EPIVAL Divalproex Sodium 250mg Enteric-Coated Tablet 100's
RXDRUG-DR-XY34509
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Features
Brand
Epival
Full Details
Dosage Strength
250 mg
Drug Ingredients
- Divalproex
Drug Packaging
Enteric-Coated Tablet 100's
Generic Name
Divalproex Sodium
Dosage Form
Enteric-Coated Tablet
Registration Number
DR-XY34509
Drug Classification
Prescription Drug (RX)
Description
Indications/Uses
Epilepsy: Divalproex sodium enteric coated tablets are indicated as monotherapy and adjunctive therapy in the treatment of adults and children 10 years or older with complex partial seizures that occur either in isolation or in association with other types of seizures.
Divalproex sodium tablets are also 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.
Mania: Divalproex sodium tablets are indicated for the treatment of the acute manic or mixed episodes associated with bipolar disorder.
A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility.
The efficacy of divalproex sodium was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
The safety and effectiveness of divalproex sodium for long-term use in mania, i.e., more than three weeks, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use divalproex sodium for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.
Migraine: Divalproex sodium tablets are indicated for prophylaxis of migraine headaches. There is no evidence that divalproex sodium is useful in the acute treatment of migraine headaches.
Because valproic acid may be a hazard to the fetus, divalproex sodium should not be considered for women of childbearing potential unless the drug is essential to the management of her medical condition (see Precautions). Divalproex sodium is contraindicated for use in prophylaxis of migraine headaches in pregnant women (see Contraindications and Precautions).
Divalproex sodium tablets are also 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.
Mania: Divalproex sodium tablets are indicated for the treatment of the acute manic or mixed episodes associated with bipolar disorder.
A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility.
The efficacy of divalproex sodium was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
The safety and effectiveness of divalproex sodium for long-term use in mania, i.e., more than three weeks, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use divalproex sodium for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.
Migraine: Divalproex sodium tablets are indicated for prophylaxis of migraine headaches. There is no evidence that divalproex sodium is useful in the acute treatment of migraine headaches.
Because valproic acid may be a hazard to the fetus, divalproex sodium should not be considered for women of childbearing potential unless the drug is essential to the management of her medical condition (see Precautions). Divalproex sodium is contraindicated for use in prophylaxis of migraine headaches in pregnant women (see Contraindications and Precautions).
Dosage/Direction for Use
Female children and women of childbearing potential: Divalproex sodium must be initiated and supervised preferably by a specialist experienced in the management of epilepsy, mania or prophylaxis of migraine. Divalproex sodium should not be used in female children, women of childbearing potential unless other treatments are ineffective or not tolerated.
Divalproex sodium 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 (according to Dosage & Administration), Divalproex sodium 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: Divalproex sodium 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.
General: Divalproex sodium tablets are administered orally and should be swallowed whole, without chewing.
Epilepsy: Divalproex sodium tablets are 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 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 Seizures (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 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 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.
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 divalproex sodium 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.
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 a divalproex sodium product, a dosing schedule of two or three times a day may be elected in selected patients.
Female children, female adolescents, women of childbearing potential and pregnant women Divalproex sodium should be initiated and supervised by a specialist experienced in the management of epilepsy. Treatment should only be initiated if other treatments are ineffective or not tolerated and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably divalproex sodium should be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation to avoid high peak plasma concentrations. The daily dose should be divided into at least two single doses.
Mania: The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during divalproex sodium treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the benefits of divalproex sodium in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with divalproex sodium, the safety of divalproex sodium in long-term use is supported by data from record reviews involving approximately 360 patients treated with divalproex sodium for greater than three months.
Migraine: The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. Divalproex sodium 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 and the benefit and risk should be carefully reconsidered at regular treatment reviews.
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 clinical response (see Somnolence in the Elderly under Precautions and Pharmacology: Pharmacokinetics: 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.
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.
Divalproex sodium 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 (according to Dosage & Administration), Divalproex sodium 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: Divalproex sodium 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.
General: Divalproex sodium tablets are administered orally and should be swallowed whole, without chewing.
Epilepsy: Divalproex sodium tablets are 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 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 Seizures (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 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 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.
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 divalproex sodium 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.
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 a divalproex sodium product, a dosing schedule of two or three times a day may be elected in selected patients.
Female children, female adolescents, women of childbearing potential and pregnant women Divalproex sodium should be initiated and supervised by a specialist experienced in the management of epilepsy. Treatment should only be initiated if other treatments are ineffective or not tolerated and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably divalproex sodium should be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation to avoid high peak plasma concentrations. The daily dose should be divided into at least two single doses.
Mania: The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during divalproex sodium treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the benefits of divalproex sodium in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with divalproex sodium, the safety of divalproex sodium in long-term use is supported by data from record reviews involving approximately 360 patients treated with divalproex sodium for greater than three months.
Migraine: The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. Divalproex sodium 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 and the benefit and risk should be carefully reconsidered at regular treatment reviews.
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 clinical response (see Somnolence in the Elderly under Precautions and Pharmacology: Pharmacokinetics: 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.
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
Overdosage with valproate may result in somnolence, heart block, hypotension and circulatory collapse/shock, and deep coma. Fatalities have been reported; however, patients have recovered from valproate levels as high as 2,120 mcg/mL.
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.
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.
Administration
Should be taken with food: Swallow whole, do not chew/crush.
Contraindications
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.
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.
Divalproex sodium is contraindicated in patients with porphyria.
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.
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.
Divalproex sodium is contraindicated in patients with porphyria.
Warnings
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 neurodevelopmental 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 mentioned as follows and in Contraindications 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 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 minimize 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 in utero.
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 please 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, or mania or prophylaxis of migraine.
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 child bearing 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 she has amenorrhea she 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.
For the indications mania and prophylaxis of migraine, if a woman is planning to become pregnant a specialist experienced in the management of mania and prophylaxis of migraine must be consulted and treatment with Divalproex sodium should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
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.
Educational materials: In order to assist healthcare professionals and patients in avoiding exposure to Divalproex sodium during pregnancy, the Marketing Authorization Holder has provided educational materials like a physician guide to reinforce the warnings and provide guidance regarding use of Divalproex sodium in women of childbearing potential and the details of the pregnancy prevention programme. A patient guide should be provided to all women of childbearing potential using Divalproex sodium.
Visual Reminder on outer packaging: In order to inform and remind patients about avoiding exposure to Divalproex sodium during pregnancy, the Marketing Authorization Holder has added a pictogram and warning to its outer packaging.
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 becomes pregnant, talk to a doctor straight away.
Do not stop taking this medicine unless the doctor tells to.
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 mentioned as follows and in Contraindications 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 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 minimize 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 in utero.
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 please 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, or mania or prophylaxis of migraine.
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 child bearing 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 she has amenorrhea she 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.
For the indications mania and prophylaxis of migraine, if a woman is planning to become pregnant a specialist experienced in the management of mania and prophylaxis of migraine must be consulted and treatment with Divalproex sodium should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
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.
Educational materials: In order to assist healthcare professionals and patients in avoiding exposure to Divalproex sodium during pregnancy, the Marketing Authorization Holder has provided educational materials like a physician guide to reinforce the warnings and provide guidance regarding use of Divalproex sodium in women of childbearing potential and the details of the pregnancy prevention programme. A patient guide should be provided to all women of childbearing potential using Divalproex sodium.
Visual Reminder on outer packaging: In order to inform and remind patients about avoiding exposure to Divalproex sodium during pregnancy, the Marketing Authorization Holder has added a pictogram and warning to its outer packaging.
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 becomes pregnant, talk to a doctor straight away.
Do not stop taking this medicine unless the doctor tells to.
Special Precautions
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 divalproex sodium products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, 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/valproate/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. 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.
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 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 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).
Asymptomatic elevations of ammonia are more common and, when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of divalproex sodium 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: 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 as follows).
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).
Hypothermia: Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with divalproex sodium 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 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 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 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.
Patients with an underlying carnitine palmitoyltransferase (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.
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, has 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, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs not noted here may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
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.
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.
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.
Information for Female patients: Since divalproex sodium has been associated with certain types of birth defects and development 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 Warnings).
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 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.
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.
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.
The safety and effectiveness of divalproex sodium enteric coated tablets 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 enteric coated tablets for the prophylaxis of migraines has not been studied in individuals below the age of 16 years.
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).
Divalproex sodium EC tablets and ER tablets: There is insufficient information available to discern the safety and effectiveness of divalproex sodium for the prophylaxis of migraines in patients over 65.
Caution should be applied when administering divalproex sodium products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, 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/valproate/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. 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.
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 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 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).
Asymptomatic elevations of ammonia are more common and, when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of divalproex sodium 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: 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 as follows).
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).
Hypothermia: Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with divalproex sodium 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 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 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 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.
Patients with an underlying carnitine palmitoyltransferase (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.
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, has 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, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs not noted here may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
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.
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.
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.
Information for Female patients: Since divalproex sodium has been associated with certain types of birth defects and development 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 Warnings).
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 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.
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.
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.
The safety and effectiveness of divalproex sodium enteric coated tablets 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 enteric coated tablets for the prophylaxis of migraines has not been studied in individuals below the age of 16 years.
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).
Divalproex sodium EC tablets and ER tablets: There is insufficient information available to discern the safety and effectiveness of divalproex sodium for the prophylaxis of migraines in patients over 65.
Use In Pregnancy & Lactation
Divalproex sodium is contraindicated as treatment for mania and prophylaxis of migraine during pregnancy. 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 (see Pharmacology: Pharmacokinetics under Actions).
Pregnancy: 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: Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to Divalproex sodium monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16-13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established based on available data.
Available data show an increased incidence of minor and major 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: Data have shown that exposure to Divalproex sodium in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
Studies in preschool children exposed in utero to Divalproex sodium show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems, possibly indicating neurodevelopmental disorders.
Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics.
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.
There are limited data on the long term outcomes.
Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.
Available data suggest that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the general population.
Female children, female adolescents and woman of childbearing potential (see Precautions): 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 and/or mania/bipolar disorder indication: In women planning to become pregnant or who are pregnant, valproate therapy should be reassessed.
For epilepsy and/or mania/bipolar disorder indication: If a woman plans a pregnancy or becomes pregnant, valproate therapy should be stopped.
For epilepsy and/or mania/bipolar disorder 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 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.
For the indication(s) mania and prophylaxis of migraine, if a woman is planning to become pregnant, preferably a specialist experienced in the management of mania or prophylaxis of migraine must be consulted and treatment with Divalproex sodium should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
Pregnant women: Divalproex sodium as treatment for mania and prophylaxis of migraine attacks is contraindicated for use during pregnancy. Divalproex sodium as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see Contraindications 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).
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 hypoglycemia 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, hyper-excitability, 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.
Breastfeeding: 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 (see Adverse Reactions).
A decision must be made whether to discontinue breast-feeding 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: Amenorrhea, 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 (see Adverse Reactions). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.
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 (see Pharmacology: Pharmacokinetics under Actions).
Pregnancy: 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: Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to Divalproex sodium monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16-13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established based on available data.
Available data show an increased incidence of minor and major 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: Data have shown that exposure to Divalproex sodium in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
Studies in preschool children exposed in utero to Divalproex sodium show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems, possibly indicating neurodevelopmental disorders.
Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics.
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.
There are limited data on the long term outcomes.
Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.
Available data suggest that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the general population.
Female children, female adolescents and woman of childbearing potential (see Precautions): 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 and/or mania/bipolar disorder indication: In women planning to become pregnant or who are pregnant, valproate therapy should be reassessed.
For epilepsy and/or mania/bipolar disorder indication: If a woman plans a pregnancy or becomes pregnant, valproate therapy should be stopped.
For epilepsy and/or mania/bipolar disorder 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 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.
For the indication(s) mania and prophylaxis of migraine, if a woman is planning to become pregnant, preferably a specialist experienced in the management of mania or prophylaxis of migraine must be consulted and treatment with Divalproex sodium should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
Pregnant women: Divalproex sodium as treatment for mania and prophylaxis of migraine attacks is contraindicated for use during pregnancy. Divalproex sodium as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see Contraindications 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).
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 hypoglycemia 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, hyper-excitability, 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.
Breastfeeding: 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 (see Adverse Reactions).
A decision must be made whether to discontinue breast-feeding 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: Amenorrhea, 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 (see Adverse Reactions). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.
Adverse Reactions
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 5.)
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation 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.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation 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.
Drug Interactions
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.
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.
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.
Protease inhibitors: Protease inhibitors such as lopinavir, ritonavir decrease valproate plasma level when co-administered.
Cholestyramine: Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
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/nortripytline 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.
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.
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.
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.
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.
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.
Protease inhibitors: Protease inhibitors such as lopinavir, ritonavir decrease valproate plasma level when co-administered.
Cholestyramine: Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
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/nortripytline 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.
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.
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.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 30°C.
Shelf life: 24 months.
Shelf life: 24 months.
Action
Pharmacotherapeutic group: Anticonvulsant and mood-stabilizing drug. ATC-Code: N03AG01.
Pharmacology: Pharmacodynamics: Valproic acid is a carboxylic acid. Other chemical names for this compound are 2-propylpentanoic acid, 2-propylvaleric acid and n-dipropylacetic acid. Valproic acid (pKa 4.8) is a colorless liquid with a characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents. Its empirical formula is C8H16O2 and has a molecular weight of 144.
Valproate sodium is the sodium salt of valproic acid and is chemically designated as sodium 2-propylpentanoate. Valproate sodium has a molecular weight of 166.2. It occurs as an essentially white and odorless, crystalline, deliquescent powder.
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.
Mechanism of action: Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms 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).
Description of clinical studies: Epilepsy: Complex Partial Seizures (CPS): The studies described in the following section were conducted using divalproex sodium tablets.
The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per eight weeks during an 8-week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range", were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. Table 1 presents the findings. (See Table 1).
Figure 1 presents the proportion of patients (X-axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y-axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium than for placebo. For example, 45% of patients treated with divalproex sodium had a ≥50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. (See Figure 1.)
The second study assessed the capacity of divalproex sodium to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if: 1) they continued to experience two or more CPS per four weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone); and 2) they made a successful transition over a two week interval to divalproex sodium. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to divalproex sodium monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
Table 2 presents the findings for all patients randomized who had at least one post-randomization assessment. (See Table 2.)
Figure 2 presents the proportion of patients (X-axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y-axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose divalproex sodium than for low dose divalproex sodium. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose divalproex sodium monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose divalproex sodium. (See Figure 2.)
In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males).
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age was 83 years old), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN.
Migraine: The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial demonstrated the effectiveness of divalproex sodium extended-release in the prophylactic treatment of migraine headache. This trial recruited patients with a history of migraine headaches with or without aura occurring on average twice or more a month for the preceding three months. Patients with cluster or chronic daily headaches were excluded. Women of childbearing potential were allowed in the trial if they were deemed to be practicing an effective method of contraception.
Patients who experienced ≥ two migraine headaches in the four-week baseline period were randomized in a 1:1 ratio to divalproex sodium extended-release or placebo and treated for twelve weeks. Patients initiated treatment on 500 mg once daily for one week, and were then increased to 1,000 mg once daily with an option to permanently decrease the dose back to 500 mg once daily during the second week of treatment if intolerance occurred. Ninety-eight of 114 divalproex sodium extended-release-treated patients (86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the 1,000 mg once daily dose for the duration of their treatment periods.
Treatment outcome was assessed on the basis of reduction in four-week migraine headache rate in the treatment period compared to the baseline period.
Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with divalproex sodium extended-release (n=122) or placebo (n=115). Four patients were below the age of 18 and three were above the age of 65.
Two hundred and two patients (101 in each treatment group) completed the treatment period. The mean reduction in four-week migraine headache rate was 1.2 from a baseline mean of 4.4 in the divalproex sodium extended-release group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The treatment difference was statistically significant (see Figure 3).
Mania: The effectiveness of divalproex sodium for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies.
Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Divalproex sodium was initiated at a dose of 250 mg t.i.d. and adjusted to achieve serum valproate concentrations in a range of 50 to 100 mcg/mL by day 7. Mean divalproex sodium doses for completers in this study were 1,118, 1,525, and 2,402 mg/kg/day at days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0 to 60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the week 3 endpoint (last-observation-carry-forward) analysis were as follows: See Table 3.
Divalproex sodium was statistically significantly superior to placebo on all three measures of outcome.
Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Divalproex sodium was initiated at a dose of 250 mg t.i.d. and adjusted within a dose range of 750 to 2,500 mg/day to achieve serum valproate concentrations in a range of 40 to 150 mcg/mL. Mean divalproex sodium doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at days 7, 14, and 21, respectively.
Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11 to 63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the week 3 endpoint (last-observation-carry-forward) analysis were as follows: See Table 4.
Divalproex sodium was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender.
A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 4. (See Figure 4.)
Migraine: The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of divalproex sodium in the prophylactic treatment of migraine headache.
Both studies employed essential identical designs and recruited patients with a history of migraine with or without aura (of at least six months in duration) who were experiencing at least two migraine headaches a month during the three months prior to enrollment. Patients with cluster headaches were excluded.
Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to divalproex sodium or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, divalproex sodium to placebo. Ninety patients completed the 8-week maintenance period.
Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on divalproex sodium, doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (t.i.d.). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL.
The mean 4-week migraine headache rates during the treatment phase was 5.7 in the placebo group compared to 3.5 in the divalproex sodium group (see Figure 5). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three divalproex sodium dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (b.i.d.). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every four days (eight days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the divalproex sodium 500, 1,000, and 1,500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the divalproex sodium 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 5). Migraine headache rates in the combined divalproex sodium 1,000/1,500 mg group were significantly lower than in the placebo group. (See Figure 5.)
Pharmacokinetics: Absorption/Bioavailability: Divalproex sodium Enteric coated tablets; Divalproex sodium sprinkle capsules; valproic acid capsules, syrup and tablets: Equivalent oral doses of divalproex sodium (Depakote) products and valproic acid (Depakene) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint.
(Whether or not rate of absorption of divalproex sodium enteric coated tablets influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.)
Co-administration of oral valproate products with food and substitution among the various divalproex sodium and valproic acid formulations should cause no clinical problems in the management of patients with epilepsy (see Dosage & Administration). Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution: Protein Binding: The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) (see Interactions for more detailed information on the pharmacokinetic interactions of valproate with other drugs).
CNS Distribution: Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).
Placental transfer (see Use in Pregnancy & Lactation): Valproate crosses the placental barrier in animal species and in humans: In animal species, valproate crosses the placenta, to a similar extent as in humans.
In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.
Metabolism: Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15 to 20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Excretion: Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half -life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations: Neonates: Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than two months.
Geriatric: The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction of valproate is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly (see Dosage & Administration).
Pediatric: Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.
Gender: There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Ethnicity: The effects of ethnicity on the kinetics of valproate have not been studied.
Renal impairment: A slight reduction (27%) in the clearance of unbound valproate has been reported in patients with renal failure (creatinine clearance <10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
Hepatic impairment: See Contraindications and Hepatotoxicity under Precautions.
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in seven patients with cirrhosis and by 16% in four patients with acute hepatitis, compared to six healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Plasma Levels and Clinical Effect: The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate that affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Mania: In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL (see Dosage & Administration).
Epilepsy: The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
Equivalent doses of valproate sodium and divalproex sodium yield equivalent plasma levels of the valproate ion.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenesis: The 2-year carcinogenicity studies were conducted in mice and rats given oral valproate doses of approximately 80 and 160 mg/kg/day (which are the maximum tolerated doses in these species but less than the maximum recommended human dose based on body surface area). Subcutaneous fibrosarcomas were observed in male rats and hepatocellular carcinomas and bronchiolo-alveolar adenomas were observed in male mice at incidences slightly higher than concurrent study controls but comparable to historical control data.
Mutagenesis: Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Valproate was not mutagenic in bacteria (Ames test) or mouse lymphoma L5178Y cells at thymidine kinase locus (mouse lymphoma assay) and did not induce DNA repair activity in primary culture of rat hepatocytes. It did not induce either chromosome aberrations in rat bone marrow or dominant lethal effects in mice after oral administration.
In literature, after intraperitoneal exposure to valproate, increased incidences of DNA and chromosome damage (DNA strand-breaks, chromosomal aberrations or micronuclei) have been reported in rodents. However, the relevance of the results obtained with the intraperitoneal route of administration is unknown.
Statistically significant higher incidences of sister-chromatid exchange (SCE) have been observed in patients exposed to valproate as compared to healthy subjects not exposed to valproate. However, these data may have been impacted by confounding factors. Two published studies examining SCE frequency in epileptic patients treated with valproate versus untreated epileptic patients, provided contradictory results. The biological significance of an increase in SCE frequency is not known.
Impairment of Fertility and developmental toxicity: Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on a mg/m2 basis). Segment I fertility studies in rats have shown oral doses up to 350 mg/kg/day (approximately equal to the maximum human daily dose on a mg/m2 basis) for 60 days to have no effect on fertility. Teratogenic effects (malformations of multiple organ systems) have been demonstrated in mice, rats, and rabbits. In published literature, behavioral abnormalities have been reported in first generation offspring of mice and rats after in utero exposure to clinically relevant doses/exposures of valproate. In mice, behavioral changes have also been observed in the 2nd and 3rd generations, albeit less pronounced in the 3rd generation, following an acute in utero exposure of the first generation. The relevance of these findings for humans is unknown.
Pharmacology: Pharmacodynamics: Valproic acid is a carboxylic acid. Other chemical names for this compound are 2-propylpentanoic acid, 2-propylvaleric acid and n-dipropylacetic acid. Valproic acid (pKa 4.8) is a colorless liquid with a characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents. Its empirical formula is C8H16O2 and has a molecular weight of 144.
Valproate sodium is the sodium salt of valproic acid and is chemically designated as sodium 2-propylpentanoate. Valproate sodium has a molecular weight of 166.2. It occurs as an essentially white and odorless, crystalline, deliquescent powder.
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.
Mechanism of action: Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms 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).
Description of clinical studies: Epilepsy: Complex Partial Seizures (CPS): The studies described in the following section were conducted using divalproex sodium tablets.
The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per eight weeks during an 8-week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range", were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. Table 1 presents the findings. (See Table 1).
Figure 1 presents the proportion of patients (X-axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y-axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium than for placebo. For example, 45% of patients treated with divalproex sodium had a ≥50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. (See Figure 1.)
The second study assessed the capacity of divalproex sodium to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if: 1) they continued to experience two or more CPS per four weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone); and 2) they made a successful transition over a two week interval to divalproex sodium. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to divalproex sodium monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
Table 2 presents the findings for all patients randomized who had at least one post-randomization assessment. (See Table 2.)
Figure 2 presents the proportion of patients (X-axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y-axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose divalproex sodium than for low dose divalproex sodium. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose divalproex sodium monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose divalproex sodium. (See Figure 2.)
In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males).
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age was 83 years old), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN.
Migraine: The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial demonstrated the effectiveness of divalproex sodium extended-release in the prophylactic treatment of migraine headache. This trial recruited patients with a history of migraine headaches with or without aura occurring on average twice or more a month for the preceding three months. Patients with cluster or chronic daily headaches were excluded. Women of childbearing potential were allowed in the trial if they were deemed to be practicing an effective method of contraception.
Patients who experienced ≥ two migraine headaches in the four-week baseline period were randomized in a 1:1 ratio to divalproex sodium extended-release or placebo and treated for twelve weeks. Patients initiated treatment on 500 mg once daily for one week, and were then increased to 1,000 mg once daily with an option to permanently decrease the dose back to 500 mg once daily during the second week of treatment if intolerance occurred. Ninety-eight of 114 divalproex sodium extended-release-treated patients (86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the 1,000 mg once daily dose for the duration of their treatment periods.
Treatment outcome was assessed on the basis of reduction in four-week migraine headache rate in the treatment period compared to the baseline period.
Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with divalproex sodium extended-release (n=122) or placebo (n=115). Four patients were below the age of 18 and three were above the age of 65.
Two hundred and two patients (101 in each treatment group) completed the treatment period. The mean reduction in four-week migraine headache rate was 1.2 from a baseline mean of 4.4 in the divalproex sodium extended-release group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The treatment difference was statistically significant (see Figure 3).
Mania: The effectiveness of divalproex sodium for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies.
Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Divalproex sodium was initiated at a dose of 250 mg t.i.d. and adjusted to achieve serum valproate concentrations in a range of 50 to 100 mcg/mL by day 7. Mean divalproex sodium doses for completers in this study were 1,118, 1,525, and 2,402 mg/kg/day at days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0 to 60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the week 3 endpoint (last-observation-carry-forward) analysis were as follows: See Table 3.
Divalproex sodium was statistically significantly superior to placebo on all three measures of outcome.
Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Divalproex sodium was initiated at a dose of 250 mg t.i.d. and adjusted within a dose range of 750 to 2,500 mg/day to achieve serum valproate concentrations in a range of 40 to 150 mcg/mL. Mean divalproex sodium doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at days 7, 14, and 21, respectively.
Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11 to 63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the week 3 endpoint (last-observation-carry-forward) analysis were as follows: See Table 4.
Divalproex sodium was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender.
A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 4. (See Figure 4.)
Migraine: The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of divalproex sodium in the prophylactic treatment of migraine headache.
Both studies employed essential identical designs and recruited patients with a history of migraine with or without aura (of at least six months in duration) who were experiencing at least two migraine headaches a month during the three months prior to enrollment. Patients with cluster headaches were excluded.
Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to divalproex sodium or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, divalproex sodium to placebo. Ninety patients completed the 8-week maintenance period.
Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on divalproex sodium, doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (t.i.d.). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL.
The mean 4-week migraine headache rates during the treatment phase was 5.7 in the placebo group compared to 3.5 in the divalproex sodium group (see Figure 5). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three divalproex sodium dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (b.i.d.). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every four days (eight days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the divalproex sodium 500, 1,000, and 1,500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the divalproex sodium 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 5). Migraine headache rates in the combined divalproex sodium 1,000/1,500 mg group were significantly lower than in the placebo group. (See Figure 5.)
Pharmacokinetics: Absorption/Bioavailability: Divalproex sodium Enteric coated tablets; Divalproex sodium sprinkle capsules; valproic acid capsules, syrup and tablets: Equivalent oral doses of divalproex sodium (Depakote) products and valproic acid (Depakene) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint.
(Whether or not rate of absorption of divalproex sodium enteric coated tablets influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.)
Co-administration of oral valproate products with food and substitution among the various divalproex sodium and valproic acid formulations should cause no clinical problems in the management of patients with epilepsy (see Dosage & Administration). Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution: Protein Binding: The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) (see Interactions for more detailed information on the pharmacokinetic interactions of valproate with other drugs).
CNS Distribution: Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).
Placental transfer (see Use in Pregnancy & Lactation): Valproate crosses the placental barrier in animal species and in humans: In animal species, valproate crosses the placenta, to a similar extent as in humans.
In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.
Metabolism: Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15 to 20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Excretion: Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half -life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations: Neonates: Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than two months.
Geriatric: The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction of valproate is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly (see Dosage & Administration).
Pediatric: Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.
Gender: There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Ethnicity: The effects of ethnicity on the kinetics of valproate have not been studied.
Renal impairment: A slight reduction (27%) in the clearance of unbound valproate has been reported in patients with renal failure (creatinine clearance <10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
Hepatic impairment: See Contraindications and Hepatotoxicity under Precautions.
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in seven patients with cirrhosis and by 16% in four patients with acute hepatitis, compared to six healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Plasma Levels and Clinical Effect: The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate that affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Mania: In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL (see Dosage & Administration).
Epilepsy: The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
Equivalent doses of valproate sodium and divalproex sodium yield equivalent plasma levels of the valproate ion.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenesis: The 2-year carcinogenicity studies were conducted in mice and rats given oral valproate doses of approximately 80 and 160 mg/kg/day (which are the maximum tolerated doses in these species but less than the maximum recommended human dose based on body surface area). Subcutaneous fibrosarcomas were observed in male rats and hepatocellular carcinomas and bronchiolo-alveolar adenomas were observed in male mice at incidences slightly higher than concurrent study controls but comparable to historical control data.
Mutagenesis: Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Valproate was not mutagenic in bacteria (Ames test) or mouse lymphoma L5178Y cells at thymidine kinase locus (mouse lymphoma assay) and did not induce DNA repair activity in primary culture of rat hepatocytes. It did not induce either chromosome aberrations in rat bone marrow or dominant lethal effects in mice after oral administration.
In literature, after intraperitoneal exposure to valproate, increased incidences of DNA and chromosome damage (DNA strand-breaks, chromosomal aberrations or micronuclei) have been reported in rodents. However, the relevance of the results obtained with the intraperitoneal route of administration is unknown.
Statistically significant higher incidences of sister-chromatid exchange (SCE) have been observed in patients exposed to valproate as compared to healthy subjects not exposed to valproate. However, these data may have been impacted by confounding factors. Two published studies examining SCE frequency in epileptic patients treated with valproate versus untreated epileptic patients, provided contradictory results. The biological significance of an increase in SCE frequency is not known.
Impairment of Fertility and developmental toxicity: Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on a mg/m2 basis). Segment I fertility studies in rats have shown oral doses up to 350 mg/kg/day (approximately equal to the maximum human daily dose on a mg/m2 basis) for 60 days to have no effect on fertility. Teratogenic effects (malformations of multiple organ systems) have been demonstrated in mice, rats, and rabbits. In published literature, behavioral abnormalities have been reported in first generation offspring of mice and rats after in utero exposure to clinically relevant doses/exposures of valproate. In mice, behavioral changes have also been observed in the 2nd and 3rd generations, albeit less pronounced in the 3rd generation, following an acute in utero exposure of the first generation. The relevance of these findings for humans is unknown.
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Anticonvulsants
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