Epilepsan ECC

Valproic acid.

Each enteric coated caplet contains: Divalproex Sodium equivalent to Valproic Acid 250 mg.
Divalproex sodium is a stable coordination compound comprised of Sodium Valproate and Valproic Acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide.
Divalproex sodium is chemically designated as sodium hydrogen bis (2-propylpentanoate). Divalproex sodium has a molecular weight of 310.41 and occurs as a white powder with a characteristic odor.
Its empirical formula is C₁₆H₃₁NaO₄.

Pharmacotherapeutic group: Anticonvulsant and mood-stabilizing drug. ATC-Code: N03AG01.
Pharmacology: Pharmacodynamics: Mechanism of action and Pharmacodynamic properties: Divalproex sodium dissociates to the Valproate ion in the gastrointestinal tract. The mechanism by which Valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

Epilepsy: Divalproex Sodium caplets are indicated as 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.
Divalproex sodium caplets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients 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.

General: Divalproex Sodium caplets are administered orally and should be swallowed whole, without chewing.
Epilepsy: Divalproex Sodium caplets are indicated as monotherapy and adjunctive therapy in complex partial seizure in adults and pediatric patients down to the age of ten years, and in simple and complex absence seizures in adults and adolescents. As the Divalproex Sodium dosage is titrated upward, concentrations of Phenobarbital, Carbamazepine, and/or Phenytoin may be affected [see INTERACTIONS].
Complex Partial Seizure (CPS): For adults and children ten years of age or older.
Monotherapy (Initial Therapy): Divalproex Sodium 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 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 anti-epilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every two weeks. This reduction may be started at initiation of Divalproex Sodium 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: Divalproex Sodium 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.
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. 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 a tone 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.
As the Divalproex Sodium dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see INTERACTIONS].
Anti-epilepsy 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.
Conversion from Valproic Acid to Divalproex Sodium: In patients previously receiving Valproic Acid therapy, Divalproex Sodium products should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on a Divalproex sodium product, a dosing schedule of two or three times a day may be elected in selected patients.
General dosing advice: Dosing in Elderly Patients: Due to 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 clinical response [see Somnolence in the Elderly under PRECAUTIONS].
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.
G.I Irritations: Patients who experience G.I irritation may benefit from administrations of the drug with food or by slowly building up the dose from an initial low level.

Overdosage with Valproate may result somnolence, heart block, hypotension and circulatory collapse/shock, and deep coma. Fatalities have been reported.
The presence of sodium content in the Valproate formulations may lead to hypernatremia when taken in overdose.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of Valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of Valproate it should be used with caution in patients with epilepsy.

Divalproex Sodium should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Hepatotoxicity under PRECAUTIONS].
Divalproex Sodium 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].
Divalproex Sodium is contraindicated in patients with known hypersensitivity to the drug [see Multi-Organ Hypersensitivity Reactions under PRECAUTIONS].
Divalproex sodium is contraindicated in patients with known urea cycle disorders [see Hyperammonemia - Urea Cycle Disorders under PRECAUTIONS].
Divalproex sodium 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.
Divalproex sodium is contraindicated in patients with porphyria.

HEPATOTOXICITY: General Population: Hepatic failure resulting in fatalities has occurred in patients receiving Valproate and its derivatives. 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 performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see PRECAUTIONS].
Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Valproate 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of Valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndrome caused by DNA mutation of the mitochondrial DNA polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproate is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorders [see CONTRAINDICATIONS]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Valproate should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Valproate for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see PRECAUTIONS].
FETAL RISK: Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, Valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis in migraine [see CONTRAINDICATIONS]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when Valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using Valproate [see PRECAUTIONS].
A Medication Guide describing the risks of Valproate is available for patients [see PATIENT INFORMATION under PRECAUTIONS].
PANCREATITIS: Cases of life-threatening pancreatitis have been reported in both children and adults receiving Valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Valproate should ordinary be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see PRECAUTIONS].
Female children/Female adolescents/Women of childbearing potential/Pregnancy: Divalproex sodium has a high teratogenic potential and children exposed in utero to Divalproex sodium have a high risk for congenital malformations and neuro developmental disorders [see USE IN PREGNANCY & LACTATION]. Divalproex sodium is contraindicated in the following situations: 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 as follows and in CONTRAINDICATIONS and USE IN PREGNANCY & LACTATION are met.
The treating physician must ensure that: Individual circumstances should be evaluated in each case, involving the patient in the discussion, to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.
The potential for pregnancy is assessed for all female patients.
The patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to Divalproex Sodium.
The patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed.
The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception (for further details refer to contraception as follows), without interruption during the entire duration of treatment with Divalproex Sodium.
The patient understands the need for regular (at least annual) review of treatment by the treating physician, preferably by a specialist experienced in the management of epilepsy.
The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception, and before contraception is discontinued.
The patient understands the hazards and necessary precautions associated with Divalproex sodium use and the need to urgently consult her physician in case of pregnancy.
The patient has received the patient guide.
These conditions also concern women who are not currently sexually active unless the treating physician considers that there are compelling reasons to indicate that there is no risk of pregnancy.
Female children: The treating physician must ensure that parents/caregivers of female children understand the need to contact the specialist once the female child using Divalproex sodium experiences menarche.
The treating physician must ensure that parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to Divalproex sodium in utero.
In patients who experienced menarche, the prescribing specialist must reassess the need for Divalproex sodium therapy annually and consider alternative treatment options. If Divalproex sodium is the only suitable treatment, the need for using effective contraception and all other measures as described in CONTRAINDICATIONS, PRECAUTIONS, and USE IN PREGNANCY & LACTATION should be discussed. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach childbearing potential.
Pregnancy must be excluded before start of treatment with Divalproex sodium.
Contraception: Women of childbearing potential who are prescribed Divalproex sodium must use effective contraception, without interruption during the entire duration of treatment with Divalproex sodium. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures. Even if patient has amenorrhea the patient must follow all the advice on effective contraception.
Annual treatment reviews preferably by a specialist: The treating physician should at least annually review whether Divalproex sodium is the most suitable treatment for the patient. The treating physician should ensure the patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to Divalproex sodium in utero.
Pregnancy planning: For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess Divalproex sodium therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued [see USE IN PREGNANCY & LACTATION]. If switching is not possible, the woman should receive further counselling regarding the Divalproex sodium risks for the unborn child to support her informed decision making regarding family planning.
In case of pregnancy: In case of pregnancy, the patient should immediately contact a specialist/ physician to re-evaluate treatment and consider alternative options.
Pharmacist must ensure that: The patients are advised not to stop Divalproex sodium medication and to immediately contact a specialist in case of planned or suspected pregnancy.
WARNING FOR WOMEN AND GIRLS: This medicine can seriously harm an unborn baby. Always use effective contraception during treatment. If the patient is thinking about becoming pregnant, or become pregnant, talk to a doctor straight away. Do not stop taking this medicine unless a doctor tells.

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 observed when administering Divalproex sodium products to patients with a 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. Experience 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. When divalproex sodium 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 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. 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, ophthalmoplegia, 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 Divalproex sodium 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 Divalproex sodium. 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. There were cases of pancreatitis without alternative etiology. Patients and guardians experiencing abdominal pain, nausea, vomiting, and/or anorexia should be warned that this could be a symptom of pancreatitis that requires 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 Divalproex sodium 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 divalproex sodium 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, divalproex sodium 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 as follows].
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.
Urea Cycle Disorders (UCD): 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: 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; Those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance; Those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 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 as follows].
Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use: Concomitant administration of topiramate and valproic acid 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 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 Urea Cycle Disorders and Hyperammonemia as follows].
Hypothermia: Hypothermia, defined as an unintentional drop in body core 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 Divalproex sodium 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: 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 test: 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 divalproex sodium 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 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]. Divalproex Sodium is partially eliminated in the urine as a ketometabolite 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 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].
Valproate stimulates the replication of HIV and CMV viruses under certain conditions. However, this is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, this should be noted when the results of routine viral load monitoring in HIV-infected patients are receiving valproate or when following clinically CMV-infected patients.
Patients with an underlying carnitine palmitoyl transferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate. 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.
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 PATIENTS: Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia could be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.
Patients and guardians should be informed of the signs and symptoms associated with hyperammonemic encephalopathy [see Hyperammonemia as previously mentioned] and be told to inform the prescriber if any of these symptoms occur.
Information for Female Patients: Since divalproex sodium has been associated with certain types of birth defects and developmental risk, female patients of childbearing age considering the use of Divalproex Sodium should be advised of the risks associated with the use of Divalproex Sodium during pregnancy [see Female children/Female adolescents/Women of childbearing potential/Pregnancy under WARNINGS].
Medication residue in the stool: There have been rare reports of medication residue in the stool, some of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients' clinical condition should be monitored. If clinically indicated, alternative treatment may be considered.
Effects on ability to drive and use machines: Since divalproex sodium 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 has indicated that pediatric patients 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 Divalproex Sodium 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.
The safety and effectiveness of Divalproex Sodium for the treatment of acute mania has not been studied in individuals below the age of 18 years.
The safety and effectiveness of Divalproex Sodium for the prophylaxis of migraines has not been studied in individuals below the age of 16 years.
Use in the Elderly: Patients over the age of 65 have higher percentage to accidental injury, infection, pain, somnolence, and tremor.
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].

Fertility, Pregnancy and lactation: Divalproex sodium is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy. Divalproex Sodium is contraindicated for use in women of childbearing potential unless the measures for prevention of pregnancy as mentioned in CONTRAINDICATIONS and PRECAUTIONS are met.
Valproate was shown to cross the placental barrier both in animal species and in humans.
Pregnancy Exposure Risk related to Divalproex Sodium: Both valproate monotherapy and Divalproex Sodium polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including Divalproex Sodium is associated with a greater risk of congenital malformations than Divalproex Sodium monotherapy.
Congenital malformations: Children of epileptic women exposed to Valproate monotherapy during pregnancy suffer from congenital malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
In utero exposure to Valproate may also result in hearing impairment/loss due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function.
Cases describe both unilateral and bilateral deafness or hearing impairment. Monitoring of signs and symptoms of ototoxicity is recommended.
Developmental disorders: Exposure to Divalproex Sodium in utero can have adverse effects on mental and physical development of the exposed children. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to Divalproex Sodium that the risk of intellectual impairment may be independent from maternal IQ. Children exposed to Valproate in utero are at increased risk of autistic spectrum disorder, childhood autism, and increased risk of developing attention deficit/hyperactivity disorder (ADHD).
Female children, female adolescents and woman of childbearing potential: If a Woman wants to plan a Pregnancy: For epilepsy indication: During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
For epilepsy indication: In women planning to become pregnant or who are pregnant, valproate therapy should be reassessed.
For epilepsy indication: If a woman plans a pregnancy or becomes pregnant, valproate therapy should be stopped.
For epilepsy indication: In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.
If a woman plans a pregnancy: For the indication epilepsy, if a woman is planning to become pregnant, a specialist (preferably) experienced in the management of epilepsy, must reassess Divalproex Sodium. Valproic Acid therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued [see PRECAUTIONS]. If switching is not possible, the woman should receive further counselling regarding the Divalproex Sodium risks for the unborn child to support her informed decision making regarding family planning.
Pregnant women: Divalproex sodium as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment [see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS], as evaluated and decided by the treating physician. If a woman using Divalproex Sodium becomes pregnant, she must be immediately referred to a specialist (preferably) to consider alternative treatment options. During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
If, despite the known risks of Divalproex Sodium in pregnancy and after careful consideration of alternative treatment preferably by the specialist, in exceptional circumstances a pregnant woman must receive Divalproex Sodium for epilepsy, it is recommended to: Use the lowest effective dose and divide the daily dose of Divalproex Sodium into several small doses to be taken throughout the day. The use of a prolonged release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations [see DOSAGE & ADMINISTRATION].
Fetal Risk: Valproate can cause major congenital malformations, particularly neural tube defects (e.g spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposures. All patients with a Divalproex Sodium exposed pregnancy and their partners should consider specialized prenatal monitoring to detect the possible occurrence of neural tube defects or other malformations. The available evidence does not suggest that folate supplementation before the pregnancy may prevent the risk of neural tube defects which may occur in all pregnancies.
Risk in the neonate: Cases of hemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken Divalproex Sodium during pregnancy. This hemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Cases of hypoglycaemia have been reported in neonates whose mothers have taken Divalproex Sodium during the third trimester of their pregnancy.
Cases of hypothyroidism have been reported in neonates whose mothers have taken Divalproex Sodium during pregnancy.
Withdrawal syndrome (such as, in particular, agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.
Lactation: Divalproex Sodium is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Hematological disorders have been shown in breastfed newborns/infants of treated women. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Divalproex Sodium therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using Divalproex Sodium [see ADVERSE REACTIONS]. Divalproex Sodium administration may also impair fertility in men. Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.

Epilepsy: Complex Partial Seizure (CPS): Divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity.
The following are adverse events in patients treated with Divalproex sodium: Body as a whole: Back pain, chest pain, malaise.
Cardiovascular: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
Other Patient Populations: Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Obesity is rare. Diarrhea, abdominal cramps, constipation and gingival disorder (mainly gingival hyperplasia) have been reported. Both anorexia with some weight loss and increased appetite wait weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.
Central Nerve System (CNS) Effects: Sedative effects have occurred in patients receiving Valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor may be dose-related, hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, memory impairment, cognitive disorder, and extrapyramidal disorders including parkinsonism have been reported with the use of Valproate. Rare cases of coma have occurred in patients receiving Valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of Valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma Valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Urea Cycle Disorders, Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use, and Hyperammonemia under PRECAUTIONS]. Additionally, there have been reports of encephalopathy in the absence of elevated ammonia levels.
Reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of Valproate products. In some cases the patients recovered with permanent sequelae [see Brain Atrophy under PRECAUTIONS]. Cerebral atrophy seen in children exposed to Valproate in utero led to various forms of neurological events, including developmental delays and psychomotor impairment. Congenital malformations and developmental disorders have been as well reported [see USE IN PREGNANCY & LACTATION].
Dermatologic: Transient hair loss, hair disorders (such as hair texture abnormal, hair colour changes, hair growth abnormal) skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been discovered including a fatal case in a six-month-old infant taking Valproate and several other concomitant medications. Toxic epidermal necrosis resulting in death occurs in a patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been discovered with concomitant administration of Lamotrigine and Valproate [see INTERACTIONS]. Nail and nail bed disorders.
Psychiatric: Emotional upset, depression, psychosis, aggression, psychomotor hyperactivity, hostility, agitation, disturbance in attention, abnormal behavior, learning disorders, and behavioral deterioration.
Musculoskeletal: Weakness: There are decreased bone mass, potentially leading to osteoporosis and osteopenia, during long-term therapy with anticonvulsant medications, including Valproate. Some studies have indicated that supplemental calcium and vitamin D may be of benefit to patients who are on chronic Valproate therapy.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and hemorrhage [see General under PRECAUTIONS and Warfarin under INTERACTIONS]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminase (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Hepatotoxicity under PRECAUTIONS].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Hyperandrogenism (hirsutism, virilism, acnea, male pattern alopecia, and/or androgen increased). Abnormal thyroid function tests including hypothyroidism [see General under PRECAUTIONS]. There have been rare spontaneous reports of polycystic ovary disease, but a cause and effect relationship has not been established.
Pancreatic: Acute pancreatitis including fatalities [see Pancreatitis under PRECAUTIONS].
Metabolic: Hyperammonemia [see Hyperammonemia under PRECAUTIONS], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is unknown. Hyperglycinemia (elevated plasma glycine concentration) has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.
Insulin resistance and dyslipidemia also may occur.
Genitourinary: Enuresis, renal failure, tubulointerstitial nephritis and urinary tract infection.
Reproductive: Male infertility including azoospermia, abnormal semen analysis, decrease sperm count, spermatozoa morphology abnormal, aspermia, and decrease spermatozoa motility have been reported.
Special Senses: Hearing loss, either reversible or irreversible, has been reported. However, a cause and effect relationship has not been established. Ear pain has also been reported.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Myelodysplastic syndrome.
Respiratory, thoracic and mediastinal disorders: Pleura effusion.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, rhabdomyolysis, biotin deficiency/biotinidase deficiency, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
Other patient population: Extrapyramidal disorders and encephalopathy in the absence of elevated ammonia levels.

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-life and higher concentrations than patients receiving polytherapy with anti-epilepsy 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 betaoxidation.
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.
Drug For Which Potentially Important Interaction: 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 [see Interactions with Carbapenem Antibiotics under PRECAUTIONS].
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 decrease in Valproate dosage may be necessary when felbamate therapy is initiated.
Rifampicin: Valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Protease Inhibitors: Protease inhibitors such as lopinavir, ritonavir decrease Valproate plasma level when coadministered.
Cholestyramine: Cholestyramine may lead to a decrease in plasma level of Valproate when coadministered.
Drugs For Which Either No Interaction or a Likely Clinically Unimportant Interaction: Antacids: Valproate did not reveal any effect on the extent of absorption of Valproate.
Chlorpromazine: Increase plasma levels of Valproate.
Haloperidol: Revealed no significant changes in Valproate through 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 glucuronyl transferases.
The following list provides information about the potential for an influence of Valproate coadministration 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: Amitriptyline/Nortriptyline: 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/nortripytline in the presence of Valproate.
Carbamazepine/Carbamazepine-10,11-Epoxide: Serum levels of Carbamazepine (CBZ) decreased while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 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. The elimination half-life of diazepam remained unchanged upon addition of Valproate.
Ethosuximide: Valproate inhibits the metabolism of Ethosuximide. Patients receiving Valproate and Ethosuximide, especially along with other anticonvulsants should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine: 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. 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.
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.
Phenytoin: Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. 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 serum 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.
Nimodipine: Concomitant treatment of nimodipine with Valproic acid may increase nimodipine plasma concentration.
Tolbutamide: The unbound fraction of tolbutamide was increased in patients treated with Valproate.
Topiramate and Acetazolamide: Concomitant administration of Valproate and topiramate or acetazolamide has been associated with hyperammonemia with and without encephalopathy. 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 Hypothermia and Hyperammonemia under PRECAUTIONS].
Warfarin: Valproate increased the unbound fraction of warfarin. The therapeutic relevance of this is unknown. However, coagulation tests should be monitored if divalproex sodium therapy is instituted in patients taking anticoagulants.
Zidovudine: The clearance of zidovudine was decreased after administration of Valproate. 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: Acetaminophen: Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to epileptic patients.
Clozapine: In psychotic patients, no interaction was observed when Valproate was coadministered 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 Valproate and Lorazepam decrease the plasma clearance of Lorazepam.
Olanzapine: Valproate 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.
Oral Contraceptive Steroids: Administration of ethinyloestradiol or levonorgestrel on Valproate therapy did not reveal any pharmacokinetic interaction.

INCOMPATIBILITIES: Not applicable.

Store below 30°C.
SHELF-LIFE: 2 years.

Anticonvulsants

N03AG01 - valproic acid ; Belongs to the class of fatty acid derivatives antiepileptic.

G