Sodium Valproate

ADMINISTRATION ROUTES:

IV, PO, NG

ALTERNATIVE NAMES:

Epilim

ICU INDICATIONS:

1. Seizures and seizure prophylaxis

PRESENTATION AND ADMINISTRATION:

IV:

Injection (vial) 400 mg (powder) plus diluent (4 mL for Injection). Store at room temperature.

Prepare solutions immediately before use. Any solution may be refrigerated for use within 24 hours.

For direct IV injection:

• Add 4 mL diluent 400 mg powder in vial
• Shake gently to dissolve. Concentration of reconstituted solution is 95 mg/mL
• Give required dose over 3 - 5 minutes

For intermittent infusion: -Prepare as for direct IV injection

• Add required dose to 50 mL of compatible IV fluid
• Infuse over a convenient period

Compatible with the following IV fluids: 0.9% Normal saline, 5% glucose, Glucose and Sodium Chloride

PO / NG:

Crushable tablets:

Epilim crushable 100 mg tablets (white)

Enteric coated tablets:

Epilim EC 200 mg tablets (lilac)

Liquids:

Epilim sugar free liquid (200 mg/5 mL) Epilim 200 mg/5 mL syrup

Note: for NG administration, use liquid

DOSAGE:

IV:

Loading dose 40 mg/kg (max dose 3 g)

Maintenance dose 500-1000 mg twice daily adjusted to response (max 2.5 g daily)

If previous oral dose satisfactory, give the same dose by intermittent or continuous infusion. E.g. a patient stabilised on oral 25 mg/kg daily should receive an infusion of 1 mg/kg/hr.

PO:

Begin at 600 mg/day given in 2 divided doses

Increase by 200 mg/day every 3 days until seizure control achieved

Usual dose 1000-2000 mg/day. Maximum dose 2500 mg/day

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Dose as in normal renal function

DOSAGE IN PAEDIATRICS:

PO, IV:

5 mg/kg/day given as 2 - 3 divided doses

increase to maximum 30 mg/kg/day given as 2 - 3 divided doses

CLINICAL PHARMACOLOGY:

Sodium valproate is an anticonvulsant. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). This GABA-ergic effect may also contribute to the antimanic properties of sodium valproate.

CONTRAINDICATIONS:

1. Hypersensitivity to sodium valproate
2. Hepatic disease or dysfunction
3. Urea cycle disorders

WARNINGS:

Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving sodium valproate. Children under the age of 2 years are at a considerably increased risk of developing fatal hepatotoxicity and this medication should only be used in this group with consideration of this risk.

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving sodium valproate. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.

Urea Cycle Disorders (UCD)

Sodium valproate is contraindicated in patients with known urea cycle disorders as it can worsen hyperammonaemia. Patients with an unexplained hyperammonaemia while taking sodium valproate should be assessed for an underlying urea cycle disorder.

Post-Traumatic Seizures

There is some evidence that valproate increases the risk of death compared to phenytoin when used for seizure prophylaxis after head injury. It should not be used for this indication.

Use in pregnancy

Sodium valproate is teratogenic and should not be used.

PRECAUTIONS:

General:

Sodium valproate is NOT indicated for toxicological seizures or seizures due to hypoglycaemia. It may also cause thrombocytopaenia.

Laboratory Tests:

Sodium valproate is a narrow therapeutic index drug with high pharmacokinetic variability. As such there may be poor correlation between sodium valproate plasma concentration and clinical response. Routine testing of valproate levels is unhelpful; some patients are well controlled with serum levels outside the therapeutic range. Serum levels should only be measured if there is a specific clinical indication such as if non-compliance or toxicity are suspected.

If measurement is required, trough levels should be taken i.e. immediately before the next due dose when intermittent dosing is used.

• Use an SST (Yellow) or Plain (Red) tube
• Therapeutic Range: 300 - 600 micmol/L (trough)
• Peak: 1 - 4 hours post dose
• Steady State: 2-3 days
• Half life: 7 - 9 hours
• Toxicity: trough level > 800 micmol/L

Drug/Laboratory Test Interactions:

None known

IMPORTANT DRUG INTERACTIONS IN ICU:

Reduce serum levels of sodium valproate are seen when valproate is co-administered with carbapenems or rifampicin.

The concomitant use of sodium valproate and clonazepam may induce absence status in patients with a history of absence type seizures.

The dose of lamotrigine should be reduced when co-administered with sodium valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and sodium valproate administration.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of sodium valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.

In an in vitro study, sodium valproate increased the unbound fraction of warfarin by up to 33%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Other clinically significant drug interactions are possible.

ADVERSE REACTIONS:

General:

Chest pain, headache, injection site inflammation & pain

Cardiovascular:

Vasodilation, hypotension

Gastrointestinal:

Abdominal pain, diarrhoea, nausea, vomiting

Neurological:

Dizziness, euphoria, hyperaesthesia, nervousness, paraesthesia, somnolence, tremor

Respiratory:

Pharyngitis