Valproic Acid

Registered South African indications:

• Epilepsy
• Acute mania in bipolar-1 affective disorder
• Migraine

Contraindications

South African recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to sodium valproate
• Pregnancy, unless its continued use is considered essential
• Women of childbearing potential, unless its continued use is considered essential
• Hepatic impairment 
• Porphyria
• Pancreatic dysfunction

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy, unless there is no suitable alternative treatment
• Women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled
• Hepatic impairment 
  - Active hepatic disease 
  - Personal or family history of severe hepatic dysfunction, especially drug-related 
• Porphyria 
• Pre-existing mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome
• Children below 2 years who are suspected of having a POLG-related disorder 

Cautions

South African recommendations 

• Breastfeeding
• Renal impairment
• Elderly
• Children below 3 years
• Mentally retarded children 
• Bone marrow abnormalities
• Congenital enzyme defects 
• Haemorrhagic diathesis
• Organic cerebral lesions 
• Severe epileptic seizure types
• Abrupt withdrawal
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Breastfeeding
• Males of reproductive potential
• Renal impairment
• Elderly
• Risk factors for hepatic impairment
  - Coadministration with multiple antiepileptic therapy
  - Infants and in particular children below 3 years and those with severe seizure disorders, organic brain disease, congenital metabolic disease or degenerative disease associated with mental retardation
  - Coadministration with salicylates
• Abrupt withdrawal
• Risk factors for mitochondrial disease
  - Pre-existing hereditary neurometabolic syndromes
  - Family history or suggestive symptoms of a POLG-related disorder
  - Unexplained encephalopathy
  - Refractory epilepsy (focal, myoclonic)
  - Status epilepticus at presentation
  - Developmental delays
  - Psychomotor regression
  - Axonal sensorimotor neuropathy
  - Myopathy cerebellar ataxia
  - Opthalmoplegia
  - Complicated migraine with occipital aura
• Risk factors for pancreatitis
  - Young children
  - Severe seizures and severe neurological impairment with combination antiepileptic therapy
• Diabetic patients (see additional prescribing points)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Epilepsy
- Generalised seizures as well as partial (focal) seizures, including complex partial seizures evolving to generalised seizures

• Oral (cap): Initial: 600mg/day, in divided doses; Titrate by 150mg at intervals of 24hrs until maintenance is reached; Maintenance: 1000-1600mg/day; Max: 2600mg/24hrs

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If adequate control is not achieved after 2 weeks, further increases to a maximum of 2600mg per day may be necessary

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Dosage in patients being treated with other antiepileptic agents should be gradually reduced concurrently with the increase of the valproic acid dose

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Acute mania in bipolar-1 affective disorders
- Acute manic episodes associated with bipolar disorders in patients intolerant to lithium or with an unsatisfactory response to lithium therapy

• Oral (cap): Initial: 600-900mg/day, divided in several doses; Titrate gradually at intervals of 2-4 days; Max: 1500mg/24hrs

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Highly agitated patients may be treated with up to 1500mg per day. Gradual dose increases should then be effected at intervals of 2-4 days and accompanied by monitoring of plasma levels

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Migraine
- Prophylaxis of migraine headaches if other drugs have not shown the desired effect

• Oral (cap): Initial: 300mg/day, in divided doses; Titrate until the desired therapeutic effect is achieved or side effects occur; Maintenance: 600-900mg/day

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Most patients can be effectively treated with 600-900mg per day and this should be accompanied by monitoring of plasma level

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Dosage (starting with a low initial dose) is determined by the physician, and should not be arbitrarily altered or exceeded. The total daily dose should be administered in divided doses. Valproic acid should be taken whole, with some liquid, during or after meals

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Indications and dosages registered in other jurisdictions

Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy

Epilepsy
- Generalised, partial or other epilepsy

• Oral (cap): Initial: 600mg/day, in divided doses; Titrate by 300mg at intervals of 3 days until control is achieved; Maintenance: 1000-2000mg/day (20-30mg/kg); Max: 2500mg/24hrs

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Maintenance: 1000-2000mg/day (20-30mg/kg): Where adequate control is not achieved within this range, the dose may be further increased up to 2500mg per day

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Valproic acid is for oral administration. Valproic acid may be given twice daily

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Daily dosage requirements vary according to age and body weight

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Valproate 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

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Substitution and combined therapy: See additional prescribing points

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Epilepsy
- Generalised seizures as well as partial (focal) seizures, including complex partial seizures evolving to generalised seizures

• Oral (cap): <20kg: 15-20mg/kg/day
• Oral (cap): >20kg: Initial: 450mg/day, in divided doses (three 150mg caps); Titrate to establish control; Maintenance: 20-30mg/kg/24hrs

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<20kg: In severe cases titrate at 1 week intervals by 5-10mg/kg/day to 40mg/kg/day, but in these cases the plasma valproate concentration of the patient must be monitored. Should the daily dose exceed 100mg, it should be administered in divided doses

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Dosage in patients being treated with other antiepileptic agents should be gradually reduced concurrently with the increase of the valproic acid dose

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Acute mania in bipolar-1 affective disorders
- Acute manic episodes associated with bipolar disorders in patients intolerant to lithium or with an unsatisfactory response to lithium therapy

• Oral (cap): Initial: 600-900mg/day, divided in several doses; Titrate gradually at intervals of 2-4 days; Max: 1500mg/24hrs

---

Highly agitated patients may be treated with up to 1500mg per day. Gradual dose increases should then be effected at intervals of 2-4 days and accompanied by monitoring of plasma levels

---

Dosage (starting with a low initial dose) is determined by the physician, and should not be arbitrarily altered or exceeded. The total daily dose should be administered in divided doses. Valproic acid should be taken whole, with some liquid, during or after meals

---

Indications and dosages registered in other jurisdictions

 Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy

Epilepsy
- Generalised, partial or other epilepsy

• Oral (cap): <20kg: 20mg/kg/day, in 2-4 divided doses
• Oral (cap): >20kg: Initial: 400mg/day (irrespective of weight); Ttitrate with spaced increases until control is achieved; Maintenance: 20-30mg/kg/day; Max: 35mg/kg/24hrs

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<20kg: In severe cases dose may be increased but only in patients in whom plasma valproic acid levels can be monitored

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>20kg: Where adequate control is not achieved within this range the dose may be increased to 35mg/kg/day

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Splitting the total daily dose into 2-4 intakes is generally recommended

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Salicylates should not be used in children younger than 16 years. Coadministration with salicylates in children younger than 3 years can increase the risk of hepatic toxicity

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

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Valproic acid is for oral administration. Valproic acid may be given twice daily

---

Daily dosage requirements vary according to age and body weight

---

Female children: Valproate should not be used in female children unless other treatments are ineffective or not tolerated and the benefit and risk should be carefully reconsidered at regular treatment reviews

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Female children: Valproate is prescribed and dispensed according to the valproate pregnancy prevention programme 

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Valproate 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

---

Substitution and combined therapy: See additional prescribing points

Pregnancy

South African recommendations

• Contraindicated 
• Valproic acid has been associated with teratogenicity when given to women in the first trimester of pregnancy. Its use should be avoided in pregnant women and women likely to become pregnant, unless its continued use is considered essential by the prescribing physician. Women who have been exposed to valproic acid in the first trimester of pregnancy should be informed of the risk and offered prenatal counselling
• Click here for the SAHPRA valproate annual risk acknowledgement form 

Recommendations in other jurisdictions

• Contraindicated
• Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy
• Valproate is contraindicated for use in women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled
• Valproic acid should not be used in female children, adolescents, and women of childbearing potential and pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential have to use effective contraception during treatment. In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible. Valproate is prescribed and dispensed according to the valproate pregnancy prevention programme (See additional prescribing points)
• In female children and women of childbearing potential valproate must be initiated and supervised by a specialist experienced in the management of epilepsy. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated and the benefit and risk should be carefully reconsidered at regular treatment reviews

Breastfeeding

South African recommendations

• Caution; no information available

Recommendations in other jurisdictions

• Caution
• Valproate is excreted in human milk with a concentration ranging from 1%-10% of total maternal serum levels. Haematological disorders have been shown in breastfed newborns/infants of treated women. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from valproic acid therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. No adverse effects in the breastfeeding infant have been reported. The decision to allow the patient to breast-feed should be taken with regard to all the known facts

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate. Valproate administration may also impair fertility in men. Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation

Renal Impairment

South African recommendations

• Caution; no information available

Recommendations in other jurisdictions

• Caution; dose adjustment recommended 
  It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading

Hepatic Impairment

South African recommendations

• Contraindicated 

Recommendations in other jurisdictions

• Contraindicated  
  Salicylates should not be used coadministered with valproate since they employ the same metabolic pathway. Hepatic impairment, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid
  Salicylates should not be used in children below 16 years. In addition, coadministration with salicylates in children under 3 years can increase the risk of liver toxicity

Elderly

South African recommendations

• Caution; no information available

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended 
  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
  Starting (initial) doses should be lower and increased slowly over time till the target clinical response is achieved. Serum drug concentration monitoring is recommended for high-risk groups

Porphyria Information

• Porphyrinogenic (P)  

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Sedation
• Lethargy
• Confusion 
• Stupor
• Hallucinations
• Seizures
• Encephalopathy 
• Coma
• Extrapyramidal symptoms 
• Parkinsonism
• Dementia (reversible)
• Cerebral atrophy (reversible)
• Ataxia
• Fine postural tremor
• Increased alertness
• Aggression
• Hyperactivity 
• Behavioural deterioration
• Increased clouding of consciousness

Gastrointestinal Disorders 

• Nausea and vomiting 
• Gastralgia
• Diarrhoea
• Pancreatitis

Hepatobiliary Disorders 

• Hepatic dysfunction
• Severe liver damage
  - Hepatic failure
• Increased hepatic enzymes

Genitourinary Disorders

• Fanconi's syndrome (reversible) 
  - Glycosuria
  - Aminoaciduria
  - Phosphaturia
  - Uricosuria
• Amenorrhoea
• Irregular periods 
• Gynaecomastia

Endocrine and Metabolic Disorders 

• Hyperammonemia (associated with neurological symptoms)
• Increased weight

Musculoskeletal Disorders 

• Decreased bone mineral density
• Osteopenia
• Osteoporosis 
• Fractures

Skin and Subcutaneous Tissue Disorders 

• Cutaneous reactions 
  - Exanthematous rash 
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome 
• Erythema multiforme 
• Transient hair loss
• Nail and nail bed disorders
• Hirsutism 
• Acne

Immune, Blood and Lymphatic System Disorders 

• Anaemia
• Thrombocytopenia
• Pancytopenia
• Leucopenia
• Reduced fibrinogen 
• Increased bleeding time
• Spontaneous bruising or bleeding
• Allergic reactions 
  - Rash 
  - Hypersensitivity reactions
• Vasculitis
• Peripheral oedema

Sensory Disorders 

• Hearing loss (reversible or irreversible)
• Diplopia

Others

• Congenital malformations 
• Developmental disorders

• Psychotropics
• Neuroleptics
• Monoamine oxidase inhibitors
• Antidepressants 
• Benzodiazepines
• Primidone
• Anti-epileptics (including newer anti-epileptics)
• Phenobarbitone
• Phenytoin
• Carbamazepine
• Lamotrigine
• Zidovudine
• Felbamate
• Vitamin K-dependent factor anticoagulants
• Warfarin
• Coumarin anticoagulants
• Mefloquine
• Chloroquine
• Highly protein-bound agents
• Acetylsalicylic acid
• Cimetidine 
• Erythromycin
• Carbapenem agents
• Colestyramine

• Hepatic function (at baseline and often during therapy, especially during the first 6 months)
• Full blood count (baseline and periodic intervals)
• Prothrombin time (PT)/partial thromboplastin time (PTT) (especially prior to surgery)
• Valproate levels

Specific cases may require

• Pregnancy status
• Serum ammonia

Additional observations

• Signs and symptoms of hepatotoxicity (especially in patients older than 2 years who are clinically suspected of having a hereditary mitochondrial disease)
  - Malaise
  - Weakness
  - Facial oedema
  - Anorexia
  - Jaundice
  - Vomiting
• Signs and symptoms of pancreatitis
  - Abdominal pain
  - Nausea and vomiting
  - Anorexia
• Suicidality
  - Suicidal thoughts
  - Depression
  - Behavioral changes
• Mental alertness
• Symptoms of unexplained lethargy and vomiting, hypothermia, or mental status change
• Signs and symptoms of motor and cognitive function decline
• Evidence of haemorrhage, bruising, or a disorder of hemostasis/coagulation
• Signs and symptoms of drug reaction with eosinophilia and systemic symptoms
  - Possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems
• Menstrual history to assess for polycystic ovary syndrome (at 3-6 month intervals for the first year, then annually) 

Teratogenicity and developmental effects (Recommendations in other jurisdictions)

• Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate 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 valproate 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
• Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphia, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalities involving various body systems
• Developmental disorders: Data have shown that exposure to valproate 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 valproate 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
• 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 valproate 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 (approx. 3-fold) and childhood autism (approx. 5-fold) compared with the general study population. Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD)

Female children, female adolescents and women of childbearing potential (Recommendations in other jurisdictions)

• If a woman plans a pregnancy: For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate 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. If switching is not possible, further counselling regarding the valproate risks for the unborn child should be received to support her informed decision making regarding family planning
• Pregnant women: If a woman using valproate becomes pregnant, she must be immediately referred to a specialist 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 valproate in pregnancy and after careful consideration of alternative treatment, in exceptional circumstances a pregnant woman must receive valproate for epilepsy, it is recommended to: Use the lowest effective dose and divide the daily dose of valproate 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
• All patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the exposed pregnancy. Specialized prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However, the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure
• Valproate therapy should not be discontinued without a reassessment of the benefits and risks of the treatment with valproate for the patient by a physician experienced in the management of epilepsy

Risk in neonate (Recommendations in other jurisdictions) 

• Cases of hemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This hemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates
• Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy
• Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate 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

Substitution (Recommendations in other jurisdictions)

• A one-to-one dose relationship of valproic acid and products containing sodium valproate has been demonstrated in pharmacokinetic trials. In patients previously receiving sodium valproate therapy, valproic acid should be initiated at the same total daily dose

Combined therapy (Recommendations in other jurisdictions)

• When starting valproic acid in patients already on other anticonvulsants, these should be tapered slowly; initiation of valproic acid therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5-10mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbitone and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of valproic acid. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced
• In children requiring doses higher than 40mg/kg/day clinical chemistry and haematological parameters should be monitored
• Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected

Diabetic patients (Recommendations in other jurisdictions)

• Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics

The most likely mode of action for valproate is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

Capsule 150mg

• Convulex 150 (Acino Pharma) originator

Capsule 300mg

• Convulex 300 (Acino Pharma) originator

Capsule 500mg

• Convulex 500 (Acino Pharma) originator

Also available in the following forms: injection, liquid, syrup and tablet.