Anticonvulsant, Antimanic, migraine headache prophylactic (USP DI 2005)
Each Teaspoonful (5ml) of syrup contains 200 mg of valproate sodium.
Valproate sodium is the sodium salt of valproic acid designated as sodium 2- propylpentanoate. Its structural formula is as below. (PDR 2008)
Molecular Weight = 166.2
Mechanism of action:
The mechanism of action has not been established. However, It is thought to be related to a direct or secondary increase in concentrations of the inhibitory neurotransmitter, gamma – aminobutyric acid (GABA) possibly caused by its decreased metabolism or decreased reuptake in brain tissues.
Another hypothesis is that valproate acts on postsynaptic receptor sites to mimic or enhance the inhibitory action of GABA. (USP DI 2007)
Absorption: Rapid absorption from gastrointestinal tract slight delay when taken with food. (USP DI 2007)
The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mg/ml to 18.5% at 130mic/ml . Protein binding of valproate is reduced in the elderly , in patients with hypoalbominemia, chronic hepatic diseases, in patients with renal impairment and in the presence of other drugs (e.g, Aspirin). Conversely, valproate may displace certain protein – bound drugs (e.g, phenytoin , carbamazepine, warfarin and tolbutamide). (PDR 2008)
Valproate concentrations in the cerebrospinal fluid approximate unbound concentrations in plasma, which is about 10% of the total concentration. (USP DI 2007)
Primarily hepatic. Some metabolites may have pharmacologic or toxic activity. (USP DI 2007)
Half life: Variable, from 6 to 16 hours, may be considerably longer in patients with hepatic function impairment. in the eldery, and in children up to 18 months of age, may be considerably shorter in patients receiving hepatic enzyme – inducing anticonvulsants. (USP DI 2007)
Time to peak serum concentration:
1 to 4 hours (USP DI 2007)
Renal, mainly as glucuronide conjugate, small amounts excreted in feces and expired air. (USP DI 2007)
Valproate sodium is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. It is also indicated for use as sole and adjunctive therapy in the treatment of patients with simple and complex absence seizures and adjunctively in patients with multiple seizure types that include absence seizures. (PDR 2008)
Valproate sodium should not be administered to patients with hepatic disease or significant hepatic dysfunction. Valproate sodium is contraindicated in patients with known hypersensitivity to the drug and patients with known urea cycle disorders. (PDR 2008)
1- Hepatic dysfunction (the drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent.
5- Hepatotoxicity: Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy.
6- Urea Cycle Disorders (UCD)
7- Somnolence in elderly ( PDR 2008 )
Valproic acid may produce teratogenic effects in the offspring of human females receiving the drug during pregnancy. The incidence of neural tube defects in the fetus may be increased in mothers receiving valproate during the first trimester of pregnancy. Other congenital anomalies (e.g craniofacial defects, cardiovascular malformations and anomalies involving various body systems), compatible and incompatible with life, have been reported.
Sufficient data to determine the incidence of these congenital anomalies is not available. (PDR 2008) Risk – benefit must be carefully considered when these medications are required to treat epilepsy in pregnant patients for whom other medications are ineffective or cannot be used. FDA pregnancy category D. (USP DI 2007)
Breast – feeding:
Drugs that affect the level of expression of hepatic enzymes, particulary those that elevate levels of glucuronosyl transferases, may increase the clearance of valproate. For example (phenytoin, carbamazepine, phenobarbital, primidone) can double the clearance of valproate. (PDR 2007)
- Aspirin: Valproate free fraction was increased 4 fold in the presence of Aspirin compared to valproate alone.
- Rifampin: Valproate dosage adjustment may be necessary when it is co-administered with rifampin.
- Felbamate: A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
- Antidepressants tricyclics, bupropion, clozapine, haloperidol, Maprotiline, Loxapine, Molindone, enhancing CNS depression When used concurrently with valproic acid. (USP DI 2007)
- Clonazepam The concomitant use of valproic acid & clonazepam may produce absence status in patients with a history of absence type seizures. (USP DI 2007)
- Diazepam: Valproate displaces diazepam from its plasma albumin binding sites & inhibits its metabolism.
- Ethosuximide: Valproate inhibits the metabolism of ethosuximide.
- Phenobarbital: Valproate was found to inhibit the metabolism of Phenobarbital . (USP DI 2007)
Those indicating need for medical attention:
- Hepatic failure resulting in death has occurred in patients receiving valproic acid.
- Behavioral, mood or mental changes, hepatotoxicity or hyperammonemia, platelet aggregation inhibition or thrombocytopenia, hematemesis, edema, hypotension, nystagmus, ophthalmological effects, otitis media. Those indicating need for medical attention only if they continue or are bothersome:
- Abdominal or stomach cramps, anorexia, change in menstrual periods, diarrhea, hair loss, alopecia, amblyopia, amnesia, back pain, headache, insomnia, rash, tinnitus. (USP DI 2007)
Administration & usage:
– Valproic acid is indicated in the treatment of simple and complex absence seizures, it is indicated as adjuncts in coditions of multiple seizures that include absence seizures and as primary agents for myoclonic seizures. It may be useful in patient with partial seizures. (USPDI 2007)
– Usual adult and adolescent dose:
- Monotherapy: oral, initially 5 to 15 mg per kg of body weight a day, the dosage being increased at one – week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated.
- Polytherapy: oral, initially, 10 to 30 mg per kg of body weight a day the dosage being increased at one – week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated . If the total daily dose exceeds 250mg , it should be divided into two or more doses (usually given every 12 hours) to lessen the possibility of gastrointestinal irritation.
Usual adult preseribing limits:
– 60 mg per kg of body weight a day
Usual pediatric dose:
Anticonvulsant – children 1 to 12 years of old-
Monotherapy: oral, initially 15 to 45 mg per kg of body weight a day. The dosage being increased at one – week intervals by 5 to 10 mg per kg of body weight a day as needed & tolerated.
Polytherapy: oral 30 to 100 mg per kg of body weight a day.
Usual geriatric dose:
Geriatric patients may need lower doses. (USP DI 2007)
Store below 30˚C. Store in a tight container. Protect from freezing. (USP DI 2007)