Valproate

Female patients: • For all female patients aged under 55 years:

For the treatment of generalised, partial or other epilepsy only when there is no other effective or tolerated treatment. • For all female patients aged over 55 years: For the treatment of generalised, partial or other epilepsy. Male patients: • For all male patients aged under 55 years initiating treatment with valproate: For the treatment of generalised, partial or other epilepsy only when there is no other effective or tolerated treatment.

• For all male patients established on treatment with valproate or male patients aged over 55 years: For the treatment of generalised, partial or other epilepsy.

Posology Epilim Chronosphere is a controlled release formulation of Epilim, which reduces peak concentration and ensures more even plasma concentration throughout the day. Epilim Chronosphere may be given once or twice daily. In patients where adequate control has been achieved, Epilim Chronosphere formulations are interchangeable with other conventional or prolonged release formulations of Epilim on an equivalent daily dosage basis.

Daily dosage should be established according to age and body weight and should be given to the nearest whole 50 mg sachet. Partial sachets should not be used. However, the wide individual sensitivity to valproate should also be considered.

Dosage Usual requirements are as follows:

Adults Dosage should start at 600 mg daily increasing by 200 mg at three-day intervals until control is achieved. e. 20 – 30 mg/kg/day body weight (to the nearest whole 50 mg sachet). Where adequate control is not achieved within this range the dose may be further increased to 2500 mg per day.

Special populations Paediatric population Children over 20 kg:

Initial dosage should be 400 mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20 – 30 mg/kg body weight per day (to the nearest whole 50 mg sachet. Where adequate control is not achieved within this range the dose may be increased to 35 mg/kg body weight per day.

In children requiring doses higher than 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.

Children under 20 kg:

Initial dosage should be 20 mg/kg of body weight per day (to the nearest whole 50 mg sachet); in severe cases this may be increased but only in patients in whom plasma valproic acid levels can be monitored. In children requiring doses higher than 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.

Elderly Although the pharmacokinetics of valproate are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased.

This will affect the clinical interpretation of plasma valproic acid levels. Renal impairment It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. 9).

4). 8). 4). Salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye’s syndrome). 1). 6). Valproate must be supervised by a specialist experienced in the management of epilepsy.

6). Where possible, existing female children and women of childbearing potential aged under 55 years should be switched to another treatment unless two specialists independently consider and document there is no other effective or tolerated treatment.

4). 4). Valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release. 6). 6). 3). 5) When starting Epilim Chronosphere in patients already on other anti-convulsants, these should be tapered slowly; initiation of Epilim Chronosphere therapy should then be gradual, with target dose being reached after about 2 weeks.

g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Epilim Chronosphere. When […]

The following CIOMS frequency rating is used, when applicable: 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); not known (cannot be estimated from the available data).

6). 1). 1).

Gastrointestinal disorders:

Very common: nausea Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea The above adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment.

These problems can usually be overcome by taking Epilim Chronosphere with or after food. 4). 4) Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder Sedation has been reported occasionally, usually when in combination with other anti-convulsants.

In monotherapy it occurred early in treatment on rare occasions and is usually transient. *Rare cases of lethargy, occasionally progressing to stupor, sometimes with associated hallucinations or convulsions, have been reported. Encephalopathy and coma have very rarely been observed.

These cases have often been associated with too high a starting dose or too rapid a dose escalation, or concomitant use of other anti-convulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.

An increase in alertness may occur; this is generally beneficial, but occasionally aggression, hyperactivity and behavioural deterioration have been reported. 4). 2), obesity *Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, are usually transient and should not cause treatment discontinuation.

However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur valproate should be discontinued. Hyperammonaemia associated with neurological symptoms has also been reported.

4). 4). 2) Uncommon: pancytopenia, leucopenia Rare: bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis The blood picture returned to normal when the drug was discontinued. Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (valproate has an inhibitory effect on the second phase of platelet aggregation).

6).

Skin and subcutaneous tissue disorders:

Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously. 6) Very rarely gynaecomastia has occurred.

6) Uncommon: vasculitis Eye disorders: Rare: diplopia Ear and labyrinth disorders: Common: deafness, a cause-and-effect relationship has not been established.

Renal and urinary disorders:

Common: urinary incontinence Uncommon: renal failure Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy, but the mode of action is as yet unclear.

General disorders and administrative site conditions:

Uncommon: hypothermia, non-severe peripheral oedema Musculoskeletal and connective tissue disorders: Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with valproate. The mechanism by which valproate affects bone metabolism has not been identified.

2) Respiratory, thoracic and mediastinal disorders: Uncommon: pleural effusion […]

6). 6). 1. • Active liver disease, or personal or family history of severe hepatitis, especially drug related. 4). • Porphyria. g. 4). 4).

ODAN-VALPROIC ACID (valproic acid) is indicated for: • use as sole or adjunctive therapy in the treatment of simple or complex absence seizures, including petit mal, and is useful in primary generalized seizures with tonic-clonic manifestations.

• use adjunctively in patients with multiple seizure types which include either absence or tonic-clonic seizures. In accordance with the International Classification of Seizures, simple absence is defined as a very brief clouding of the sensorium or loss of consciousness (lasting usually 2 to 15 seconds), accompanied by certain generalized epileptic discharges without other detectable clinical signs.

Complex absence is the term used when other signs are also present. See

1 Dosing Considerations Patients receiving combined antiepileptic therapy require careful monitoring when another agent is started, stopped or when the dose is altered (see 9 DRUG INTERACTIONS). As the dosage of ODAN-VALPROIC ACID (valproic acid) is titrated upward, blood concentrations of phenobarbital, and/or phenytoin may be affected (see 9 DRUG INTERACTIONS).

Antiepileptic drugs (AEDs) 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.

Any changes in dosage and administration, or the addition or discontinuance of concomitant drugs, should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. , carbamazepine) or other drugs with valproate interactions, (see 9 DRUG INTERACTIONS), it is advisable to monitor serum valproate concentrations.

Dosing in Elderly Patients:

ODAN-VALPROIC ACID, valproic acid Product Monograph Page 7 of 58 Unclassified / Non classifié Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced.

Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, urinary tract infection, and other adverse events. Dose reductions or discontinuation of ODAN-VALPROIC ACID should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.

4 Geriatrics).

Dose-Related Adverse Events:

The frequency of adverse events (particularly elevated liver enzymes and thrombocytopenia) may be dose related. The probability of thrombocytopenia appears to increase significantly at total valproate concentration of ≥ 110 mcg/mL [females] or ≥ 135 mcg/mL [males] (see 7 WARNINGS AND PRECAUTIONS, Hematologic, Dose-related Adverse Events: Thrombocytopenia).

Therefore, the benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse effects. Female children, women of childbearing potential and pregnant women with epilepsy Valproic Acid treatment must be initiated and supervised by a specialist experienced in the management of epilepsy.

1 Pregnant Women). Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Program (see 7 WARNINGS AND PRECAUTIONS, Pregnancy Prevention Program). In the exceptional circumstance when valproate is the only treatment option during pregnancy in epileptic women, valproic acid should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation.

During pregnancy, the daily dose of immediate release formulations should be divided into at least two single doses. Available data show an increased risk of major congenital malformations and neurodevelopmental disorders in the children of mothers treated during pregnancy with either valproate monotherapy or valproate polytherapy, compared to the population not exposed to valproate.

Male patients of reproductive potential The prescribers should discuss with the patient the need for effective contraception, including for the female partner, while using valproate and for 3 months after stopping the treatment. , allowing a new spermatogenesis without valproate exposure) is not known.

The male patient should also be informed about the need for regular (at least annual) review of treatment by a specialist experienced in the management of epilepsy. The specialist should at least annually review whether valproate is the most suitable treatment for the patient.

During this review, the specialist should ensure the male patient has acknowledged the risk and understood the precautions needed with valproate use (Annual Risk Acknowledgement Form). Educational materials are available for healthcare professionals and male patients.

A patient guide should be provided to all men of reproductive potential using valproate. 1 Recommended Dose and Dosage Adjustment ODAN-VALPROIC ACID (valproic acid) is administered orally. The recommended initial dosage is 15 ODAN-VALPROIC ACID, valproic acid Product Monograph Page 8 of 58 Unclassified / Non classifié 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. When the total daily dose exceeds 250 mg, it should be given in a divided regimen (Table 1). 9 1,250 2 1 2 Therapeutic Blood Levels: A good correlation has not been established between daily dose, total serum valproate concentration and therapeutic effect.

However, therapeutic valproate serum concentrations for most patients with epilepsy will range from 50 to 100 mcg/mL (350 to 700 micromole/L). Some patients may be controlled with lower or higher serum concentrations (see 7 […]

). • Sucrose or Fructose Intolerance ODAN-VALPROIC ACID oral solution contains sucrose, which may be harmful to the teeth. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine.

When prescribing to diabetic patients, the sucrose content should be taken into account (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING). ODAN-VALPROIC ACID, valproic acid Product Monograph Page 16 of 58 Unclassified / Non classifié ODAN-VALPROIC ACID oral solution contains sorbitol.

Patients with rare hereditary problems of fructose intolerance should not take this medicine. , low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving ODAN-VALPROIC ACID be monitored for platelet count and coagulation parameters prior to planned surgery.

Clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of ODAN-VALPROIC ACID dosage or withdrawal of therapy (see 7 WARNINGS AND PRECAUTIONS, Hematologic, Dose-related Adverse Events: Thrombocytopenia).

• Dose-related Adverse Events: Thrombocytopenia The frequency of adverse effects thrombocytopenia (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. 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 addition, the findings from a crossover clinical trial conducted with divalproex sodium extended-release tablets, in 44 epilepsy patients, indicate that the frequency of treatment- emergent mild thrombocytopenia (platelet count between 100 to150 x 109/L) was significantly higher after 12 weeks of treatment with divalproex sodium extended-release tablets than after 12 weeks of treatment with divalproex sodium (7 versus 3 low counts, respectively).

The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse events. Hepatic/Biliary/Pancreatic: • Serious or Fatal Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives.

These incidences usually have occurred during the first 6 months of treatment with valproic acid. Caution should be observed when administering ODAN-VALPROIC ACID to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism: Urea Cycle Disorders and Risk of Hyperammonemia, Patients at Risk of Hypocarnitinemia and, Hepatic/Biliary/Pancreatic: Patients with Mitochondrial Disease), 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 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease.

The risk in this age group decreased considerably in patients receiving valproic acid as monotherapy. Similarly, patients aged 3 to 10 years were at somewhat greater risk if they received multiple anticonvulsants than those who received only valproic acid.

Above the age of 2 ODAN-VALPROIC ACID, valproic acid Product Monograph Page 17 of 58 Unclassified / Non classifié years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patients.

No deaths have been reported in patients over 10 years of age who received valproic acid alone. If ODAN-VALPROIC ACID is to be used in children 2 years old or younger, it should be used with extreme caution and as a sole agent. In this patient population, concomitant use of salicylates and ODAN- VALPROIC ACID should be avoided due to the risk of liver toxicity.

3 Pediatrics). Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia, and vomiting. Patients should be monitored closely for appearance of these symptoms.

Patients and parents should be instructed to report such symptoms. Because of the non-specific nature of some of the early signs, hepatotoxicity should be suspected in patients who become unwell, other than through obvious cause, while taking ODAN-VALPROIC ACID.

4 Drug- Drug Interactions, Table 3). 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.

In high-risk patients, it might also be useful to monitor serum fibrinogen […]

and 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity for statement regarding serious or fatal hepatic dysfunction. 1 Pediatrics Pediatrics (< 18 years of age): When ODAN-VALPROIC ACID is used in children under the age of 2 years, it should be used with extreme caution and as a sole agent.

Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. 3 Pediatrics. 2 Geriatrics Geriatrics (≥ 65 years of age): The safety and efficacy of valproic acid in elderly patients with epilepsy has not been evaluated in clinical trials.

Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic and renal dysfunctions, and limited experience with valproic acid in this population. 3 Pharmacokinetics, Special Populations and Conditions, Geriatrics.

2 CONTRAINDICATIONS ODAN-VALPROIC ACID (valproic acid) is contraindicated in: • Patients with known hypersensitivity to the drug, any ingredient in the formulation or component of the container. For a complete listing of ingredients (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

• in pregnancy unless there is no suitable alternative treatment (see

1 Epilepsy Valproic acid oral solution is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Valproic acid oral solution is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which 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.

1 ) for statement regarding fatal hepatic dysfunction. 2 Important Limitations Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.

1 ), and Patient Counseling Information ( 17 )] . For prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )] .

2 DOSAGE AND ADMINISTRATION Valproic acid oral solution is intended for oral administration. 1 Epilepsy Valproic acid oral solution is intended for oral administration. Patients should be informed to take valproic acid oral solution every day as prescribed.

If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. Valproic acid is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures.

2 )] . Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Valproic acid oral solution 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. 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 2 weeks. This reduction may be started at initiation of valproic acid therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction.

The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Valproic acid oral solution 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 tablets, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies ( 14 )] .

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 Drug Interactions ( 7 )] .

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 concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL.

3 )] . 2 )] . 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.

The following table is a guide for the initial daily dose of valproic acid oral solution (15 mg/kg/day): Table 1. 2 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of 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 reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.

3 )] . Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. 8 )] . The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

I. I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 2 )] .

14 )] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Most common adverse reactions (reported >5%) are abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss.

4 ). gov/medwatch. 1 Epilepsy The data described in the following section were obtained using divalproex sodium tablets. Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium was generally well tolerated with most adverse reactions rated as mild to moderate in severity.

Intolerance was the primary reason for discontinuation in the divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures.

Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.

Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Divalproex Sodium (n = 77) % Placebo (n = 70) % Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose divalproex sodium group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium monotherapy treatment of complex partial seizures.

Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.

Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures 1 Body System/Reaction High Dose (n = 131) % Low Dose (n = 134) % Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group.

The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with divalproex sodium in the controlled trials of complex partial seizures: Body as a Whole : Back pain, chest pain, malaise.

Cardiovascular System :

Tachycardia, hypertension, palpitation.

Digestive System :

Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.

Hemic and Lymphatic System :

Petechia.

Metabolic and Nutritional Disorders :

SGOT increased, SGPT increased.

Musculoskeletal System :

Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Nervous System :

Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.

Respiratory System :

Sinusitis, cough increased, pneumonia, epistaxis.

Skin and Appendages :

Rash, pruritus, dry skin.

Special Senses :

Taste perversion, abnormal vision, deafness, otitis media.

Urogenital System :

Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 2 Mania Although valproic acid has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.

Body as a Whole :

Chills, neck pain, neck rigidity.

Cardiovascular System :

Hypotension, postural hypotension, vasodilation.

Digestive System :

Fecal incontinence, gastroenteritis, glossitis.

Musculoskeletal System :

Arthrosis.

Nervous System :

Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.

Skin and Appendages :

Furunculosis, maculopapular rash, seborrhea.

Special Senses :

Conjunctivitis, dry eyes, eye pain.

Urogenital System :

Dysuria. 3 Migraine Although valproic acid has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.

Body as a Whole :

Face edema.

Digestive System :

Dry mouth, stomatitis.

Urogenital System :

Cystitis, metrorrhagia, and vaginal hemorrhage. 4 Postmarketing Experience The following adverse reactions have been identified during post approval use of divalproex sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic :

Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

Psychiatric :

Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.

Neurologic :

Paradoxical convulsion, parkinsonism There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.

There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or fully after valproate discontinuation.

Musculoskeletal :

Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Hematologic :

Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Endocrine :

Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.

There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Metabolism and nutrition:

Weight gain.

Reproductive:

Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.

Genitourinary :

Enuresis and urinary tract infection.

Special Senses :

Hearing loss.

Other :

Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.

1 )] . 1 )] . 12 )] . 6 )] . 1 )] . 1 )