient must be closely monitored. For children, the usual dose is 30 mg/kg daily. For adults, the usual dose is 20-30 mg/kg daily. For elderly patients, the dosage should be determined based on the control of seizure status. The daily dose should be determined based on the patient's age and weight. However, significant individual differences in clinical sensitivity to valproate should be considered. The correlation between daily dose, blood drug concentration levels, and efficacy remains unclear to date, and dosage is primarily determined based on clinical efficacy. When seizures are uncontrolled or adverse reactions are suspected, in addition to clinical monitoring, plasma valproate concentration levels should be measured; the reported effective range is 40–100 mg/L (300–700 μmol/L). For newly diagnosed epilepsy patients or those who have not previously used other antiepileptic drugs, the dosage should be increased every 2–3 days, reaching the optimal dose within one week. For patients taking other fast-acting sodium valproate formulations and whose condition is well controlled, the recommended daily dose should remain unchanged when using this product as a substitute. In patients previously receiving other antiepileptic drugs, the use of extended-release sodium valproate tablets should be gradual, reaching the optimal dose within two weeks, with other treatments gradually reduced and discontinued. If other antiepileptic drugs need to be added, they should be added gradually. (See [Drug Interactions]). The above dosages are suitable for adults and children weighing over 17 kg. This formulation is not suitable for children under 6 years of age. (Risk of aspiration may exist) This product can control epileptic seizures. In patients using medication to prevent grand mal seizures, antiepileptic drugs should not be discontinued abruptly, as sudden discontinuation greatly increases the risk of status epilepticus with hypoxia and life-threatening complications. Mania: Administration: Oral administration. In patients not receiving other psychotropic medications, the dosage should be increased every 2-3 days, reaching the optimal dose within one week. In patients taking other psychotropic medications, the dosage should be adjusted according to the characteristics of the medication and the individual's clinical response. Dosage: Antimania should begin with a low dose. The recommended starting dose is 500 mg/day, divided into two doses, once in the morning and once in the evening. The dose should be increased as quickly as possible, reaching 1000 mg/day on the third day and 1500 mg/day by the end of the first week. Thereafter, the dose can be adjusted according to the patient's condition and the blood concentration of dpakine, maintaining a range of 1000-2000 mg/day, with a maximum dose not exceeding 3000 mg/day. The therapeutic blood concentration should be within the range of 50-125 ug/mL. Dosage reduction should be considered for elderly patients.

【Adverse Reactions】
Gastrointestinal System: Some patients may experience gastrointestinal abnormalities (nausea, stomach pain, and diarrhea), often occurring at the beginning of treatment. These abnormalities usually disappear after a few days of continued medication. Rare, sometimes fatal, cases of pancreatitis have been reported. (See [Precautions]) Hepatobiliary System: • Rare cases of dose-independent, severe (sometimes fatal) liver dysfunction have been reported. (See [Precautions]) Congenital and familial/hereditary abnormalities: • Teratogenic risk (see [Use in pregnant and lactating women]). Central nervous system: • Isolated cases of reversible Parkinson's disease have been reported. • Very rare cases of insidious and progressive episodes of confusion, which can progress to complete dementia and may reverse weeks to months after discontinuation of treatment. • Confusion: Some patients have been reported to experience stupor or somnolence during sodium valproate treatment, sometimes leading to transient coma (encephalopathy). These symptoms are isolated or associated with an increased incidence of seizures during treatment and are relieved upon discontinuation of valproate treatment or dose reduction. These symptoms are more frequently reported when used in combination therapy (especially with phenobarbital) or after a sudden increase in valproate dosage. • Isolated moderate hyperammonemia without changes in liver function tests is common; treatment discontinuation is not necessary in these cases. Hyperammonemia with neurological symptoms has also been reported. Further investigation should be considered in these cases. (See [Precautions]) • Transient and/or dose-dependent adverse reactions have been reported, including hair loss, postural tremor, and somnolence. • Ataxia has been reported occasionally. Immune System: • Lupus erythematosus or vasculitis are rare. Metabolic/Nutritional System: • Hyponatremia is extremely rare. • Non-severe peripheral edema has been reported rarely. • Fanconi syndrome (metabolic acidosis, hyperphosphatemia, aminoaciduria, glycosuria) has been reported in the literature; these reactions are reversible upon discontinuation of valproic acid-containing medications. However, the mechanism of these reactions remains unclear. • Cases of weight gain have been observed. Weight gain is a risk factor for polycystic ovary syndrome, and patients' weight should be closely monitored. (See [Precautions]) Genitourinary System: • Enuresis and urinary incontinence have been reported extremely rarely. Kidney damage has been reported in isolated cases. • Cases of amenorrhea and irregular menstrual cycles have been reported. Hematolymphatic System: • Occasionally, there have been reports of dose-related thrombocytopenia, and occasionally, cases of decreased fibrinogen or increased bleeding time, usually without associated clinical symptoms and signs, especially at high doses. Valproate inhibits the second phase of platelet aggregation. Rare reports include anemia, hypertrophic erythrocytes, leukopenia, and pancytopenia. If permissible, asymptomatic patients with thrombocytopenia may be managed by dose reduction based on platelet levels and seizure control, which usually resolves the thrombocytopenia. Skin and Subcutaneous Tissue: • Transient alopecia areata is common and dose-related. • Skin reactions such as rashes have occurred. Rare reports indicate that some patients may develop toxic epidermal necrolysis, Stevens-Johnson syndrome, and various erythema. Special Sensory System: • Rare reports include reversible or irreversible hearing loss. Systemic System: • Headaches have also been reported.

【Contraindications】
Patients with hypersensitivity to valproate, divalproate, valproamide or any component of this product; patients with acute hepatitis; patients with chronic hepatitis; patients with a history or family history of severe hepatitis, especially drug-related hepatic porphyria; patients with urea cycle disorders.

【Precautions】
Special Note: In rare cases, the use of an antiepileptic drug may lead to an increase in the frequency of seizures or the type of seizures that differ from those observed in certain types of epilepsy. When using valproate, the above phenomena are primarily related to concomitant antiepileptic drug treatment or pharmacokinetic interactions (see [Drug Interactions]), toxic reactions (liver disease or encephalopathy) (see [Precautions] and [Adverse Reactions]), or drug overdose. Because this drug is converted to valproate in the body after administration, other drugs containing active ingredients that can be converted to the same compound should not be taken concurrently with this product to prevent valproate overdose (e.g., divalproate, valproamide, etc.). Warning 1. Hepatotoxicity: Conditions for occurrence: There are very rare reports of severe liver damage, including fatal cases. Experience in epilepsy treatment suggests that the highest risk patients are infants, especially when using multiple anticonvulsants in combination, children under 3 years of age, and those with severe seizures, particularly those with brain injury, intellectual disability, and/or congenital metabolic or degenerative diseases. The incidence of these conditions decreases significantly after age 3 and gradually declines with age. In most cases, this liver damage occurs within the first 6 months of treatment, usually between the second and 12th weeks, and during multidrug therapy for epilepsy. Warning Signs: Clinical symptoms are crucial for early diagnosis. Jaundice should be considered, especially in patients at risk of developing: Nonspecific symptoms: usually sudden onset, such as weakness, anorexia, lethargy, and drowsiness, sometimes associated with recurrent vomiting and abdominal pain. Recurrence of symptoms in patients with epilepsy. Patients (or the child's family) should be informed to report to the doctor immediately if any of these symptoms occur. A clinical physical examination and biological testing of liver function should be performed immediately. Laboratory Tests: Liver function should be monitored regularly before treatment begins and for the first 6 months after treatment begins. Among routine tests, those reflecting protein synthesis, particularly prothrombin time, are most relevant. If an abnormally low prothrombin time is confirmed, especially when accompanied by other biological abnormalities (significantly decreased fibrinogen and coagulation factor levels; increased bilirubin concentration and elevated transaminase levels), sodium valproate treatment should be discontinued. As a precaution, if salicylic acid derivatives are used concurrently, treatment with this product should also be discontinued because it shares the same metabolic pathway. Extra caution should be exercised when this product is used in patients with a history of liver disease. This risk is particularly pronounced in patients using multiple anticonvulsants, children, patients with congenital metabolic disorders, patients with severe seizures accompanied by intellectual disability, and patients with organic brain disease. 2. Pancreatitis: Severe, even fatal, pancreatitis has been reported in a very small number of patients. This reaction is related to the patient's age and treatment duration, and there may be a certain risk of reaction in children. Pancreatitis leading to adverse reactions is commonly observed in young children or patients with severe seizures, brain injury, or those taking multiple antiepileptic drugs. If pancreatitis is accompanied by liver dysfunction, the risk of death increases. Patients and their guardians should be warned that abdominal pain, nausea, vomiting, and/or loss of appetite may be symptoms of pancreatitis. Immediate medical evaluation is necessary. If pancreatitis has been diagnosed, this product should normally be discontinued. Other treatments should be administered for the underlying disease state, depending on clinical indications. 3. Teratogenicity: Based on published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who use this drug during pregnancy. Sodium valproate may produce teratogenic effects such as neural tube defects (e.g., spina bifida). Therefore, it should only be used in women of childbearing age when the benefits of treatment outweigh the risks of harm to the fetus. (See [Use in Pregnant and Lactating Women]) 4. Urea Cyclic Disorders (UCD): This product is not recommended for patients with urea cycle enzyme deficiencies. Urea cycle disorders are a group of uncommon genetic abnormalities, particularly in cases of ornithine carbamoyltransferase deficiency. Sporadic cases of coma due to hyperammonemia have been reported in these patients. UCD should be evaluated in the following patients before initiating treatment with this product: 1) Patients with a history of unexplained encephalopathy or coma, a history of protein-related encephalopathy, a history of pregnancy-related encephalopathy or postpartum encephalopathy, or a history of elevated plasma ammonia or glutamate levels; 2) Patients with periodic vomiting, occasional extreme excitability, motor ataxia, low blood urea nitrogen, or protein avoidance; 3) Patients with a family history of UCD or unexplained infant death (especially in boys); 4) Patients with other signs and symptoms of UCD. Patients who develop unexplained hyperammonemia-induced encephalopathy while receiving treatment with this product should receive immediate treatment (including discontinuation of sodium valproate treatment) and be evaluated for underlying urea cycle disorders. 5. In patients taking antiepileptic drugs for any indication, antiepileptic drugs may increase suicidal ideation and behavior. Patients using any antiepileptic drug for any indication should be monitored for the onset or exacerbation of depression, suicidal ideation or behavior, and/or abnormal changes in mood or behavior. 6. Drowsiness in elderly patients: In elderly patients, the dosage should be increased more slowly, and fluid and nutrient intake, dehydration, drowsiness, and other adverse events should be monitored regularly. (See [Dosage and Administration]). 7. Thrombocytopenia: Thrombocytopenia has been reported with valproic acid treatment. Due to the drug's inhibition of phase 2 platelet aggregation and its ability to cause abnormalities in coagulation parameters (e.g., low fibrinogen), platelet counts and coagulation function are recommended before starting treatment and during the inter-cycle intervals. 8. Use in pregnant women: Based on published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who use this drug during pregnancy. The incidence of neural tube defects may be increased in fetuses of mothers who receive sodium valproate treatment during the first trimester of pregnancy. The U.S. Centers for Disease Control and Prevention (CDC) has determined that the risk of spina bifida in children born to women exposed to valproic acid is approximately 1% to 2%. Other congenital abnormalities (such as craniofacial defects, cardiovascular malformations, and abnormalities involving multiple body systems) have been reported; these may or may not be life-threatening. Insufficient data exist to determine the incidence of these congenital abnormalities. The high incidence of fetal congenital abnormalities in women with seizure disorders receiving antiepileptic drug treatment cannot be considered a causal relationship. There are inherent methodological problems in obtaining sufficient data on the teratogenicity of drugs in humans; genetic factors or the epileptic state itself may play a more significant role than drug treatment in causing fetal congenital malformations. Patients treated with sodium valproate may experience coagulation abnormalities. If sodium valproate is used in pregnant women, coagulation parameters should be carefully monitored. In treating and counseling women of childbearing age, prescribing physicians will want to weigh the benefits and risks of treatment. If this medication will be used during pregnancy, or if the patient is expected to become pregnant during the use of this medication, the potential risks to the fetus should be explained to the patient. In patients using antiepileptic drugs to prevent grand mal seizures, the antiepileptic drugs should not be abruptly discontinued, as this may promote status epilepticus with hypoxia, which is life-threatening. For some patients with mild epilepsy and low seizure frequency, where discontinuation of medication would not pose a serious threat, discontinuation of medication may be considered before and during pregnancy, although there is no guarantee that absence seizures will not pose some risks to embryonic or fetal development. In pregnant women receiving sodium valproate, existing and acceptable diagnostic procedures should be considered to detect neural tube defects and other defects. Precautions: Liver function should be measured before treatment (see [Contraindications]) and monitored regularly for the first 6 months of treatment, especially in high-risk patients (see [Precautions]). As with most antiepileptic drugs, a slight increase in transaminase levels should be noted, especially at the beginning of treatment, but this is usually transient and moderate and clinically insignificant. Further biological testing (including prothrombin time) is recommended for these patients; dose adjustment may be considered as appropriate, and the above tests should be repeated. Monotherapy with sodium valproate is recommended for children, but the potential benefits of sodium valproate should be weighed against the risks of liver damage or pancreatitis before initiating treatment in such patients (see [Precautions]). Blood tests (such as blood cell count, bleeding time, and agglutination tests) should be performed before treatment, surgery, or in the event of spontaneous bruising or bleeding (see [Adverse Reactions]). Due to the risks of hepatotoxicity and bleeding, acetylsalicylic acid should be avoided in children taking this product to treat epilepsy. Patients with renal insufficiency may require dose reduction. Dosage should be adjusted based on clinical monitoring as plasma concentration monitoring can be misleading. Pancreatitis should be considered in cases of acute abdominal pain or gastrointestinal symptoms including nausea, vomiting, and/or anorexia. Treatment should be discontinued in patients with elevated pancreatic enzyme levels, and necessary treatment measures should be implemented. This product is not recommended for patients with urea cycle enzyme deficiencies. Sporadic cases of coma due to hyperammonemia have been reported in these patients. Children with unexplained hepatic and gastrointestinal dysfunction (such as anorexia, vomiting, cytolysis), depression or coma, intellectual disability, or a family history of neonatal or infant death, must undergo metabolic testing, especially fasting and postprandial ammonia levels, before receiving any valproate treatment. Although immunological abnormalities are rarely observed during treatment, the potential benefits and risks should be weighed in patients with systemic lupus erythematosus. All patients should be aware of the risk of weight gain before receiving sodium valproate treatment and take appropriate measures to reduce its occurrence. At the start of treatment, if the patient is a woman of childbearing age, pregnancy should be confirmed, and effective contraception should be used before starting treatment (see [Use in Pregnant and Lactating Women]). Because valproate is partially metabolized to ketone bodies, caution should be exercised regarding the potential for false-positive results in ketone body excretion tests in diabetic patients suspected of having ketoacidosis. Regarding the treatment of acute mania with sodium valproate, there are currently no controlled clinical trial data on the safety and efficacy of long-term use (more than 4 weeks). Therefore, if extending the treatment duration of sodium valproate is chosen, the clinician should assess the necessity of continued medication based on the individual patient's condition. Hyperammonemia: Hyperammonemia has been reported to be associated with sodium valproate treatment, even with normal liver function tests. In patients presenting with unexplained somnolence and vomiting or altered mental status, the possibility of hyperammonemic encephalopathy should be considered, and blood ammonia levels should be measured. If blood ammonia is elevated, sodium valproate treatment should be discontinued. Appropriate treatment for hyperammonemia should be initiated, and such patients should be examined to determine if they have urea cycle disorders. Asymptomatic elevations in blood ammonia levels are more common; when asymptomatic elevations are present, close monitoring of plasma ammonia levels is necessary. If blood ammonia remains elevated, discontinuation of sodium valproate treatment should be considered. In patients presenting with unexplained drowsiness and vomiting or altered mental status, the possibility of hyperammonemia encephalopathy should be considered, and blood ammonia levels should be measured (see [Contraindications]). Effects on driving and operating machinery: Patients should be aware of the risk of drowsiness, especially drivers or machinery operators. This drowsiness should be monitored closely during polyphagic anticonvulsant therapy or when taking other medications concurrently.

【Use in Special Populations】
Precautions for Children: Sodium valproate is recommended as monotherapy in children, but the potential benefits of sodium valproate should be weighed against the risks of liver damage or pancreatitis before initiating treatment in such patients (see [Precautions]). Due to the risks of hepatotoxicity and bleeding, acetylsalicylic acid should be avoided in children taking this product. Children with unexplained liver and gastrointestinal disorders (such as anorexia, vomiting, cell lysis), depression or coma, intellectual disability, or a family history of neonatal or infant death should undergo metabolic testing, especially fasting and postprandial ammonia levels, before receiving any valproate treatment. The safety and efficacy of sodium valproate in treating mania associated with bipolar disorder in children and adolescents under 18 years of age have not been studied.

Pregnancy and Lactation Precautions:Pregnancy: Based on available data, sodium valproate is not recommended for use during pregnancy. The risk of birth defects induced by sodium valproate administration during pregnancy is 3-4 times higher than in the general population, at 3%. The most common malformations are neural conduit closure defects (approximately 2%–3%), craniofacial defects, limb malformations, cardiovascular malformations, and multiple malformations involving different systems of the body. Doses greater than 1000 mg/day and combined use with other anticonvulsants are significant risk factors for these malformations. Current epidemiological data do not show that intrauterine exposure to valproate leads to a decrease in overall IQ in children. However, a slight decrease in verbal expression ability and/or an increased need for speech-related adjunctive therapy have been observed in these children. Further results show sporadic case reports of autism and related disorders in children exposed to sodium valproate in utero. Further clinical studies are needed to confirm these results. Planning Pregnancy: Women planning pregnancy should take a comprehensive approach to consider the availability of alternative treatments. If sodium valproate use is deemed unavoidable (or there are no other options), the recommended daily dose is the lowest effective dose, preferably in a sustained-release formulation. If a sustained-release formulation is unavailable, a divided dose of the regular formulation may be considered to avoid peak plasma concentrations of valproic acid. To date, there is no evidence to support the effectiveness of folic acid supplementation when women take sodium valproate during pregnancy. However, considering its beneficial effects in other situations, folic acid supplementation at a dose of 5 mg/day may be considered one month before conception and two months after conception. Regardless of whether the patient takes folic acid, the same malformation screening should be performed. During pregnancy: If there are no other options besides continuous treatment with sodium valproate (no alternative methods), the lowest effective dose is recommended. If possible, doses exceeding 1000 mg/day should be avoided. Before birth: Patients treated with sodium valproate may experience coagulation abnormalities. If sodium valproate is used in pregnant women, coagulation tests should be performed on the mother before birth, including platelet count, fibrinogen level, and aPTT (aplastic time to thrombosis). Newborn: This product may cause neonatal hemorrhage syndrome unrelated to vitamin K deficiency. Routine hematological tests on the mother may not fully reflect the possibility of hematological abnormalities in the newborn. Platelet count, fibrinogen level, and aPTT testing must be performed on the newborn. Additionally, there are reports of hypoglycemia in newborns during the first week after birth. Breastfeeding: Valproic acid concentrations in breast milk are very low, only 1% to 10% of maternal serum concentrations. Although no clinical abnormalities have been reported in breastfed infants monitored during the neonatal period to date, breastfeeding is not a contraindication to sodium valproate administration. A comprehensive assessment of various factors is necessary.

Precautions for the elderly: Compared to younger adult patients, elderly patients (over 68 years of age) have a decreased ability to clear sodium valproate, and the incidence of adverse events may be increased. Therefore, the initial dose should be lower in these patients. Furthermore, the rate of dose escalation should be slower, and regular monitoring of fluid and nutrient intake, dehydration, drowsiness, and other adverse events is required. If a patient experiences a decrease in food and fluid intake, or excessive drowsiness, a reduction in the sodium valproate dose or discontinuation of sodium valproate treatment should be considered. The final therapeutic dose should be determined based on tolerability and clinical response. See other relevant sections in this instruction manual, or as directed by your physician.

【Drug Interactions】
No reports.

【Pharmacological Action】
Valproate exerts its pharmacological effects primarily through the central nervous system. Animal studies have shown its ability to counteract various types of seizures. Laboratory and clinical studies have shown that valproate exerts its anticonvulsant effect through two pathways. The first pathway is a direct pharmacological action related to plasma and brain valproate concentrations. The second pathway is indirect, possibly related to valproate metabolites in the brain, or to alterations in neurotransmitters or direct membrane effects. The widely accepted hypothesis is that valproate administration leads to an increase in γ-aminobutyric acid (GABA) levels in the body. Valproate can reduce the duration of sleep cycles during the middle of the night and increase the duration of slow-wave sleep.

【Storage】
Store in a dry place below 25℃.

【Specifications】
0.5g (calculated as sodium valproate)

【Packaging Specifications】
0.5g*30 tablets

【Shelf Life】
36 months.

【Standard】
JX20100232

【Manufacturer】
Company Name: Hsin-Tung Biotechnology Co., Ltd.