VALPROATE-AFT

What it is

Valproate-AFT is a sterile, non-pyrogenic solution for injection or infusion containing sodium valproate in strengths of 300 mg/3 ml, 400 mg/4 ml, and 1000 mg/10 ml. Valproate-AFT may be given by direct slow intravenous injection or by slow intravenous infusion in 0.9% NaCl (normal saline), 5% glucose solution or glucose saline, using a separate intravenous line.

Approved indications

— Treatment of patients with epilepsy who would normally be maintained on oral sodium valproate and for whom oral therapy is temporarily not possible. — Treatment of patients with mania who would normally be maintained on oral sodium valproate and for whom oral therapy is temporarily not possible.

Dosing overview

Patients already satisfactorily treated with sodium valproate may be continued at their current dosage using continuous infusion; for example, a patient stabilised on 25 mg/kg administered daily should be continued with an infusion at the rate of 1 mg/kg/hr. Other patients may be given a slow intravenous injection over 3–5 minutes, usually 400–800 mg depending on body weight (up to 10 mg/kg) followed by continuous infusion of 1–2 mg/kg/hr up to a maximum of 2500 mg/day, according to the patient's clinical response. The daily requirement for children is usually in the range 20–30 mg/kg/day; where adequate control is not achieved within this range the dose may be increased up to 40 mg/kg/day but only in patients in whom plasma valproic acid levels can be monitored. Valproate-AFT should be replaced by oral sodium valproate therapy as soon as practicable.

Key safety warnings

Severe liver damage and hepatic failure resulting in fatalities have occurred in patients whose treatment included valproic acid or sodium valproate, with patients on multiple anticonvulsant therapy and children (particularly those under 3 years) at highest risk; incidents usually occurred during the first six months of therapy, with maximum risk between 2 and 12 weeks. Jaundice and serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as loss of seizure control, malaise, weakness, lethargy, facial oedema, anorexia, vomiting, abdominal pain, drowsiness and jaundice, which are an indication for immediate withdrawal of the medicine. Cases of life-threatening pancreatitis have been reported in both children and adults receiving sodium valproate, with some cases occurring shortly after initial use while others have occurred after several years of use; there have also been cases in which pancreatitis recurred after rechallenge with sodium valproate. Patients and guardians should be warned that acute abdominal pain, nausea, vomiting and anorexia can be symptoms of pancreatitis requiring prompt medical attention; if pancreatitis is diagnosed, sodium valproate should be discontinued. Antiepileptic drugs, including sodium valproate, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication; patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and any unusual changes in mood or behaviour. This medicine should not be used in female children, female adolescents, women of child-bearing potential and pregnant women unless alternative treatments are ineffective or not tolerated because of its high teratogenic potential and risk of developmental disorders in infants exposed in utero to valproate.

Contraindications

Pregnancy. Pre-existing, acute or chronic hepatic dysfunction or family history of severe hepatitis, particularly medicine-related. Known hypersensitivity to the medicine. Known urea cycle disorders. Known hepatic porphyria. Patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase γ (POLG, for example Alpers-Huttenlocher Syndrome) and in children under two years of age who are suspected of having POLG-related disorder. Sodium valproate should not be injected intramuscularly as it may produce tissue necrosis.

Regulatory history

Valproate-AFT was first listed on the ARTG on 14 February 2019 across six registrations covering strengths of 300 mg/3 ml, 400 mg/4 ml and 1000 mg/10 ml in both ampoule and vial presentations.