DEPAKENE Valproic Acid 250mg / 5mL Syrup 120mL

Epilepsy: Valproic acid is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

 

Female children and women of childbearing potential: Valproic Acid must be initiated and supervised preferably by a specialist experienced in the management of epilepsy, mania or prophylaxis of migraine. Valproic Acid should not be used in female children, women of childbearing potential unless other treatments are ineffective or not tolerated.
Valproic Acid is prescribed and dispensed in accordance to the measures for prevention of pregnancy mentioned in Contraindications and Precautions.
After the treating physician determines the suitability of the patient, Valproic Acid should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see Use in Pregnancy & Lactation).
Prophylaxis of migraine attacks: Valproic acid should only be initiated and supervised by a specialist experienced in the management of migraine. Treatment should only be initiated if other treatments are ineffective or not tolerated (see Contraindications, Precautions and Use in Pregnancy & Lactation) and the benefit and risk should be carefully reconsidered at regular treatment reviews.
Patients with renal insufficiency: It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on hemodialysis. Divalproex sodium/Valproate/Valproic acid is dialysable (see Overdosage). Dosing should be modified according to the clinical monitoring of the patient.
Valproic acid is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of ten years, and in simple and complex absence seizures. As the valproic acid dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected (see Interactions).
Complex Partial Seizures (CPS): For adults and children ten years of age or older.
Monotherapy (Initial Therapy): Valproic acid has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day.
The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions (see Thrombocytopenia under Precautions).
Conversion to Monotherapy: Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every two weeks. This reduction may be started at initiation of valproic acid therapy, or delayed by one to two weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy: Valproic acid may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium, no adjustment of carbamazepine or phenytoin dosage was needed (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy (see Interactions).
Simple and Complex Absence Seizures: The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures will range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
As the valproic acid dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected (see Interactions).
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
Table 3 is a guide for the initial daily dose of Valproic acid (15 mg/kg/day): See Table 3.

Conversion from Valproic Acid To Divalproex Sodium: In patients previously receiving valproic acid (Depakene) therapy, divalproex sodium (Depakote) products should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on divalproex sodium products, a dosing schedule of two or three times a day may be elected in selected patients.
General Dosing Advice: Geriatric: Due to a decrease in clearance of unbound valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response (see Somnolence in the Elderly under Precautions and Pharmacology: Pharmacokinetics: Special Population: Geriatric under Actions).
Dose-Related Adverse Events: The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males) (see Thrombocytopenia under Precautions). The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Valproic acid capsules, syrup and tablets are antiepileptics for oral administration.
G.I. Irritation: Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

 

Overdosage

May be taken with or without food: May be taken w/ meals if GI discomfort occurs.

Valproic Acid should not be administered to patients with hepatic disease or significant hepatic dysfunction (see Hepatotoxicity under Precautions).
Valproic Acid is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g. Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder (see Hepatotoxicity under Precautions).
Valproic Acid is contraindicated in Patients with known systemic primary carnitine deficiency with uncorrected hypocarnitinemia (see Patients at risk of hypocarnitinemia under Precautions).
Valproic Acid is contraindicated in patients with known hypersensitivity to the drug (see Multi-Organ Hypersensitivity Reactions under Precautions).
Valproic Acid is contraindicated in patients with known urea cycle disorders (see Hyperammonemia: Urea Cycle Disorders under Precautions).
Valproic Acid is contraindicated in the following situation: Treatment of epilepsy: in pregnancy unless there is no suitable alternative treatment (see Precautions and Use in Pregnancy & Lactation); in women of childbearing potential, unless the measures for prevention of pregnancy as mentioned in Precautions and Use in Pregnancy & Lactation are met.
Treatment of mania and prophylaxis of migraine attacks: in pregnancy (see Precautions and Use in Pregnancy & Lactation); in women of childbearing potential, unless the measures for prevention of pregnancy as mentioned in Precautions and Use in Pregnancy & Lactation are met.
Valproic Acid is contraindicated in patients with porphyria.

 

Warnings

Hepatotoxicity/Hepatic dysfunction: Conditions of occurrence: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents usually have occurred during the first six months of treatment.
Caution should be applied when administering valproic acid products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, those with congenital metabolic disorders including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see Precautions), those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of three years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When valproic acid is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy (seizure control) should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Suggestive signs: 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.
Detection: Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of therapy, especially in patients at risk (refer to Interactions). 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.
The drug 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 (see Contraindications).
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 (see Contraindications).
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, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders.
In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with valproic acid for the development of acute liver injury with regular clinical assessments and liver function test monitoring.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproic acid. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. Patients and guardians experiencing abdominal pain, nausea, vomiting, and/or anorexia should be warned that these could be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.
Suicidal Behavior and Ideation: An increase in the risk of suicidal thoughts or behavior in patients taking antiepileptic drugs (AEDs) for any indication has been reported. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing 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 an increase risk of suicidal thoughts and behavior. Should suicidal thoughts and behaviors 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 (and caregivers of patients), 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 thought about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Interaction with Carbapenem Antibiotics: The concomitant use of INN and carbapenem agents is not recommended (see Carbapenem Antibiotics under Interactions).
Thrombocytopenia: See General as follows.
Hyperammonemia: Hyperammonemia has been reported in association with valproic acid 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 measured.
Hyperammonemia should also be considered in patients who present with hypothermia (see Hypothermia as follows). If ammonia is increased, valproic acid therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders (see Contraindications and Precautions).
Asymptomatic elevations of ammonia are more common and, when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproic acid therapy should be considered.
Urea Cycle Disorders (UCD) hyperammonemia: Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to 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 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 BUN, protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 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 urea cycle disorders (see Contraindications and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use, Patients at risk of hypocarnitinemia as follows and Hepatotoxicity/Hepatic dysfunction as previously mentioned).
Patients at risk of hypocarnitinemia: Valproate administration may trigger occurrence or worsening of hypocarnitinemia that can result in hyperammonaemia (that may lead to hyperammonemic encephalopathy). Other symptoms such as liver toxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis, Fanconi syndrome have been observed, mainly in patients with risk factors for hypocarnitinemia or pre-existing hypocarnitinemia. Valproate may decrease carnitine blood and tissue levels and therefore impair mitochondrial metabolism including the mitochondrial urea cycle. Patients at increased risk for symptomatic hypocarnitinemia when treated with valproate include patients with metabolic disorders including mitochondrial disorders related to carnitine (see also Patients with known or suspected mitochondrial disease and urea cycle disorders and risk of hyperammonemia as previously mentioned), impairment in carnitine nutritional intake, patients younger than 10 years old, concomitant use of pivalate-conjugated medicines or of other antiepileptics.
Patients should be warned to report immediately any signs of hyperammonemia such as ataxia, impaired consciousness, vomiting for further investigation. Carnitine supplementation should be considered when symptoms of hypocarnitinemia are observed.
Patients with known systemic primary carnitine deficiency and corrected for hypocarnitinemia should be treated with valproate only if the benefits of valproate treatment outweigh the risks in these patients and there is no suitable therapeutic alternative. In these patients, close monitoring for recurrence of hypocarnitinemia should be implemented.
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of thegreater risk of rhabdomyolysis when taking valproate. Carnitine supplementation should be considered in these patients. (See also Interactions, Adverse Reactions and Overdosage).
Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use: Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia (see Hypothermia as follows). In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a 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. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons (see Contraindications and Precautions).
Hypothermia: Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproic acid 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 (see Topiramate under Interactions and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use and Hyperammonemia as previously mentioned). 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.
Brain Atrophy: There have been post marketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use valproate products; in some cases, patients recovered with permanent sequelae (see Adverse Reactions). The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be discontinued in the presence of suspected or apparent signs of brain atrophy.
Reports of cerebral atrophy with various forms of neurological problems including developmental delays and psychomotor impairment have also been reported in children who were exposed in-utero to valproate products (see Use in Pregnancy & Lactation).
General: Laboratory tests: Because of reports of thrombocytopenia (see Thrombocytopenia as previously mentioned), 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. Prior to planned surgery, it is recommended that patients receiving valproic acid be monitored for platelet count and coagulation parameters. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since divalproex sodium/valproate sodium may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy (see Interactions).
Valproic acid is partially eliminated in the urine as a keto-metabolite that may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.
Recommendations: Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since divalproex sodium/valproate sodium may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy (see Interactions).
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The therapeutic benefit that may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
It seems prudent not to use valproate sodium in patients with acute head trauma for the prophylaxis of post-traumatic seizures until further information is available.
Multi-Organ Hypersensitivity Reactions: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multi-organ hypersensitivity reactions have been rarely reported in close temporal association after the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40). 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, hepatorenal 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 amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
Information for Female patients: Since valproic acid has been associated with certain types of birth defects and development risk, female patients of childbearing age considering the use of valproic acid should be advised of the risks associated with the use of valproic acid during pregnancy (see Precautions).
Aggravated convulsions: As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately.
Information related to excipients: This medicinal product contains 3 g of sucrose per 5 ml dose sucrose. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
May be harmful to the teeth.
This medicinal product contains Propylhydroxybenzoate E216 and Methylhydroxybenzoate E218. Those may cause allergic reactions (possibly delayed).
This medicinal product contains Sorbitol Solution E420.
Patients with rare hereditary problems of fructose intolerance should not take this medicine. This medicinal product contains E123, amaranth. This may cause allergic reactions.
Effects on Ability to Drive and Use Machines: Since Valproic Acid may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
Use in Children: Experience with oral valproate has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions (see Hepatotoxicity as previously mentioned). When valproic acid injection is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, valproic acid should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium/valproate/valproic acid for the development of acute liver injury with regular clinical assessments and liver function test monitoring.
The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4-day old) and juvenile (14-day old) rats are similar to those seen in young adult rats. However, additional findings, including renal alterations in juvenile rats and renal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosage approximately equivalent to the human maximum recommended daily dose on a mg/m² basis. They were not seen at 90 mg/kg, or 40% of the maximum human daily dose on a mg/m² basis.
Use in the Elderly: No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
Somnolence in the elderly: A study of elderly patients with dementia revealed 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 (see Dosage & Administration).
In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence (see Dosage & Administration).

 

Use In Pregnancy & Lactation

The following adverse reactions possibly related to valproates are displayed by MedDRA system organ class classification. Frequency groupings are classified according to the subsequent conventions: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000) and Not known (cannot be estimated from the available data). (See Table 4.)

Pediatric population: The safety profile of valproate in the pediatric population is comparable to adults, but some adverse reactions are more severe or principally observed in the pediatric population. There is a particular risk of severe liver damage in infants and young children especially under the age of three years. Young children are also at particular risk of pancreatitis. These risks decrease with increasing age (see Pharmacology under Actions).
Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behavior, psychomotor hyperactivity and learning disorder are principally observed in the pediatric population.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

 

Effects of Co-Administered Drugs on Valproate Clearance: Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme-inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
Drugs For Which a Potentially Important Interaction Has Been Observed: Aspirin: A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and in inhibition if metabolism of valproate. Valproate free fraction was increased four-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.
Carbapenem Antibiotics: A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (ertapenem, imipenem, meropenem) and may result in loss of seizure control. The mechanism of this interaction is not well understood. 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.
Cholestyramine: Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
Estrogen-Containing Hormonal Contraceptives: Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products, preferably during on-off intervals of the hormonal contraceptive cycle.
Felbamate: A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentrations by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentrations to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Metamizole: Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.
Methotrexate: Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.
Protease inhibitors: Protease inhibitors such as lopinavir, ritonavir decrease valproate plasma level when co-administered.
Rifampin: A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after five nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.
Drugs For Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed: Antacids: A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac-160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine: A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg b.i.d.) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol: A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg b.i.d.) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine: Cimetidine and ranitidine do not affect the clearance of valproate.
Effects of Valproate on Other Drugs: Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs For Which a Potentially Important Valproate Interaction Has Been Observed: Amitriptyline/Nortriptyline: Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (ten males and five females) who received valproate (500 mg b.i.d.) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide: Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
Clonazepam: The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam: Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide: Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine: In a steady-state study involving ten healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital: Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg b.i.d. for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for 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.
Phenytoin: Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg t.i.d.) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Valproic acid metabolites levels may be increased in case of concomitant use with phenytoin or phenobarbital. Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemia.
Pivalate-conjugated medicines: Concomitant administration of valproate and pivalate-conjugated medicines that decrease carnitine levels (such as cefditoren pivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) may trigger occurrence of hypocarnitinemia (see Patients at risk of hypocarnitinemia under Precautions). Concomitant administration of these medicines with valproate is not recommended. Patients in whom co-administration cannot be avoided should be carefully monitored for signs and symptoms of hypocarnitinemia.
Primidone: Primidone is metabolized into a barbiturate and therefore, may also be involved in a similar interaction with valproate as phenobarbital.
Propofol: A clinically significant interaction between valproate and propofol may occur leading to an increased blood level of propofol. Therefore, when co-administered with valproate, the dose of propofol should be reduced.
Nimodipine: Concomitant treatment of nimodipine with valproic acid may increase nimodipine plasma concentration by 50%.
Tolbutamide: From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.
Cannabidiol: In patients of all ages receiving concomitantly cannabidiol at doses 10 to 25 mg/kg and valproate, clinical trials have reported ALT increases greater than 3 times the upper limit of normal in 19% of patients.
Drug Interaction between valproate and cannabidiol may result in an increased risk of elevation of liver transaminases (see Precautions).
Appropriate liver monitoring should be exercised when valproate is used with cannabidiol, and dose reductions or discontinuation should be considered in case of significant anomalies of liver parameters.
Topiramate and acetazolamide: Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia.
Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.
Concomitant administration of topiramate with valproic acid has also been associated with hypothermia in patients who have tolerated either drug alone. Blood ammonia levels should be measured in patients with reported onset of hypothermia (see Precautions).
Warfarin: In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if divalproex sodium therapy is instituted in patients taking anticoagulants.
Zidovudine: In six patients, who were seropositive for HIV, the clearance of zidovudine (100 mg every eight hours) was decreased by 38% after administration of valproate (250 or 500 mg every eight hours); the half-life of zidovudine was unaffected.
Quetiapine: Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.
Drugs For Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed: Acetaminophen: Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.
Clozapine: In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.
Lithium: Co-administration of valproate (500 mg b.i.d.) and lithium carbonate (300 mg t.i.d.) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam: Concomitant administration of valproate (500 mg b.i.d.) and lorazepam (1 mg b.i.d.) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Olanzapine: Valproic acid may decrease the olanzapine plasma concentration.
Rufinamide: Valproic acid may lead to an increase in plasma level of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.

 

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Anticonvulsants