VALPROS I-IV Sodium Valproate 400mg Lyophilized Powder for IV Injection 1's

Valpros: For the treatment of generalized, partial or other epilepsy.
For the treatment and prevention of mania associated with bipolar disorders.
Valpros i-IV: Sodium valproate is indicated as an intravenous (IV) alternative in patients for whom oral administration of valproate products is temporarily not feasible in the following conditions: Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures; Monotherapy and adjunctive therapy in the treatment of patients with simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.

 

Valpros: General Dosing Recommendation: The controlled release tablets should be swallowed whole and not crushed or chewed since this may cause inappropriate release and absorption of the drug.
Daily dosage requirements vary according to age and body weight. Dosage must be carefully and slowly adjusted according to individual requirements and response.
Sodium valproate + valproic acid controlled release tablets may be given once or twice daily.
Epilepsy: Therapeutic Dose Range: 1,000 mg to 2,000 mg/day (i.e., 20 to 30 mg/kg/body weight/ day); Where adequate control is not achieved within this range, the dose may be further increased to 2,500 mg/day.
Or, as prescribed by a physician.
Combined Therapy with Anticonvulsants: When sodium valproate + valproic acid is to be given to patients already on other anticonvulants, these should be tapered slowly; initiation of sodium valproate + valproic acid should then be gradual, with a target dose being reached after about two weeks.
In certain cases, it may be necessary to raise the dose by 5 to 10 mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity (e.g., Phenytoin, phenobarbital and carbamazepine). Once the enzyme inducers have been withdrawn, it may be possible to maintain seizure control on a reduced dose of sodium valproate + valproic acid.
When barbiturates are being given concomitantly and if sedation is observed, the dosage of barbiturate should be reduced.
Bipolar Disorder: Recommended Initial Dose: 20 mg/kg/day; The dose may be adjusted according to individual clinical response. The maximum dose should not exceed 3,000 mg daily.
Recommended Maintenance Dose: 1,000 mg to 2,000 mg/day; Doses should be adjusted according to individual clinical response.
Prophylactic treatment should be established individually with the lowest effective dose.
Or, as prescribed by a physician.
Special Population: Elderly: Although the pharmacokinetics of sodium valproate + valproic acid are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control.
In the elderly, the volume of distribution is increased and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the interpretation of
plasma valproic acid levels.
Patients with Renal Insufficiency: Dose reduction may be necessary. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.
Valpros i-IV: Sodium valproate 400 mg injection is intended for intravenous (IV) use only. It is administered by slow IV injection (3 to 5 minutes) or slow IV infusion.
The use of sodium valproate injection for periods of more than 14 days has not been studied. Patients should be switched to oral valproate products as soon as it is clinically feasible.
Sodium valproate should be diluted with at least 500 mL of a compatible diluent (0.9% sodium chloride, 5% glucose and Lactated Ringer's solution). It should be administered intravenously at an infusion rate of 1 to 2 mg/kg body weight per hour.
Any unused portion of the vial contents should be discarded.
Sodium valproate injection should not be injected intramuscularly as it may produce tissue necrosis.
Sodium valproate injection should not be administered at the same time as other IV additives via the same IV line. The IV solution is suitable for infusion by PVC, polyethylene or glass containers.
Dosing requirements vary according to age and body weight and should be adjusted individually to achieve adequate seizure control.
Recommended Daily Intravenous (IV) Dose: Monotherapy: Adults: Patients already satisfactorily treated with sodium valproate may be continued at their current dosage using continuous infusion. For example, a patient stabilized on 25 mg/kg body weight administered daily should be continued with an infusion rate of 1 mg/kg body weight per hour.
Other patients may be given a slow intravenous injection over 3 to 5 minutes, usually 400 to 800 mg depending on body weight (up to 10 mg/kg), followed by continuous infusion of 1 to 2 mg/kg body weight per hour to a maximum of 2,500 mg per day, according to the patient's clinical response.
Adjunctive Therapy: When starting sodium valproate in patients already on other anticonvulsants, these should be tapered slowly. Initiation of sodium valproate therapy should be gradual, with the target dose being reached after about two weeks. In some cases, it may be necessary to increase the dose by 5 to 10 mg/kg body weight per day when used in combination with anticonvulsants which induce liver enzyme activity (e.g., phenytoin, phenobarbital and carbamazepine). Once known enzyme inducers have been withdrawn, it may be possible to maintain symptom control on a reduced dose of sodium valproate.
Special Population: Pediatric:20 to 30 mg/kg body weight per day; Where adequate control is not achieved within this range, the dose may be increased up to 40 mg/kg body weight per day but only in patients in whom plasma valproate levels can be monitored. Clinical chemistry and hematological parameters should be monitored if more than 40 mg/kg body weight per day.
Elderly: Due to a decrease in unbound valproate clearance and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Subsequent dose should be increased more slowly. Likewise, regular monitoring of fluid and nutritional intake, dehydration, somnolence, and other adverse events is recommended. Dosage reduction or discontinuance of valproate should be considered in the elderly with decreased food or fluid intake and in those with excessive somnolence. The ultimate therapeutic dose in these patients should be determined on the basis of tolerability and clinical response.
Patients with impaired renal function: Lower doses may be required since free drug levels may be high owing to lowered serum albumin and poor urinary excretion of free drug metabolites. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring.
Or, as prescribed by a physician.

 

Overdosage

CR tab: Should be taken with food: Swallow whole, do not chew/crush.

Valpros: Known hypersensitivity to sodium valproate, valproic acid or to any ingredient in the product; Patients with pre-existing, acute or chronic hepatic dysfunction or family history of severe hepatic dysfunction, particularly drug related; Patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-γ gene (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years old who are suspected of having a POLG-related disorder; Patients with known urea cycle disorders; Patients with porphyria.
Valpros i-IV: Hypersensitivity to sodium valproate or any ingredient of the product; Urea cycle disorder; Porphyria; Pre-existing or acute hepatic dysfunction; Personal or family history of severe hepatitis, particularly medicine related.

 

Warnings

Valpros: Hepatotoxicity: General information on hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be done prior to therapy and at frequent intervals thereafter, particularly during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.
In progressively older patient groups, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Patients with known or suspected mitochondrial disease: Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase-γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be done in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.
Sodium valproate + valproic acid should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug.
Pancreatitis: Young children are at particular risk but this risk decreases with increasing age. Severe seizures, neurological impairment or anticonvulsant polytherapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.
Urea Cycle Disorders (UCD): Sodium valproate + valproic acid is contraindicated in patients with known UCD.
Hyperammonemic encephalopathy, sometimes fatal, has been reported after initiation of valproate therapy in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase (OTC) deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); and 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying UCD.
Ornithine Transcarbamylase Deficiency: The females who are heterozygous for OTC deficiency have a spectrum of clinical and biochemical findings, depending on the extent of inactivation of the X-chromosome. Females may show a range of symptoms due to hyperammonemia which, may be episodic, and therefore difficult to diagnose. The acute symptoms include headaches, vomiting, irritability, bizarre behavior, lethargy, ataxia, tremors, seizures (generalized tonic-clonic or focal) and coma. Valproate may precipitate hyperammonemia symptoms in those who have pre-existing OTC deficiency. As the symptoms may include seizures, any female with valproate-associated symptomatic hyperammonemia should be evaluated for OTC deficiency. Investigations should include measurement of plasma amino acids and the immediate cessation of valproate should result in clinical improvement.
Hyperammonemia: There has been report of hyperammonemia in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying UCD.
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
Concomitant use of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in levels of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Hypothermia: Hypothermia, defined as an unintentional drop in body temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities, including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
Suicidal Behavior and Ideation: AEDs, including sodium valproate + valproic acid, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Anyone considering prescribing sodium valproate + valproic acid or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Thrombocytopenia: The frequency of adverse effects, particularly elevated liver enzymes and thrombocytopenia, may be dose-related. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts, and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving sodium valproate + valproic acid be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Weight Gain: Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimize the risk.
Surgery: Prolongation of bleeding time, sometimes with thrombocytopenia, has occurred with valproate therapy. Platelet function should be monitored before surgery is undertaken in patients receiving sodium valproate + valproic acid.
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding.
Multi-Organ Hypersensitivity Reactions: Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience among drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
Carnitine Palmitoyltransferase (CPT) Type II Deficiency: Patients with an underlying CPT type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.
Monitoring Drug Plasma Concentration: Periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy since valproate may interact with concurrently administered drugs which are capable of enzyme induction.
Abrupt withdrawal: The possible risk of fits after sudden cessation of sodium valproate + valproic acid should be considered. If it is the only anticonvulsant used and has to be withdrawn for more than 12 hours because of surgery, control of epilepsy may be lost.
Effect on Ability to Drive or Operate Machinery: Use of sodium valproate + valproic acid may provide seizure control such that the patient may be eligible to hold a driving license. However, patients should be warned of the risk of transient drowsiness, particularly in cases of anticonvulsant polytherapy, too high starting dose, too rapid dose escalation, or association with benzodiazepines.
Use in Children: The potential benefit of sodium valproate + valproic acid should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy. The concomitant use of salicylates should be avoided in children under 3 years old due to the risk of liver toxicity and the concomitant use of barbiturates may require dosage adjustment. Monotherapy is recommended in these children, when prescribing sodium valproate + valproic acid. Young children are at particular risk for pancreatitis; however, this risk decreases with increasing age. The safety and efficacy of sodium valproate for the treatment of manic episodes in bipolar disorder have not been evaluated in patients less than 18 years old.
Use in the Elderly: A study involving elderly patients with dementia, a significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patient with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and higher blood urea nitrogen (BUN). In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.
Valpros i-IV: Hepatotoxicity (see Warnings): The incidents usually occurred during the first six months of therapy, the period of maximum risk being 2 to 12 weeks, and usually involved multiple anticonvulsant therapy. Monotherapy is to be preferred in this group of patients; the benefits of therapy should be weighed against the risks. Clinical symptoms are usually more helpful than laboratory investigations in the early stages of hepatic failure. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms, usually of sudden onset, such as loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia, vomiting, abdominal pain, drowsiness, and jaundice. These are indications for immediate withdrawal of the medicine. Patients should be monitored closely for appearance of these symptoms and should be instructed to report any such signs to the clinician for investigation should they occur. Liver function tests should be done prior to therapy and at frequent intervals thereafter until 6 months after the controlling dose is reached, when less frequent monitoring may be appropriate. It is also advisable to monitor tests which reflect protein synthesis, e.g., prothrombin time, serum fibrinogen and albumin levels, particularly in those who seem most at risk and those with a prior history of hepatic disease. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Raised liver enzymes are not uncommon during treatment with valproate, particularly if used in conjunction with other anticoagulants, and are usually transient or respond to dosage reduction. Patients with such biochemical abnormalities should be reassessed clinically and tests of liver function should be monitored more frequently. An abnormally low prothrombin rate, particularly in association with other relevant abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of treatment and the substitution of alternative medicines to avoid precipitating convulsions. Uneventful recovery has been recorded in several cases where therapy with valproate has ceased, but death has occurred in some patients in spite of the medicine being withdrawn.
Sodium valproate should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug.
Pancreatitis (see Warnings): Severe pancreatitis, which may result in fatalities, has been very rarely reported. Some cases have occurred shortly after initial use while others have occurred after several years of use. There have also been cases in which pancreatitis recurred after rechallenge with sodium valproate.
Young children are at particular risk but this risk decreases with increasing age. Severe seizures, neurological impairment or anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.
Urea Cycle Disorders (UCD): The use of valproate in patients with known UCD (a group of uncommon genetic abnormalities) is contraindicated. Hyperammonemic encephalopathy, which is sometimes fatal, has been reported after initiation of valproate in patients with UCD particularly ornithine transcarbamylase deficiency.
Metabolic investigations should be done prior to treatment. Evaluation for UCD should be considered in the following patients: History of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; Signs and symptoms of UCD [e.g., cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), protein avoidance]; Family history of UCD or a family history of unexplained infant deaths (particularly males); Other signs or symptoms of UCD.
Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment, including discontinuation of valproate therapy, and be evaluated for underlying UCD.
Hyperammonemia: Hyperammonemia, which may be present in the absence of abnormal liver function tests, can occur in patients during valproate therapy.
Likewise, concomitant use of valproate with topiramate has been shown to produce hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. This adverse event is not due to pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk for hyperammonemia with or without encephalopathy.
Hyperammonemia may occasionally present clinically, with or without lethargy or coma, as vomiting, ataxia and increasing clouding of consciousness. Should these symptoms occur, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for the treatment of hyperammonemia should be initiated.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including sodium valproate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence of worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing sodium valproate or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Post-traumatic Seizure: Sodium valproate injection should not be used in patients with acute head trauma for the prophylaxis of post-traumatic seizures.
Hypothermia: Hypothermia, an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with sodium valproate therapy both in conjunction with and in the absence of hyperammonemia. Hypothermia may be manifested by a variety of clinical abnormalities such as lethargy, confusion, coma, and significant alterations in other major organ systems (i.e., cardiovascular and respiratory). Consideration should be given to discontinuing valproate therapy in patients who develop hypothermia. Examination of blood ammonia levels should be included in the clinical management and assessment of patient.
Weight Gain: Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimize the risk.
Multi-organ Hypersensitivity Reaction: Although there have been rare reports of multi-organ hypersensitivity reactions associated with valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40 days), many of these cases resulted in hospitalization and even death. Patients typically presented with fever and rash associated with other organ system involvement. If this reaction is suspected, sodium valproate should be discontinued and an alternative treatment should be started.
Serious Skin Reactions: Serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with concomitant lamotrigine and sodium valproate use.
Thrombocytopenia: The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of 110 mcg/mL or greater (females) or 135 mcg/mL or greater (males). Blood tests (e.g., blood cell count, including platelet count, bleeding time and coagulation tests) are recommended before initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of sodium valproate dose or withdrawal of therapy.
Lupus erythematosus: Although immune disorders have been noted only exceptionally during the use of sodium valproate, the potential benefit of sodium valproate should be weighed against its potential risk in patients with systemic lupus erythematosus.
Effects on Ability to Drive and/or Operate Machines: Since valproate may produce central nervous system (CNS) depression, particularly when combined with another CNS depressant such as alcohol, patients should be warned that sodium valproate may impair ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving a motor vehicle).
HIV and CMV viruses Replication: In vitro studies showed that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) viruses under certain experimental conditions. The clinical consequence, if any, is not known. However, these data should be considered when interpreting the results from regular monitoring of the viral load in HIV-infected patients taking sodium valproate or when following CMV-infected patients clinically.
Abrupt Withdrawal: The possible risk of convulsions after sudden cessation of sodium valproate injection should be considered. If it is the only anticonvulsant used and has to be withdrawn for more than 12 hours because of surgery, control of epilepsy may be lost.
Use in Children: The safety of intravenous sodium valproate has not been studied in children below 2 years old. If a decision is made to use sodium valproate injection in this age group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.
The safety and efficacy of sodium valproate for the treatment of manic episodes in bipolar disorder have not been evaluated in patients below 18 years old.
Use in the Elderly: A case review study showed that a higher percentage of patients above 65 years old reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with somnolence and tremor. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant drug use among these patients.
A study in elderly patients with dementia showed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence.
No unique safety concerns were identified in patients >65 years old receiving intravenous sodium valproate.

 

Use In Pregnancy & Lactation

Valpros: Neoplasms Benign, Malignant and Unspecified (including cysts and polyps): Myelodysplastic syndrome.
Blood and Lymphatic System Disorders: Thrombocytopenia, anemia, aplastic anemia, leukopenia, pancytopenia with or without bone marrow depression, decreased blood fibrinogen, red cell hypoplasia, neutropenia; bone marrow failure, including pure red cell aplasia, agranulocytosis; anemia including macrocytic with or without folate deficiency, anemia macrocytosis, ecchymosis, petechia, lymphocytosis, bone marrow suppression, acute intermittent porphyria.
Immune System Disorders: Angioedema, anaphylaxis, allergic reaction, cutaneous vasculitis.
Endocrine Disorders: Hypothyroidism, hyperandrogenism (e.g., hirsutism, virilism, androgen increased), parotid gland swelling, hyperglycemia.
Gastrointestinal Disorders: Nausea, upper abdominal pain, diarrhea, gingival disorder (mainly gingival hyperplasia), stomatitis, vomiting, abdominal cramp, upper abdominal pain, anorexia, increased appetite, pancreatitis, constipation, gastralgia, dyspepsia, flatulence, hematemesis, eructation, periodontal abscess, taste perversion, fetal incontinence, gastroenteritis, glossitis, dry mouth.
Hepatobiliary Disorders: Hepatic dysfunction, including hepatic failure; liver injury, AST and ALT increased.
Metabolism and Nutrition Disorders: Hyperammonemia, asymptomatic elevations of ammonia, hyponatremia, syndrome of inappropriate secretion of ADH (SIADH).
Psychiatric Disorders: Depression, excitement, hyperactivity, behavioral disorders, confusional state, hallucinations, aggression, agitation, disturbance in attention, abnormal behavior, psychomotor hyperactivity, learning disorder, emotional lability, thinking abnormal, anxiety, abnormal gait, personality disorder, emotional upset, psychosis, hostility, behavioral deterioration, developmental delay.
Nervous System Disorders: Drowsiness, sedation, tremor, stupor, somnolence, convulsion, memory impairment, headache, nystagmus, dizziness, ataxia, coma, encephalopathy, lethargy, paresthesia, reversible dementia associated with reversible cerebral atrophy and cognitive disorder; reversible parkinsonism, extrapyramidal disorder which may not be reversible; twitching, hypertonia, incoordination, abnormal dreams, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Eye Disorders: Diplopia, amblyopia/blurred vision, abnormal vision, conjunctivitis, dry eyes, eye pain.
Ear and Labyrinth Disorders: Deafness, either reversible or irreversible, tinnitus, otitis media, hearing loss.
Cardiac Disorders: Chest pain, tachycardia, hypertension, palpitation, hypotension, postural hypotension, bradycardia.
Vascular Disorders: Hemorrhage, vasculitis, vasodilation.
Respiratory, Thoracic and Mediastinal Disorders: Pleural effusion, flu syndrome, bronchitis, rhinitis, pharyngitis, dyspnea, sinusitis, cough increased, pneumonia, epistaxis.
Skin and Subcutaneous Tissue Disorders: Hypersensitivity, transient and/or dose-related alopecia, hirsutism, acne, pruritus, urticaria, Stevens-Johnson Syndrome, angioedema, rash, hair disorder (e.g., hair texture abnormal, hair color changes, hair growth abnormal), toxic epidermal necrolysis, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, dry skin, furunculosis, maculopapular rash, seborrhea, photosensitivity.
Musculoskeletal and Connective Tissue Disorders: Decreased bone mineral density, osteopenia, osteoporosis, and fractures, systemic lupus erythematosus, rhabdomyolysis, back pain, neck pain, neck rigidity, myalgia, twitching, arthralgia, leg cramps, myasthenia, arthrosis, bone pain.
Renal and Urinary Disorders: Enuresis, tubulointerstitial nephritis, Fanconi's syndrome, urinary incontinence, urinary frequency, dysuria, cystitis, enuresis, urinary tract infection.
Reproductive System and Breast Disorders: Irregular menses, amenorrhea, breast enlargement, galactorrhea, dysmenorrhea, male infertility, polycystic ovaries, vaginitis, metrorrhagia, vaginal hemorrhage.
Investigations: Coagulation factors decreased, abnormal coagulation tests (such as prolonged prothrombin time, activated partial thromboplastin time, thrombin time and INR) and biotin deficiency/biotinidase deficiency; decreased carnitine concentrations.
General Disorders and Administration Site Conditions: Edema, peripheral edema, face edema, hypothermia, increased weight, weight loss, pain, asthenia, fever, fatigue, malaise, chills, weakness.
Valpros i-IV: Body as a Whole: Pain (unspecified), peripheral edema.
Cardiovascular: Chest pain, vasodilation, vasculitis.
Endocrine/Metabolic/Nutritional: Weight gain, hyperammonemia, hyponatremia.
Nervous/Psychiatric: Headache, dizziness, nervousness, sedation, ataxia, paresthesia, hypesthesia, extrapyramidal symptoms including parkinsonism, tremor, reversible dementia, somnolence, hallucination, convulsion, encephalopathy, coma, euphoria, lethargy, confusion, abnormal gait, aggression, alertness increased, hyperactivity, behavioral deterioration.
Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting, pancreatitis, gastralgia.
Hematologic: Thrombocytopenia; anemia; leukopenia; pancytopenia; bone marrow failure, including red cell aplasia; agranulocytosis; blood fibrinogen reduced; increased prothrombin time.
Hepatic: Hepatic dysfunction; severe liver damage, including hepatic failure; increased liver enzymes.
Respiratory: Pharyngitis, pneumonia.
Skin and appendages: Injection site inflammation, injection site pain, injection site reaction, sweating, transient hair loss, hirsutism, acne, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, drug rash with eosinophilia systemic symptoms (DRESS) syndrome, allergic reactions.
Special senses: Hearing loss, taste perversion.
Urogenital/Reproductive: Fanconi's syndrome, amenorrhea, irregular periods, gynecomastia.
Adverse events that have been reported with all dosage forms of valproate: Body as a Whole: Asthenia, fever, hypothermia, chills, infection, malaise, fatigue, edema of the extremities, face edema.
Cardiovascular: Tachycardia, bradycardia, hypertension, hypotension, postural hypotension, vasodilation, palpitation.
Endocrine/Metabolic/Nutritional: Anorexia, weight loss, increased appetite, syndrome of inappropriate secretion of ADH (SIADH), parotid gland swelling, abnormal thyroid function tests, decreased carnitine concentrations, hyperglycinemia.
Nervous/Psychiatric: Drowsiness, hypertonia, incoordination, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, asterixis, insomnia, abnormal dreams, amnesia, dementia, dysarthria, vertigo, cerebral atrophy, emotional lability, thinking abnormal, emotional upset, depression, anxiety, stupor, personality disorder, excitement, psychosis, hostility, agitation.
Gastrointestinal: Periodontal abscess, dry mouth, glossitis, stomatitis, abdominal cramps, dyspepsia, indigestion, constipation, gastroenteritis, flatulence, hematemesis, eructation, fecal incontinence.
Hematologic: Ecchymosis, petechia, neutropenia, altered bleeding time, bruising, hematoma formation, epistaxis, hemorrhage, lymphocytosis, macrocytosis, hypofibrinogenemia, eosinophilia, anemia including macrocytic anemia with or without folate deficiency, aplastic anemia, acute intermittent porphyria, bone marrow suppression, lupus erythematosus.
Hepatic: Serum bilirubin increased.
Musculoskeletal: Back pain, neck pain, neck rigidity, myalgia, twitching, arthralgia, arthrosis, leg cramps, myasthenia, weakness, bone pain.
Respiratory: Flu syndrome, bronchitis, rhinitis, dyspnea, sinusitis, cough increased.
Skin and appendages: Alopecia, rash, pruritus, dry skin, photosensitivity, furunculosis, maculopapular rash, seborrhea.
Special senses: Diplopia, amblyopia/blurred vision, abnormal vision, spots before eyes, conjunctivitis, dry eyes, eye pain, nystagmus, deafness, otitis media, tinnitus.
Urogenital/Reproductive: Urinary incontinence, urinary frequency, enuresis, dysuria, cystitis, vaginitis, vaginal hemorrhage, dysmenorrhea, metrorrhagia, galactorrhea.

 

Valpros: Alcohol: Valproate may potentiate the CNS depressant activity of alcohol. Concomitant use is not recommended.
Antiepileptic drugs (e.g., phenytoin, carbamazepine, phenobarbital, lamotrigine, primidone, felbamate): Several AEDs often used in conjunction with valproate have the ability to increase the intrinsic clearance of valproate, presumably by enzymatic induction of metabolism.
Valproate may displace carbamazepine from protein binding sites and may inhibit the metabolism of both carbamazepine and its metabolites, potentiating the toxic effects of carbamazepine. Clinical monitoring is recommended particularly at the beginning of combined therapy, with dosage adjustment when necessary.
Valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended and lamotrigine dosage should be decreased as appropriate.
Valproate may block the metabolism of barbiturates resulting in increased phenobarbital plasma levels, which particularly in children, may be associated with sedation.
Concomitant use of phenobarbital and sodium valproate + valproic acid can cause CNS depression without significant elevation of serum level of either drug. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Concomitant use of phenytoin and sodium valproate + valproic acid may lead to breakthrough seizures. Most reports have noted a decrease in total plasma phenytoin concentration, however, increases in total phenytoin levels have been reported. An initial fall in total phenytoin levels with subsequent increase in phenytoin levels has also been reported. Furthermore, a decrease in total serum phenytoin with an increase in the free versus protein bound phenytoin levels has been reported with possible overdose symptoms (valproate displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended. When phenytoin plasma levels are determined, the free form should be evaluated. The dosage of phenytoin may require adjustment when given concomitantly with valproate as required by the clinical situation.
Valproate increases primidone plasma levels with exacerbation of its adverse effects (e.g., sedation); these signs cease with long-term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Valproate may decrease felbamate mean clearance by up to 16%. On the other hand, combination of felbamate and sodium valproate + valproic acid decreases valproate clearance by 22% to 50% and consequently increase the valproate plasma concentrations. Valproate dosage should be monitored when given in combination with felbamate.
Anticoagulants: The concomitant use of sodium valproate with drugs that exhibit extensive protein binding (e.g., aspirin, warfarin) may result in alteration of serum drug levels.
The effect of valproate on anticoagulants is unknown. Caution is recommended when administering anticoagulants and other products which have anticoagulant properties.
Concomitant use of sodium valproate + valproic acid and aspirin may result in displacement of valproate from protein binding sites, resulting in a rise in free levels of valproate. In addition, aspirin appears to inhibit the metabolism of valproate. Caution is advised when aspirin is given concomitantly with sodium valproate + valproic acid. Patients requiring long-term aspirin therapy may require a reduction in sodium valproate + valproic acid dose.
Carbapenem antibiotics (e.g., panipenem, meropenem, imipenem): Decreases in blood levels of valproate have been reported when it is co-administered with carbapenem agents resulting in a 60 to 100% decrease in valproate levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, concomitant use of carbapenem agents in patients stabilized on valproate should be avoided. If treatment with these antibiotics cannot be avoided, close monitoring of valproate blood levels should be done.
Cimetidine or Erythromycin: Concomitant use may increase valproate serum levels (as a result of reduced hepatic metabolism).
Cholestyramine: May decrease the absorption of valproate.
Ethosuximide: Valproate may inhibit ethosuximide metabolism, particularly in the presence of other anticonvulsants. Patients receiving this combination should be monitored clinically.
Mefloquinone and chloroquine: These drugs increase valproate metabolism and may lower the seizure threshold; therefore, epileptic seizures may occur in cases of combined therapy.
Dose adjustment of sodium valproate + valproic acid may be necessary.
Psychotropic agents [e.g., monoamine oxidase inhibitors (MAOIs), antipsychotics (e.g., clozapine, haloperidol, olanzapine, quetiapine), antidepressants (e.g., fluoxetine), and benzodiazepines (e.g., clonazepam, diazepam, lorazepam, midazolam)]: Valproate may potentiate the effects of psychotropic agents; therefore, clinical monitoring is advised and the dose of these drugs should be reduced accordingly.
Concomitant use of clozapine and sodium valproate + valproic acid may potentiate an increase in clozapine or valproate levels.
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate revealed no significant changes in valproate trough plasma levels.
Concomitant use of olanzapine and sodium valproate + valproic acid may result in significant increase in the risk of adverse events associated with olanzapine e.g., neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder, and somnolence.
Concomitant use of sodium valproate + valproic acid and quetiapine may increase the risk of neutropenia/leukopenia.
Fluoxetine may inhibit the metabolism of sodium valproate + valproic acid as it does with TCAs, carbamazepine, and diazepam.
The concomitant use of sodium valproate + valproic acid and clonazepam may produce absence status.
Valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Monitoring of free diazepam levels may be necessary if the patient becomes sedated.
Concomitant use of sodium valproate + valproic acid and lorazepam results in decreased lorazepam plasma clearance.
Concomitant use of sodium valproate + valproic acid results in increased free plasma midazolam leading to an increase in of the midazolam response.
Lithium: Sodium valproate + valproic acid has no effect on serum lithium levels.
Rifampicin: Rifampicin may decrease valproate blood levels resulting in a lack of therapeutic effect. Therefore, sodium valproate + valproic acid dosage adjustment may be necessary when it is co-administered with rifampicin.
Temozolomide: Concomitant use with sodium valproate + valproic acid may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Tolbutamide: In vitro studies showed that the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with sodium valproate + valproic acid. The clinical relevance of this displacement is unknown.
Topiramate: Concomitant use with sodium valproate + valproic acid has been associated with encephalopathy and/or hyperammonemia. Patients treated with these drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.
Tricyclic Antidepressants (TCAs) (e.g., chlorpromazine, amitriptyline/nortriptyline): Valproate may inhibit the metabolism of TCAs. Clinical monitoring of free antidepressant levels may be necessary.
Chlorpromazine may inhibit the metabolism of sodium valproate + valproic acid.
Concomitant use of amitriptyline and sodium valproate + valproic acid resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Concomitant use of these drugs has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking sodium valproate + valproic acid concomitantly with amitriptyline. Lowering the amitriptyline/nortriptyline dose in the presence of sodium valproate + valproic acid should be considered.
Vitamin K-dependent factor anticoagulant: The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased after displacement from plasma protein binding sites by valproate. The prothrombin time should be closely monitored.
Zidovudine: Sodium valproate + valproic acid may increase zidovudine plasma concentrations leading to increased zidovudine toxicity.
Antacids: Concomitant use with sodium valproate + valproic acid did not reveal any effect on the extent of valproate absorption.
Paracetamol: Concomitant use with sodium valproate + valproic acid had no effect on the pharmacokinetics of paracetamol.
Oral contraceptives steroids: Concomitant use with sodium valproate + valproic acid did not reveal any pharmacokinetic interaction.
Other Interactions: Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. Altered thyroid function tests associated with valproate has also been reported.
In vitro studies suggest that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) viruses under certain experimental conditions. The clinical consequence, if any, is not known. In addition, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be taken into consideration when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV
infected patients clinically.
There have been reports of altered thyroid function test results associated with valproate. The clinical significant of this is unknown.
Valpros i-IV: Alcohol: Valproate may potentiate the CNS depressant activity of alcohol.
Aspirin: Concomitant use of sodium valproate and aspirin may result in displacement of valproate from protein binding sites, resulting in an increased free valproate concentration. Also, aspirin appears to inhibit the metabolism of valproate.
Caution is advised when patients on sodium valproate are prescribed with aspirin. Likewise, patients requiring long-term aspirin therapy may require a reduction in dosage of sodium valproate.
Vitamin K-dependent factor anticoagulants (e.g., coumarin, warfarin): Close monitoring of prothrombin time should be done in case of concomitant use of vitamin K-dependent factor anticoagulants with sodium valproate since valproate may possibly enhance the anticoagulant effect of these drugs.
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased after displacement from the plasma protein binding site by valproate. Prothrombin time should be closely monitored.
Carbapenem antibiotics (e.g., ertapenem, imipinem, meropenem): Decreases in blood levels of valproic acid have been reported when it is coadministered with carbapenem agents resulting in a 60 to 100% decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, coadministration of carbapenem agents in patients stabilized on valproic acid should be avoided. If treatment with these antibiotics cannot be avoided, serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates.
Rifampicin: May decrease the valproate blood levels resulting in a lack of therapeutic effect. Valproate dosage adjustment may be necessary when it is coadministered with rifampicin.
Antidepressants [e.g., monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)]: These may have the potential to inhibit the metabolism of valproate via the cytochrome P450 system. However, within normal therapeutic doses, any significant interaction is not expected. Antidepressants can lower the seizure threshold of non-stabilized epileptic patients, and so careful and regular monitoring of their condition is indicated.
Fluoxetine may inhibit the metabolism of valproate as it does with TCAs, carbamazepine and diazepam.
Clozapine: Caution is advised during concomitant use as competitive protein binding may potentiate an increase in clozapine or valproate levels.
Chlorpromazine: May inhibit the metabolism of valproate.
Olanzapine: Adding olanzapine to valproate may significantly increase the risk of certain adverse events associated with olanzapine (e.g., neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder, and somnolence).
Carbamazepine: Valproate may displace carbamazepine from protein binding sites and may inhibit the metabolism of both carbamazepine and its metabolite carbamazepine 10, 11 epoxide and consequently potentiate carbamazepine toxicity. Clinical monitoring is recommended particularly at the beginning of combined therapy, with dosage adjustment when appropriate.
Felbamate: May increase valproate serum concentrations. Valproate dosage should be monitored when given in conjunction with felbamate. Valproate may decrease felbamate mean clearance by up to 16%.
Lamotrigine: Sodium valproate reduces lamotrigine metabolism and increases its mean half-life by nearly two-fold. This interaction may lead to increased lamotrigine toxicity, in particular, serious skin rashes. Clinical monitoring is recommended and lamotrigine dosage should be decreased as appropriate.
Phenobarbital: Sodium valproate increases phenobarbital plasma concentrations and sedation may occur, particularly in children. Clinical monitoring is recommended throughout the first 15 days of combined treatment with an immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital levels when appropriate.
There is evidence of severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.
Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone: Sodium valproate increases primidone plasma levels causing an exacerbation of side effects (e.g., sedation); these signs cease with long-term treatment. Clinical monitoring is recommended particularly when initiating combined therapy with dosage adjustment as necessary.
Phenytoin: Phenytoin total plasma levels are decreased by sodium valproate; the free form of phenytoin is increased leading to possible overdosage symptoms. Thus, clinical monitoring is recommended with the free form of phenytoin being measured.
There have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin in patients with epilepsy. The dosage of phenytoin should be adjusted as required by the clinical situation.
Topiramate: Concomitant use of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant use of these drugs has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported. In patients taking valproate and topiramate, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
Clonazepam: The concomitant use of sodium valproate and clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam: Sodium valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Monitoring of free diazepam levels may be necessary if the patient becomes sedated.
Lorazepam: Concomitant use with sodium valproate may cause a decrease in lorazepam plasma clearance.
Zidovudine: In patients who were seropositive for human immunodeficiency virus (HIV), the clearance of zidovudine was decreased by 38% after administration of valproate; the half-life of zidovudine was unaffected.
Temozolomide: Concomitant use of temozolomide and sodium valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Mefloquine and chloroquine: Increase valproate metabolism and thus epileptic seizures may occur with combined therapy. The dosage of sodium valproate may need adjustment.
Cimetidine or erythromycin: Valproate plasma levels may be increased when used concomitantly with cimetidine or erythromycin as a result of reduced hepatic metabolism.
Cholestyramine: May decrease the absorption of valproate.
Ethosuximide: There is evidence that sodium valproate may inhibit ethosuximide metabolism, particularly in the presence of other anticonvulsants. Patients receiving this combination should be monitored clinically.
Oral contraceptive: Sodium valproate usually has no enzyme-inducing effect; thus, sodium valproate injection does not reduce the efficacy of oestroprogestative agents in women receiving hormonal contraception, including oral contraceptive pill.
Interference with clinical laboratory and other tests: Sodium valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies. This may give false positive in the urine testing of possible diabetics.
There have been reports of altered thyroid function test results associated with sodium valproate. The clinical significance of this is unknown.

 

Caution For Usage

Storage

Action

Anticonvulsants