VALPROATE WINTHROP

What it is

VALPROATE is a solution for injection containing the active ingredient sodium valproate 100 mg/mL. It is a clear and colourless solution for injection in a Type I glass ampoule. VALPROATE 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

VALPROATE is used for the treatment of patients with epilepsy or mania, who would normally be maintained on oral sodium valproate, and for whom oral therapy is temporarily not possible. — Epilepsy, in patients who would normally be maintained on oral sodium valproate and for whom oral therapy is temporarily not possible — Mania, in patients 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 and method of administration is as above. 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.

Key safety warnings

Cases of life-threatening pancreatitis have been reported in both children and adults receiving sodium valproate. Some cases have occurred 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. Some of the cases have been described as haemorrhagic with a rapid progression from initial symptoms to death. Patients and guardians should be warned that acute abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical attention. Severe liver damage and/or hepatic failure resulting in fatalities, have occurred in patients whose treatment included valproic acid or sodium valproate. Patients most at risk are those on multiple anticonvulsant therapy and children, particularly those under the age of 3 years and those with congenital metabolic or degenerative disorders, organic brain disease or severe seizure disorders associated with brain damage and/or mental retardation. Jaundice, serious or fatal hepatotoxicity may be preceded by nonspecific symptoms, usually of sudden onset, such as loss of seizure control, malaise, asthenia, weakness, lethargy, facial oedema, anorexia, vomiting, abdominal pain, drowsiness, jaundice. Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders. Data from a meta-analysis 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%. Antiepileptic drugs, including sodium valproate increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour, and appropriate treatment should be considered.

Contraindications

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 eg Alpers-Huttenlocher Syndrome) and in children under two years of age who are suspected of having POLG-related disorder. In pregnancy for treatment of epilepsy, unless there is no suitable alternative treatment, and in women of childbearing potential, unless the physician has provided information in regard to the potential effects of valproate during pregnancy and recommendations on the use of valproate. In pregnancy for treatment of mania, and in women of childbearing potential, unless the physician has provided information in regard to the potential effects of valproate during pregnancy and the recommendations on the use of valproate.

Regulatory history

VALPROATE sodium valproate solution for injection was first listed on the ARTG on 2024-08-19 in six variants: 300 mg/3 mL and 400 mg/4 mL vials, with multiple sponsor registrations.