Sodium Valproate/ Valproic Acid

Registered South African indications:

• Epilepsy
• Mania

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy, unless there is no suitable alternative treatment (for the indication of epilepsy)
• Pregnancy (for the indication of bipolar disorder) (South African recommendations)
• Women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled  
• Breastfeeding
• Hepatic impairment (Recommendations in other jurisdictions)
  - Active hepatic disease
  - Personal or family history of severe hepatic impairment, especially drug-related
• Severe hepatic impairment (Child-Pugh class C) (South African recommendations)
  - Acute hepatitis
  - Chronic hepatitis
  - Personal or family history of hepatic impairment especially drug related
  - 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

Cautions

• Breastfeeding (Recommendations in other jurisdictions)
• Males of reproductive potential
• Renal impairment
• Mild to moderate (Child-Pugh class A and B) 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 young children below 3 years 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 mitochondrial enzyme polymerase ƴ (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 salicylates in chilldren
• Coadministration with other antiepileptics 
• May impair ability to drive and operate machinery

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

Dosages below include:

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

South African registered indications and dosages

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)

• Oral (tab): Initial: 600mg/day, where applicable in divided doses; Titrate by 200mg at intervals of 3 days until control is achieved; Maintainance: 1000-2000mg/day (20- 30mg/kg/day); Max: 2500mg/24hrs

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If adequate control has not been achieved after 2 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

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If increased sedation is observed, dosage of barbiturates or benzodiazepines (e.g. lorazepam) should be reduced as that of sodium valproate/ valproic acid is increased; dosage of both sodium valproate/ valproic acid and other medicines should be adjusted, during the stabilization 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/ valproic acid alone

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Mania
- Treatment and prevention associated with bipolar disorders

• Oral (tab): Initial: 1000mg, dly

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The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose, which produces the desired clinical effect. Doses should be adjusted according to individual clinical response. Prophylactic treatment should be established individually with the lowest effective dose

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Sodium valproate/ valproic acid is a controlled release formulation, which reduces peak concentration and ensures a more even plasma concentration throughout the day. Sodium valproate/ valproic acid may be given once or twice daily

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Daily dosage requirements vary according to age and body weight. In patients where adequate control has been achieved, sodium valproate/ valproic acid formulations are interchangeable with other conventional or prolonged release formulations on an equivalent daily dosage basis

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Combined therapy: See additional prescribing points 

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Method of administration: For oral use. Sodium valproate/ valproic acid should be taken with or without food. The tablets should be swallowed whole, if necessary, with a little water (but not aerated mineral water) and not crushed or chewed

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Indications and dosages registered in other jurisdictions
Epilepsy
- Generalised, partial or other

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

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Sodium valproate/ valproic acid is a prolonged release formulation which reduces peak concentration and ensures more even plasma concentrations throughout the day. Sodium valproate/ valproic acid may be given once or twice daily

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Daily dosage requirements vary according to age and body weight. In patients where adequate control has been achieved Sodium valproate/ valproic acid formulations are interchangeable with other conventional or prolonged release formulations on an equivalent daily dosage basis

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Combined therapy: See additional prescribing points 

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Method of administration: Sodium valproate/ valproic acid is for oral administration. The tablets should be swallowed whole and not crushed or chewed. In view of the sustained release process and the nature of the excipients in the formula, the inert matrix of the tablet is not absorbed by the digestive tract; it is eliminated in the stools after the active substances have been released

Paed. forms avail. in SA and covered in this monograph: tab

Dosages below include:

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

South African registered indications and dosages

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)

• Oral (tab): <20kg: 20mg/kg/day
• Oral (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

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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. Above 40mg/kg/day, clinical chemistry and haematological parameters should be monitored

---

Sodium valproate/ valproic acid is a controlled release formulation, which reduces peak concentration and ensures a more even plasma concentration throughout the day. Sodium valproate/ valproic acid may be given once or twice daily

---

Daily dosage requirements vary according to age and body weight. In patients where adequate control has been achieved, sodium valproate/ valproic acid formulations are interchangeable with other conventional or prolonged release formulations on an equivalent daily dosage basis

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Not established for use in the treatment of manic episodes in bipolar disorder in children below 18 years

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Combined therapy: See additional prescribing points 

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Method of administration: For oral use. Sodium valproate/ valproic acid should be taken with or without food. The tablets should be swallowed whole, if necessary, with a little water (but not aerated mineral water) and not crushed or chewed

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Indications and dosages registered in other jurisdictions
Epilepsy
- Generalised, partial or other

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

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<20kg: An alternative formulation of sodium valproate or valproic acid should be used, due to the tablet size and need for dose titration. Sodium valproate liquid, syrup, crushable tablets or valproic acid capsules are alternatives

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≥20kg: In children requiring doses higher than 40mg/kg/day, clinical chemistry and haematological parameters should be monitored

---

Sodium valproate/ valproic acid is a prolonged release formulation which reduces peak concentration and ensures more even plasma concentrations throughout the day. Sodium valproate/ valproic acid may be given once or twice daily

---

Daily dosage requirements vary according to age and body weight. In patients where adequate control has been achieved Sodium valproate/ valproic acid formulations are interchangeable with other conventional or prolonged release formulations on an equivalent daily dosage basis

---

Combined therapy: See additional prescribing points 

---

Method of administration: Sodium valproate/ valproic acid is for oral administration. The tablets should be swallowed whole and not crushed or chewed. In view of the sustained release process and the nature of the excipients in the formula, the inert matrix of the tablet is not absorbed by the digestive tract; it is eliminated in the stools after the active substances have been released

Pregnancy

South African recommendations

• Contraindicated
• For the indication of epilepsy: Contraindicated in pregnancy, unless there is no suitable alternative treatment
• For the indication of bipolar disorder: Contraindicated in pregnancy
• Sodium valproate/ valproic acid is contraindicated in women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled
• Sodium valproate/ valproic acid has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neuro-developmental disorders
• Pregnancy exposure risk related to sodium valproate/ valproic acid: Both monotherapy and polytherapy including other anti-epileptics are associated with abnormal pregnancy outcomes. Anti-epileptic polytherapy that includes sodium valproate/ valproic acid may be associated with a greater risk of congenital malformations than sodium valproate/ valproic acid monotherapy. In animals: teratogenic effects have been demonstrated in mice, rats and rabbits
• If a woman plans a pregnancy, it is the opportunity of reviewing the indication for sodium valproate/ valproic acid therapy. During pregnancy, sodium valproate/ valproic acid treatment should be reviewed and the risks and benefits should be carefully considered and discussed with the patient. If considered appropriate, folate supplementation should be started before pregnancy and at a relevant dosage (5mg daily) as it may minimise the risk of neural tube defects. Monotherapy at the minimum effective daily dosage. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable. Specialised prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defect or another malformation (See additional prescribing points)
• Click here for the SAHPRA valproate annual risk acknowledgement form 

Recommendations in other jurisdictions

• Contraindicated
• For the indication of epilepsy: Contraindicated in pregnancy, unless there is no suitable alternative treatment 
• Valproate is contraindicated for use in women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled
• Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neuro-developmental disorders 
• 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. Valproate is prescribed and dispensed according to the valproate pregnancy prevention programme. The benefits and risks should be carefully reconsidered at regular treatment reviews. 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
• Pregnancy exposure risk related to valproate: Both valproate monotherapy and valproate polytherapy including other anti-epileptics are frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neurodevelopmental disorders in both valproate monotherapy and polytherapy compared to the population not exposed to valproate. Valproate was shown to cross the placental barrier in both animal species and humans. In animals: teratogenic effects have been demonstrated in mice, rats and rabbits

Breastfeeding

South African recommendations

• Contraindicated 
• Sodium valproate/ valproic acid crosses the placenta. When given to breastfeeding mothers, sodium valproate/ valproic acid is excreted in breast milk. Excretion of valproate in breast milk results in a concentration between 1-10% of maternal serum levels. Mothers taking sodium valproate/ valproic acid should not breastfeed their infants

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, polycystic ovaries and increased testosterone levels have been reported in women using sodium valproate/ valproic acid. Sodium valproate/ valproic acid administration may also impair fertility in men. 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 valproate. It is not known with certainty if fertility would be affected by sodium valproate/ valproic acid 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

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. Valproate is dialysable. Dosing should be modified according to clinical monitoring of the patient

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 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 of age. In addition, in conjunction with valproate, concomitant use in children under 3 years of age can increase the risk of liver toxicity

Elderly 

• Caution; no dose adjustment recommended 
  Although the pharmacokinetics of sodium valproate/ valproic acid is modified in the elderly, this is of 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 

• Extrapyramidal disorder
• Hallucinations
• Sedation
• Reversible cerebral atrophy
• Reversible dementia
• Cognitive disorder
• Increased clouding of consciousness
• Encephalopathy
• Coma
• Headache
• Tremor
• Extrapyramidal disorder
• Stupor
• Somnolence
• Seizure
  - Aggravated seizures
• Memory impairment
• Increased alertness
• Aggression
• Agitation
• Hyperactivity 
  - Psychomotor hyperactivity
• Behavioural deterioration
• Lethargy
• Reversible parkinsonism
• Ataxia
• Paraesthesia
• Confusional state
• Disturbance in attention
• Learning disorder
• Abnormal behaviour
• Neuro-developmental disorders

Respiratory Disorders 

• Pleural effusion

Gastrointestinal Disorders 

• Abdominal pain
• Nausea and vomiting
• Diarrhoea
• Stomatitis
• Gastralgia
• Gingival disorder
  - Gingival hyperplasia
• Pancreatitis

Hepatobiliary Disorders 

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

Genitourinary Disorders

• Urinary incontinence
• Renal failure
• Enuresis
• Tubulointerstitial nephritis
• Reversible Fanconi syndrome
  - Glycosuria
  - Amino aciduria
  - Phosphaturia
  - Uricosuria
• Polycystic ovaries
• Dysmenorrhea
• Amenorrhea
• Male infertility
• Gynaecomastia 

Endocrine and Metabolic Disorders 

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

Musculoskeletal Disorders 

• Decreased bone mineral density
• Osteopenia
• Osteoporosis
• Fractures 
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders 

• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Alopecia
  - Male pattern alopecia
• Hair disorder
  - Abnormal hair texture 
  - Abnormal hair growth 
  - Hair colour changes
• Rash
• Nail and nail bed disorders
• Angioedema
• Erythema multiforme
• Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome 

Immune, Blood and Lymphatic System Disorders 

• Anaemia
• Haemorrhage
• Vasculitis
• Thrombocytopenia
• Pancytopenia
• Leucopenia
• Bone marrow failure 
  - Pure red cell aplasia
  - Agranulocytosis
  - Macrocytic anaemia
  - Macrocytosis
• Decreased coagulation factors
• Abnormal coagulation tests
  - Prolonged prothrombin time 
  - Prolonged activated partial thromboplastin time
  - Prolonged thrombin time 
  - Prolonged international normalized ratio (INR)
• Myelodysplastic syndrome 
• Reduced blood fibrinogen 
• Spontaneous bruising or bleeding 
• Hypersensitivity
• Hypothermia
• Non-severe peripheral oedema
• Systemic lupus erythematosus

Sensory Disorders 

• Deafness
• Nystagmus
• Diplopia

Others

• Congenital malformations

• Antipsychotics
• Monoamine oxidase inhibitors
• Antidepressants
• Benzodiazepines
• Phenobarbitone
• Olanzapine
• Anti-epileptics (including newer anti-epileptics)
• Primidone
• Phenytoin
• Carbamazepine
• Lamotrigine
• Topiramate
• Acetazolamide
• Quetiapine
• Felbamate
• Rufinamide
• Propofol
• Zidovudine
• Nimodipine
• Anti-malarial agents
• Mefloquine
• Chloroquine
• Highly protein-bound agents
• Acetylsalicylic acid
• Vitamin K-dependent factor anticoagulants
• Warfarin
• Coumarin anticoagulants
• Cimetidine
• Erythromycin
• Carbapenem antibiotics
• Panipenem
• Imipenem
• Meropenem
• 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 haematologic organ systems)
• Menstrual history to assess for polycystic ovary syndrome (at 3-6 month intervals for the first year, then annually) 

Combined therapy

• When starting sodium valproate/ valproic acid in patients already on other antiepileptics, these should be tapered slowly. The initiation of sodium valproate/ valproic acid 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/ valproic acid. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced
• General considerations: The concentration of valproate in plasma that appears to be associated with therapeutic effects is approximately 30-100μg/ml (South African recommendations)
• 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

Oestrogen-containing products, including oestrogen-containing hormonal contraceptives

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

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/ valproic acid 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/ valproic acid
  - The patient understands the need for regular (at least annual) treatment review by a medical practitioner experienced in the management of epilepsy or bipolar
  - 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/ valproic acid 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/ valproic acid 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/ valproic acid in utero
• In patients who experienced menarche, the medical practitioner must reassess the need for sodium valproate/ valproic acid therapy annually and consider alternative treatment options. If sodium valproate/ valproic acid 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/ valproic acid to alternative treatment before they reach adulthood

Pregnancy test

• Pregnancy must be excluded before start of treatment with sodium valproate/ valproic acid. Treatment with sodium valproate/ valproic acid 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/ valproic acid must use effective contraception without interruption during the entire duration of treatment with sodium valproate/ valproic acid. 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/ valproic acid 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/ valproic acid therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued. If switching is not possible, the woman should receive further counselling regarding the risks of sodium valproate/ valproic acid for the unborn child to support her informed decision-making regarding family planning

In case of pregnancy

• If a woman using sodium valproate/ valproic acid becomes pregnant, she must be immediately referred to a medical practitioner to re-evaluate treatment with sodium valproate/ valproic acid and consider alternative treatment options. The patients with 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/ valproic acid dispensing and that the patients understand its content
  - Patients are advised not to stop their sodium valproate/ valproic acid medication and to immediately contact a medical practitioner in case of planned or suspected pregnancy

Urine testing of diabetics

• Sodium valproate/ valproic acid  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 and valproic acid are antiepileptics. The most likely mode of action for sodium valproate/ valproic acid is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

COMBINATION PREPARATIONS

Sodium Valproate/ Valproic Acid

Tablet 133.2mg/58mg

• Epilim CR 200 (Sanofi) originator
• Epilizine CR 200 (Winthrop)
• Eprolep CR 200 (Brimpharm SA)
• Navalpro CR 200 (Pharmacare) 
• Rubilim CR 200 (Ruby Pharmaceuticals)

Tablet 199.8mg/87mg

• Epilim CR 300 (Sanofi) originator
• Epilizine CR 300 (Winthrop)
• Eprolep CR 300 (Brimpharm SA)
• Navalpro CR 300 (Pharmacare) 
• Rubilim CR 300 (Ruby Pharmaceuticals)
• Valeptic CR 300 (Adcock Ingram)

Tablet 333mg/145mg 

• Epilim CR 500 (Sanofi) originator
• Epilizine CR 500 (Winthrop)
• Eprolep CR 500 (Brimpharm SA)
• Navalpro CR 500 (Pharmacare)
• Rubilim CR 500 (Ruby Pharmaceuticals)
• Valeptic CR 500 (Adcock Ingram)

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