Sodium Valproate

Registered South African indications:

• Epilepsy
• Acute and maintenance treatment of manic episodes associated with bipolar disorders (tab)

Sodium valproate has a high teratogenic potential and when used in pregnancy, may cause various major and minor congenital abnormalities of body organs and/or body structures as well as may harm the developing brain of the foetus resulting in negative effects in childhood which may include neurodevelopmental disorders such as late walking and talking, poor language skills, memory problems, lower intellectual abilities. Exposure to sodium valproate in utero is associated with an increased risk to develop autistic spectrum disorder, childhood autism and attention deficit hyperactivity disorder (ADHD). Sodium valproate treatment should be initiated and supervised by a medical practitioner experienced in the treatment of epilepsy and sodium valproate should not be prescribed if the relevant Risk Minimisation Measures/Pregnancy Prevention Programme, cannot be implemented and supervised and patients are not committed to adhere to these measures.

 

Contraindications

South African recommendations
(inj, inf, liq, tab)

• 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
• Breastfeeding
• Severe hepatic impairment (Child-Pugh class C) 
  - Active hepatic disease
  - Acute hepatitis
  - Chronic hepatitis
  - Personal or family history of hepatic impairment especially drug-related (inj)
  - Personal or family history of severe hepatitis, especially if medicine-related (liq, tab)
  - Hepatic porphyria
• Porphyria
• Children younger than 2 years suspected of having a POLG-related disorder
• Presence of mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase ƴ (POLG, e.g. Alpers-Huttenlocher Syndrome) 
• Known urea cycle disorders

(syr)

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled
• Severe hepatic impairment (Child-Pugh class C)
  - Pre-existing hepatic disease or family history of severe hepatic impairment
• Porphyria
• Children younger than 2 years suspected of having a POLG-related disorder
• Presence of mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase ƴ (POLG, e.g. Alpers-Huttenlocher Syndrome)
• Known urea cycle disorders
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use

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
• Breastfeeding
• Hepatic impairment
  - Active hepatic disease 
  - Personal or family history of severe hepatic impairment especially drug-related
• Mild to moderate (Child-Pugh class A and B) (syr)
• Porphyria 
• Children younger than 2 years suspected of having a POLG-related disorder 
• Presence of mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase ƴ (POLG, e.g. Alpers-Huttenlocher Syndrome) 
• Known urea cycle disorders

Cautions

• Breastfeeding (syr) (South African recommendations)
• Breastfeeding (Recommendations in other jurisdictions)
• Males of reproductive potential
• Renal impairment
• Mild to moderate (Child-Pugh class A and B) hepatic impairment without active hepatic disease (South African recommendations)
• Elderly
• Children below 18 years (male and female)
• Risk factors for hepatic impairment (South African recommendations)
  - Infants and young children below 3 years with severe seizure disorders, brain damage, mental retardation and/or congenital metabolic disease or degenerative disease
  - Coadministration with multiple antiepileptics
• Risk factors for hepatic impairment (Recommendations in other jurisdictions)
  - 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 multiple antiepileptics 
• Risk factors for pancreatitis
  - Young children
  - Severe seizures 
  - Severe neurological impairment
  - Coadministration with antiepileptic therapy
• Risk factors for underlying mitochondrial diseases
  - Hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome
  - 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
• Pre-existing systemic lupus erythematosus 
• Urine testing of diabetics (See additional prescribing points)
• Underlying carnitine palmitoyltransferase (CPT) type II deficiency
• Alcohol intake  
• Abrupt withdrawal
• Coadministration with other antiepileptics 
• Sudden increase in dose or a too high starting dose (inj) (South African recommendations)
• Coadministration with other sorbitol-containing products (syr) (South African recommendations)
• Coadministration with other sorbitol-containing products (liq) (Recommendations in other jurisdictions)
• Hereditary fructose intolerance (HFI) (syr) (South African recommendations)
• Hereditary fructose intolerance (HFI) (liq, syr) (Recommendations in other jurisdictions)
• Glucose-galactose malabsorption (syr) (Recommendations in other jurisdictions)
• Sucrase-isomaltase insufficiency (syr) (Recommendations in other jurisdictions)
• May impair ability to drive and operate machinery 
• Sodium-controlled diet (inj) (South African recommendations)

Forms avail. in SA and covered in this monograph: inj, inf, liq, syr, tab

Dosages below include:

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

South African registered indications and dosages

Treatment with sodium valproate should be initiated and supervised by a medical practitioner experienced in the management of epilepsy

Epilepsy
Generalised epilepsy, particularly with the following patterns of seizures
- Absence
- Myoclonic 
- Tonic-clonic
- Atonic
- Mixed
Partial epilepsy
- Simple or complex seizures 
- Secondary generalised seizures 
- Specific syndromes (West, Lennox-Gastaut)

• IV: 400-800mg depending on body mass (up to 10mg/kg), given as a slow injection over 3-5min; Followed by continuous or repeated infusion; Max: 2500mg/24hrs
• Oral (liq, tab): Initial: 600mg/day, where applicable in divided doses; Titrate by 200mg at intervals of 3 days until control is achieved; Maintenance: 1000-2000mg/day (20-30mg/kg/day); Max: 2500mg/24hrs

---

Intravenous sodium valproate indicated for whom oral therapy is temporarily not possible

---

Patients already satisfactorily treated with sodium valproate may be continued at their current dosage using continuous or repeated infusion (inj)

---

Intravenous sodium valproate should be reconstituted immediately prior to use. Instructions on reconstitution before administration: See additional prescribing points

---

Sodium valproate may be given by direct slow intravenous injection or by infusion using a separate intravenous line (inj)

---

Intravenous sodium valproate should be replaced by oral sodium valproate therapy as soon as practicable (inj)

---

If adequate control has not been achieved after two weeks, the dose may be further increased, in stages, to a maximum of 2500mg/day, or one other anti-epileptic medicine may be added at a low dosage. In patients already receiving other therapy, the same pattern should be followed (liq, tab)

---

If increased sedation is observed, dosage of barbiturates or benzodiazepines (e.g. lorazepam) should be reduced as that of sodium valproate is increased; dosage of both sodium valproate and other agents should be adjusted during the stabilisation period, to give optimum control at the lowest possible combined dosage level, and it may be found possible to maintain optimum control with sodium valproate alone (liq, tab)

---

Sodium valproate should be given in divided doses (liq, tab)

---

Combined therapy and general considerations: See additional prescribing points (inj, liq)

---

Epilepsy
- Petit mal, grand mal, mixed generalised epilepsy and temporal lobe (or psychomotor) epilepsy

• Oral (syr): Initial: 600mg/day, in two divided doses; Titrate by 200mg at intervals of 3 days; Maintenance: 1000-2000mg/day; Max: 2500mg/24hrs

---

If adequate control has not been achieved after two weeks, the dose may be further increased, in stages, to a maximum of 2500mg/day or an additional antiepileptic agent may be added at a low dosage (syr)

---

Sodium valproate is for oral administration (liq, syr, tab)

---

Sodium valproate should not be diluted (liq, syr)

---

Sodium valproate should preferably be taken with or after food (liq, syr)

---

Sodium valproate may be crushed and mixed with food or drink (tab)

---

Daily dosage requirements vary according to age and body weight (inj, liq, syr, tab)

---

Acute and maintenance treatment of manic episodes associated with bipolar disorders

• Oral (tab): Initial: 1000mg/day; Increased as rapidly as possible to achieve the lowest therapeutic dose, to produce the desired clinical effect; Doses should be adjusted according to individual clinical response; Maintenance treatment should be established individually with the lowest effective dose

---

Indications and dosages registered in other jurisdictions

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

Epilepsy
- Epileptic patients who would normally be maintained on oral sodium valproate, and for whom oral therapy is temporarily not possible,

• IV: 400-800mg depending on body weight (up to 10mg/kg), given as a slow injection over 3-5min; Followed by continuous or repeated infusion: Max: 2500mg/24hrs

---

Patients already satisfactorily treated with oral sodium valproate may be continued at their current dosage using continuous or repeated infusion. Other patients' dose is mentioned above (inj)

---

Sodium valproate injection may be given by direct slow intravenous injection or by infusion using a separate intravenous line in normal saline, dextrose 5%, or dextrose saline (inj)

---

Daily dosage requirements vary according to age and body weight (inj)

---

Each vial of sodium valproate injection is for single dose injection only. Instructions on reconstitution before administration: See additional prescribing points (inj)

---

Sodium valproate injection should not be administered via the same IV line as other IV additives. The intravenous solution is suitable for infusion by polypropylene, polyethylene or glass containers (inj)

---

 Sodium valproate injection should be replaced by oral sodium valproate therapy as soon as practicable (inj)

---

Combined therapy: See additional prescribing points (inj)

---

- Generalised, partial or other

• Oral (liq, syr, tab): Initial: 600mg/day; Titrate by 200mg at intervals of 3 days until control is achieved; Maintenance: 1000-2000mg/day (20-30mg/kg/day); Max: 2500mg/24hrs

---

Where adequate control is not achieved within maintenance range the dose may be further increased to 2500mg per day (liq, syr,tab)

---

Daily dosage requirements vary according to age and body weight. Sodium valproate may be given twice daily (liq, syr, tab)

---

In patients where adequate control has been achieved sodium valproate controlled release formulations are interchangeable with other sodium valproate conventional or prolonged release formulations on an equivalent daily dosage basis (liq, syr, tab)

---

Method of administration: Sodium valproate is for oral administration. Sodium valproate should not be diluted (liq)

---

Method of administration: Sodium valproate is for oral administration. If it is necessary to dilute sodium valproate, the recommended diluent is syrup BP, but syrup containing SO₂ as a preservative should not be used. The diluted product will have a 14-day shelf life (syr)

---

Method of administration: Sodium valproate is for oral administration. Uncoated tablets may be crushed if necessary (tab)

---

Combined therapy: See additional prescribing points (liq, syr)

Paed. forms avail. in SA and covered in this monograph: inj, inf, liq, syr, tab

Dosages below include:

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

South African registered indications and dosages

Treatment with sodium valproate should be initiated and supervised by a medical practitioner experienced in the management of epilepsy

Epilepsy
Generalised epilepsy, particularly with the following patterns of seizures
- Absence
- Myoclonic 
- Tonic-clonic
- Atonic
- Mixed
Partial epilepsy
- Simple or complex seizures 
- Secondary generalised seizures
- Specific syndromes (West, Lennox-Gastaut)

• IV: 20-30mg/kg/day, given as a slow injection over 3-5min
• Oral (liq, tab): <20kg: 20mg/kg/day
• Oral (liq, tab): ≥20kg: Initial: 400mg/day irrespective of mass, where applicable in divided doses, with spaced increases until control is achieved; Maintenance: 20-30mg/kg/day; Max: 35mg/kg/24hrs

---

For the indication of epilepsy: Among the oral pharmaceutical forms, oral solution and crushable tablets are more appropriate for administration to children younger than 11 years (liq, tab)

---

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

Above 40mg/kg/day, clinical chemistry and haematological parameters should be monitored (inj, liq, tab)

---

Intravenous sodium valproate indicated for whom oral therapy is temporarily not possible

---

Patients already satisfactorily treated with sodium valproate may be continued at their current dosage using continuous or repeated infusion (inj)

---

Intravenous sodium valproate should be reconstituted immediately prior to use. Instructions on reconstitution before administration: See additional prescribing points (inj)

---

Sodium valproate may be given by direct slow intravenous injection or by infusion using a separate intravenous line (inj)

---

Intravenous sodium valproate should be replaced by oral sodium valproate therapy as soon as practicable (inj)

---

Sodium valproate may be crushed and mixed with food or drink (tab)

---

Sodium valproate should be given in divided doses (liq, tab)

---

Epilepsy
- Petit mal, grand mal, mixed generalised epilepsy and temporal lobe (or psychomotor) epilepsy

• Oral (syr): <20kg: Initial: 20mg/day, in two divided doses
• Oral (syr): ≥20kg:  Initial: 400mg/day irrespective of weight, in 2 divided doses gradually increased until control is achieved; Maintenance: 20-30mg/kg/day; Max: 35mg/kg/24hrs 

---

<20kg: In severe cases dose may be increased but only in patients in whom plasma valproic acid levels can be monitored. Above 40mg/kg/day, clinical chemistry and haematological parameters should be monitored (liq, syr)

---

Sodium valproate is for oral administration. Sodium valproate should not be diluted (liq, syr)

---

Sodium valproate should preferably be taken with or after food (liq, syr)

---

Sodium valproate may be crushed and mixed with food or drink (tab)

---

Daily dosage requirements vary according to age and body weight (inj, liq, syr)

---

Combined therapy and general considerations: See additional prescribing points (inj, liq, syr)

---

The safety and efficacy of sodium valproate for the treatment of manic episodes in bipolar disorder have not been established in studies in patients aged less than 18 years (tab)

---

Indications and dosages registered in other jurisdictions

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

Epilepsy
- Epileptic patients who would normally be maintained on oral sodium valproate, and for whom oral therapy is temporarily not possible 

• IV: 20-30mg/kg/day, given as a slow injection over 3-5min; Followed by continuous or repeated infusion: Max: 40mg/kg/24hrs

---

Where adequate control is not achieved within 20-30mg/kg/day, dose may be increased up to 40mg/kg/day but only in patients in whom plasma valproic acid levels can be monitored. Above 40mg/kg/day clinical chemistry and haematological parameters should be monitored (inj)

---

Patients already satisfactorily treated with oral sodium valproate may be continued at their current dosage using continuous or repeated infusion. Other patients' dose is mentioned above (inj)

---

Sodium valproate injection may be given by direct slow intravenous injection or by infusion using a separate intravenous line in normal saline, dextrose 5%, or dextrose saline (inj)

---

Daily dosage requirements vary according to age and body weight (inj)

---

Each vial of sodium valproate injection is for single dose injection only. Instructions on reconstitution before administration: See additional prescribing points (inj)

---

Sodium valproate injection should not be administered via the same IV line as other IV additives. The intravenous solution is suitable for infusion by polypropylene, polyethylene or glass containers (inj)

---

 Sodium valproate injection should be replaced by oral sodium valproate therapy as soon as practicable (inj)

---

Combined therapy: See additional prescribing points (inj)

---

- Generalised, partial or other

• Oral (liq, syr, tab): <20kg: Initial: 20mg/kg/day
• Oral (liq, syr, tab): ≥20kg: Initial: 400mg/day irrespective of weight, with spaced increases until control is achieved; Maintenance: 20-30mg/kg/day; Max: 35mg/kg/24hrs

---

<20kg: In severe cases Initial dose may be increased but only in patients in whom plasma valproic acid levels can be monitored. In children requiring doses higher than 40mg/kg/day, clinical chemistry and haematological parameters should be monitored (liq, syr, tab)

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≥20kg: Where adequate control is not achieved within maintenance range, the dose may be increased to 35mg/kg body weight per day. In children requiring doses higher than 40mg/kg/day, clinical chemistry and haematological parameters should be monitored (liq, syr)

---

Where adequate control is not achieved within maintainance range the dose may be further increased to 2500mg per day (liq, syr, tab)

---

Daily dosage requirements vary according to age and body weight. Sodium valproate may be given twice daily (liq, syr, tab)

---

In patients where adequate control has been achieved sodium valproate controlled release formulations are interchangeable with other sodium valproate conventional or prolonged release formulations on an equivalent daily dosage basis (liq, syr, tab)

---

Method of administration: Sodium valproate is for oral administration. Sodium valproate should not be diluted (liq)

---

Method of administration: Sodium valproate is for oral administration. If it is necessary to dilute sodium valproate, the recommended diluent is syrup BP, but syrup containing SO₂ as a preservative should not be used. The diluted product will have a 14-day shelf life (syr)

---

Method of administration: Sodium valproate is for oral administration. Uncoated tablets may be crushed if necessary (tab)

---

Combined therapy: See additional prescribing points (liq, syr, tab)

Pregnancy

South African recommendations

• Contraindicated 
• Contraindicated in pregnancy, unless there is no suitable alternative treatment
• Sodium valproate has a high teratogenic potential and when used in pregnancy, may cause various major and minor congenital abnormalities of body organs and/or body structures as well as may harm the developing brain of the foetus resulting in negative effects in childhood which may include neurodevelopmental disorders such as late walking and talking, poor language skills, memory problems, lower intellectual abilities. Exposure to sodium valproate in utero is also associated with an increased risk to develop autistic spectrum disorder, childhood autism and attention deficit hyperactivity disorder (ADHD). Sodium valproate treatment should be initiated and supervised by a medical practitioner experienced in the treatment of epilepsy or bipolar disorder and sodium valproate should not be prescribed if the relevant risk minimisation measures/pregnancy prevention programme, cannot be implemented and supervised and patients are not committed to adhere to these measures
• Contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (See additional prescribing points)
• 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 (inj)
• Click here for the SAHPRA valproate annual risk acknowledgement form 

Recommendations in other jurisdictions

• Contraindicated
• Contraindicated in pregnancy, unless there is no suitable alternative treatment
• Contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled
• Female children and women of childbearing potential: Sodium valproate must be initiated and supervised by a specialist experienced in the management of epilepsy. Sodium valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated. Sodium valproate is prescribed and dispensed according to the sodium valproate pregnancy prevention programme. The benefits and risks should be carefully reconsidered at regular treatment reviews. Sodium 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

Breastfeeding

South African recommendations

• Contraindicated (inj, liq, tab)
• Mothers on sodium valproate should not breastfeed their infants. Cases of haematological changes and somnolence have been reported in infants of mothers taking sodium valproate when breastfeeding their infants (inj)
• Sodium valproate is excreted in breastmilk. Mothers on sodium valproate should not breastfeed their infants. Cases of haematological changes and somnolence have been reported in infants of mothers taking sodium valproate when breastfeeding their infants (liq, tab)

• Caution; not recommended (syr)
• Sodium valproate is excreted in human breast milk with a concentration ranging from 1-10% of maternal serum levels and should be avoided during breastfeeding. Haematological disorders have been shown in breastfed newborns/infants of treated women (syr)

Recommendations in other jurisdictions

• Caution 
• Valproate is excreted in human milk with a concentration ranging from 1-10% of 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 valproate therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility 

South African recommendations

• Amenorrhoea, menstrual disorders, polycystic ovaries, increased testosterone levels, and impairment of ovarian function and of fertility have been reported in female patients using sodium valproate. Sodium valproate administration may also impair fertility in male patients. Fertility dysfunctions may not always be reversible after treatment discontinuation. Very low concentrations of valproate have been detected in semen of males on treatment with sodium valproate. It is not known with certainty if fertility would be affected by sodium valproate treatment in children less than 18 years of age, as valproate may interact with sex hormones

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. Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. Limited number of case reports suggest that a strong dose reduction may improve fertility function. However, in some cases, the reversibility of male infertility was unknown

Renal Impairment 

South African recommendations

• Caution; dose adjustment recommended 
  It may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (inj, liq, tab)
  Metabolites may accumulate; valproate binding serum albumin is decreased and volume of distribution is increased. In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (syr)

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring

Hepatic Impairment

South African recommendations

• Mild to moderate (Child-Pugh class A and B) without active hepatic disease: Caution; not recommended
• Severe (Child-Pugh class C): Contraindicated 

Recommendations in other jurisdictions

• Contraindicated
  Salicylates should not be used coadministered with sodium 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 under 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 dose adjustment recommended (inj, liq, tab)
  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 (inj, liq, tab)
• Caution; dose adjustment recommended (syr)
  Serum concentrations of free (unbound) valproic acid tend to be higher; lower daily dosages recommended (syr)

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended 
  Although the pharmacokinetics of sodium 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

Porphyria Information 

• Porphyrinogenic (P) 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Tremor
• Congenital malformations 
• Developmental disorders
• Teratogenicity
• Neurodevelopmental problems
  - Late walking and talking
  - Poor language skills
  - Memory problems
  - Lower intellectual abilities
  - Autistic syndrome
  - Attention deficit hyperactivity disorder (ADHD)
• Extrapyramidal disorder
• Stupor
• Somnolence
• Insomnia
• Seizure
• Loss of seizure control
• Memory impairment
• Headache
• Dizziness
• Coma
• Encephalopathy
• Lethargy
• Reversable parkinsonism
• Ataxia
• Paraesthesia
• Aggravated seizures
• Reversible dementia (associated with reversible cerebral atrophy, cognitive disorder)
• Sedation
• Increased alertness
• Hyperactivity
  - Psychomotor hyperactivity
• Behavioural deterioration
• Confusion
  - Confusional state
• Increased clouding of consciousness 
• Hallucinations
• Aggression 
• Agitation
• Disturbance in attention
• Abnormal behaviour
• Behavioural, mood or mental changes
• Emotional lability
• Depression
• Drowsiness
• Thinking abnormalities
• Unusual excitement
• Restlessness
• Irritability
• Nervousness
• Learning disorders
• Amnesia
• Suicidal ideation
• Malaise

Cardiovascular Disorders 

• Palpitations
• Postural hypotension
• Hypertension

Respiratory Disorders 

• Pleural effusion
• Dyspnoea
• Pneumonia
• Bronchitis
• Increased cough
• Pharyngitis
• Epitaxis
• Rhinitis
• Sinusitis

Gastrointestinal Disorders 

• Nausea and vomiting
• Gingival disorders
  - Gingival hyperplasia
• Periodontal abscess
• Stomatitis
• Gastralgia
• Diarrhoea 
• Pancreatitis
• Acute abdominal pain
• Minor gastric irritation
• Indigestion
• Dyspepsia
• Stomatitis
• Haematemesis
• Anorexia
• Constipation
• Dry mouth
• Faecal incontinence
• Flatulence
• Gastroenteritis
• Glossitis

Hepatobiliary Disorders 

• Hepatic injury
• Hepatic impairment
• Severe liver damage
  - Hepatic failure
• Increased hepatic enzymes 
• Serious or fatal hepatotoxicity
• Jaundice
• Fulminant hepatitis

Genitourinary Disorders

• Irregular periods
• Dysmenorrhea
• Amenorrhea
• Polycystic ovaries
• Vaginitis
• Vaginal haemorrhage
• Ovarian function impairment 
• Female fertility impairment
• Male infertility
• Gynaecomastia
• Urinary incontinence
• Renal failure 
• Enuresis
• Tubulointerstitial nephritis
• Reversible Fanconi syndrome
  - Glycosuria
  - Amino aciduria
  - Phosphaturia
  - Uricosuria

Endocrine and Metabolic Disorders 

• Hyponatraemia
• Increased weight
• Obesity
• Increased appetite
• Hyperammonemia (including in association with neurological symptoms)
• Syndrome of inappropriate secretion of antidiuretic hormone secretion (SIADH)
• Hyperandrogenism
  - Hirsutism
  - Virilism
  - Acne
  - Male pattern alopecia
  - Increased androgen 
• Hypothyroidism
• Hyperglycaemia

Musculoskeletal Disorders 

• Decreased bone mineral density
• Osteopenia
• Osteoporosis
• Fractures 
• Rhabdomyolysis
• Trembling of hands and arms
• Back pain
• Neck pain
• Neck rigidity
• Leg cramps 
• Arthralgia
• Arthrosis
• Hypertonia
• Myalgia
• Myasthenia

Skin and Subcutaneous Tissue Disorders 

• Ecchymosis
• Furunculosis
• Petechial pruritus
• Alopecia
• Hair disorder
  - Abnormal hair texture 
  - Abnormal hair growth 
  - Hair colour changes
• Nail and nail bed disorders
• Angioedema
• Rash
• Hair disorder
  - Abnormal hair texture
  - Hair colour changes
  - Abnormal hair growth
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome 
• Erythema multiforme
• Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome 
• Dry skin

Immune, Blood and Lymphatic System Disorders 

• Anaemia
• Thrombocytopenia
• Red cell hypoplasia
• Pancytopenia
• Leucopenia
• Bone marrow failure 
  - Pure red cell aplasia
  - Agranulocytosis
  - Macrocytic anaemia
  - Macrocytosis
• Reduced blood fibrinogen
• Decreased coagulation factors
• Abnormal coagulation tests
  - Prolonged prothrombin time 
  - Prolonged activated partial thromboplastin time
  - Prolonged thrombin time 
  - Prolonged international normalized ratio (INR)
• Bruising
  - Spontaneous bruising
• Spontaneous bleeding
• Haemorrhage
• Hypersensitivity
• Vasculitis
• Oedema
  - Non-severe peripheral oedema
• Systemic lupus erythematosus 
• Neoplasms (benign, malignant and unspecified)
  - Cysts
  - Polyps
• Myelodysplastic syndrome 
• Flu-like symptoms
• Hypothermia

Sensory Disorders 

• Amblyopia
• Conjunctivitis
• Dry eyes
• Painful eyes
• Nystagmus
• Diplopia
• Deafness
• Tinnitus
• Otitis media
• Vertigo
• Ear disorders or pain
• Taste perversion

• Antipsychotics
• Neuroleptics/antipsychotics
• Monoamine oxidase inhibitors
• Lithium
• Barbiturates
• Antidepressants 
• Benzodiazepines
• Olanzapine
• Anti-epileptics (including newer anti-epileptics)
• Phenobarbitone
• Primidone
• Phenytoin
• Carbamazepine
• Lamotrigine
• Topiramate
• Acetazolamide
• Quetiapine
• Felbamate
• Rufinamide
• Propofol
• Zidovudine
• Nimodipine
• Hydantoin antiepileptics
• Clonazepam
• Anti-malarial agents
• Mefloquine 
• Chloroquine
• Highly protein-bound agents
• Anticoagulants
• Products which have anticoagulant properties
• Acetylsalicylic acid
• Salicylates
• Vitamin K-dependent factor anticoagulants
• Warfarin
• Coumarin anticoagulants
• Cimetidine
• Erythromycin
• Carbapenem antibiotics
• Panipenem
• Imipenem
• Meropenem
• Ertapenem
• Colestyramine
• Rifampicin
• Protease inhibitors
• Lopinavir 
• Ritonavir
• Oestrogen-containing agents (See additional prescribing points)
• Oestrogen-containing hormonal contraceptives (See additional prescribing points)
• Metamizole

• 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
• Signs and symptoms of motor and cognitive function decline
• Symptoms of unexplained lethargy and vomiting, hypothermia, or mental status change
• 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) 

Reconstitution instructions, special precautions for disposal and other handling (South African recommendations)

• Each vial of sodium valproate is for single-dose injection only. Sodium valproate should be reconstituted immediately prior to use any unused portion must be discarded
• To reconstitute, inject the solvent provided into the vial, allow to dissolve and extract the appropriate dose. Refer to the product professional information for the concentration of reconstituted sodium valproate. Sodium valproate may be given by direct slow intravenous injection or by infusion using a separate intravenous line in 0,9% sodium chloride, dextrose 5%, or 2,5% dextrose/0,45% sodium chloride
• If the reconstituted solution is further diluted for use as an infusion solution, the dilute solution may be stored for up to 24 hours if kept at 2-8ºC before use, discarding any remaining solution after 24 hours
• Sodium valproate should not be administered via the same IV line as other IV additives. The intravenous solution is suitable for infusion in PVC, polythene or glass containers

Oestrogen-containing products, including oestrogen-containing hormonal contraceptives

South African recommendations

• Coadministration with oestrogen-containing agents, including oestrogen-containing hormonal contraceptives, may potentially result in decreased sodium valproate efficacy. Prescribers should monitor clinical response (seizure control) when initiating or discontinuing oestrogen-containing products (syr)
• On the opposite sodium valproate does not reduce the efficacy of hormonal contraceptives (syr)

International manufacturer recommendations

• Coadministration with oestrogen-containing agents, including oestrogen-containing hormonal contraceptives, may potentially result in decreased sodium valproate efficacy. Prescribers should monitor clinical response (seizure control) when initiating or discontinuing oestrogen-containing products
• On the opposite sodium valproate does not reduce the efficacy of hormonal contraceptives 

Pregnancy prevention programme

• Sodium valproate has a high teratogenic potential and children exposed in utero to sodium valproate have a high risk for congenital malformations and neurodevelopmental disorders

Conditions of pregnancy prevention programme

• The medical practitioner must ensure that
  - Individual circumstances should be evaluated in each case. Involving the patient in the discussion to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks
  - The potential for pregnancy is assessed for all female patients
  - The patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to sodium valproate 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, without interruption during the entire duration of treatment with sodium valproate
  - The patient understands the need for regular (at least annual) treatment review by a medical practitioner experienced in the management of epilepsy
  - The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception and before contraception is discontinued
  - The patient understands the need to urgently consult her physician in case of pregnancy
  - The patient has received the patient guide
  - The patient has acknowledged that she has understood the hazards and necessary precautions associated with sodium valproate use (annual risk acknowledgement form)
• These conditions also concern women who are not currently sexually active unless the medical practitioner considers that there are compelling reasons to indicate that there is no risk of pregnancy

Female children 

• The medical practitioner must ensure that parents/caregivers of female children understand the need to contact the medical practitioner once the female child using sodium valproate experiences menarche
• The medical practitioner 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 infants exposed to sodium valproate in utero
• In patients who experienced menarche, the medical practitioner must reassess the need for sodium valproate therapy annually and consider alternative treatment options. If sodium valproate is the only suitable treatment, the need for using effective contraception and all other conditions of the pregnancy prevention programme must be discussed. Every effort should be made by the medical practitioner to switch female children on sodium valproate to alternative treatment before they reach adulthood

Pregnancy test

• Pregnancy must be excluded before start of treatment with sodium valproate. Treatment with sodium valproate must not be initiated in women of childbearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a healthcare provider, to rule out unintended use in pregnancy

Contraception

• Women of childbearing potential who are prescribed sodium valproate must use effective contraception without interruption during the entire duration of treatment with sodium valproate. 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 by a medical practitioner

• The medical practitioner should at least annually review whether sodium valproate is the most suitable treatment for the patient. The medical practitioner should discuss the annual risk acknowledgement form, at initiation and during each annual review, and ensure that the patient has understood its content

Pregnancy planning

• If a woman is planning to become pregnant, a medical practitioner experienced in the management of epilepsy must reassess sodium 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, the woman should receive further counselling regarding the risks of valproate for the unborn child to support her informed decision-making regarding family planning

In case of pregnancy

• If a woman using sodium valproate becomes pregnant, she must be immediately referred to a medical practitioner to re-evaluate treatment with sodium valproate and consider alternative treatment options. The patients with sodium valproate-exposed pregnancy and their partners should be referred to a medical practitioner experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy

Pharmacists or healthcare professionals

• Pharmacists or healthcare professionals must ensure that
  - The patient card is provided with every sodium valproate dispensing and that the patients understand its content
  - Patients are advised not to stop their sodium valproate medication and to immediately contact a medical practitioner in case of planned or suspected pregnancy

Combined therapy

South African recommendations

• When starting sodium valproate in patients already on other antiepileptics, these should be tapered slowly. The initiation of sodium valproate therapy should then be gradual, with the target dose 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 antiepileptics which induce liver enzyme activity, e.g. phenytoin, phenobarbital (phenobarbitone) and carbamazepine. Once known enzyme inducers have been withdrawn, or if side effects, such as tremor, are experienced, it may be possible to maintain seizure control on a reduced dose of sodium valproate (inj, liq)
• When barbiturates are being coadministered and particularly if sedation is observed (particularly in children) the dosage of barbiturates should be reduced (inj)

International manufacturer recommendations

• When starting sodium valproate in patients already on other antiepileptics, these should be tapered slowly. The initiation of sodium valproate therapy should then be gradual, with the target dose 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 antiepileptics which induce liver enzyme activity, e.g. phenytoin, phenobarbital (phenobarbitone) and carbamazepine. Once known enzyme inducers have been withdrawn, or if side effects, such as tremor, are experienced, it may be possible to maintain seizure control on a reduced dose of sodium valproate
• When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturates 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

General considerations (South African recommendations)

• The concentration of valproate in plasma that appears to be associated with therapeutic effects is approximately 30-100μg/ml. 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 (inj, liq)

Urine testing of diabetics

• Sodium valproate is excreted mainly through the kidneys, partly in the form of ketone bodies, and this may give false positive readings in the urine testing of diabetics

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

Injection (per 4ml) 400mg

• Epilim intravenous (Sanofi Aventis) originator
• Epilizine intravenous 400 (Zentiva)
• Navalpro 400mg/4ml (Pharmacare)
• Cerepiv IV (Sandoz SA)

Liquid (per 5ml) 200mg

• Epilim liquid sugar free (Sanofi Aventis) originator

Syrup (per ml) 50mg

• Convulex syrup (Acino Pharma) originator

Tablet  100mg

• Epilim 100 crushable (Sanofi Aventis) originator

Also available in the following forms: capsule and tablet.