Depakote

1 What is Depakote?

Brand: Depakote, Depakote DR, Depakote ER, Depakote Sprinkles

Generic: Divalproex sodium

Brand Name:

Depakote, Depakote DR, Depakote ER, Depakote Sprinkles.

Divalproex sodium is the coordination compound of valproic acid with sodium valproate. 

It is widely prescribed to treat different types of seizures such as generalized tonic-clonic seizures, absence seizures, tonic, atonic and myoclonic seizures and partial seizures with or without secondary generalization. 

It is also regarded as mood-stabilizing drug and clinically used in treatment and prophylaxis of bipolar disorder. This drug appears to act by multiple mechanisms:

  • A phenytoin-like frequency-dependent prolongation of sodium channel inactivation
  • Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation as well as probably by increasing its synthesis from glutamic acid. However, responses to exogenously applied GABA are not altered.
  • Weak attenuation of T-type calcium channel

Oral absorption of valproic acid is good. It is 90% bound to plasma proteins; completely metabolized in liver by oxidation and glucuronide conjugation, and then excreted in urine. 

As its plasma half-life is 10-15 hours, its anticonvulsant effects are longer lasting.  

On the contrary, oral absorption of divalproex is slower, but bioavailability is the same associated with better gastric tolerance. 125, 250 and 500 mg tablets are available in the market. 

2 What to Know Before Using

Epilepsy is a recurrent tendency to spontaneous, intermittent, abnormal electrical activity in part of the brain, manifesting as seizures. 2/3rd cases of epilepsy are idiopathic, often familial. 

Cortical scarring resulting from head injury, cortical dysgenesis, space-occupying lesion, stroke, sarcoidosis, hemorrhage, alcohol or benzodiazepine withdrawal and certain metabolic disturbances may cause epilepsy (seizures).

You should not delay to visit a doctor after a first-ever seizure. Before you start a drug therapy, you must be confirmed what type of seizure it is. 

Prompt diagnosis of such medical emergency lessens the upcoming complications

Involvement of patients in all decisions is must. Concordance depends on communication and doctor-patient negotiation. Living with active epilepsy creates many problems such as inability to drive or operate machinery, drug side-effects etc. and fears of sudden death. 

Neurologists may have little time to explore these issues. You can enlist the help of an epilepsy nurse specialist, who can provide you with telephone advices and annual reviews to monitor drug efficacy and side-effects.

Most patients are seizure-free within a few years of starting drugs. More than 50% remain so when drugs are withdrawn. 

After assessing risks and benefits for the individual patient, withdrawal may be tried, if the patients meet these criteria: normal CNS examination, normal IQ, normal EEG prior to withdrawal, seizure-free for more than 2 years, and no juvenile myoclonic epilepsy.

If drugs don’t work then, neurosurgical resection may be done after identifying a single epileptogenic focus or a small low-grade tumor. 

This procedure offers up to 70% chance of seizure freedom. An alternative is vagal nerve stimulation, which can reduce seizure frequency and severity in about 33% cases.

3 Proper Usage

In order to treat generalized tonic-clonic seizures, divalproex is used as the first-line drug. It is also prescribed to treat partial seizures and absence seizures. 

Because of its mood stabilizing effect, mania and bipolar disorders may warrant the use of such medication as an alternative to lithium. 

Additionally, it has some prophylactic efficacy in migraine

Dose: initially 300mg/12h, increase by 100mg/12h every 3 days up to max 30mg/kg or 2.5g daily.

You should treat with one drug and with one doctor in charge only. Slowly build up doses over 2-3 months until seizures are controlled, side-effects are bad, or maximum dosage is reached. 

If ineffective or not tolerated, switch to the next most appropriate drug. To switch drugs, introduce the new drug, and only withdraw the 1st drug once established on the 2nd. 

Dual therapy is necessary in less than 10% of patients if all appropriate drugs have been tried singly at the optimum dose.

4 Precautions to Take

Drugs should not be advised after one fit, unless risk of recurrence is high (e.g. structural brain lesion, focal CNS deficit, or unequivocal epileptiform EEG). 

After a 2nd fit, drugs are probably indicated. Drug choice depends on seizure type and epilepsy syndrome, other medications and co-morbidities, plans for pregnancy, and patient preference. Driving should be avoided until seizure-free for at least one year or more. 

Some drug interactions may take place when divalproex is used simultaneously with some other drugs:

Divalproex increases plasma levels of phenobarbitone and lamotrigine by inhibiting their metabolism.

  • It inhibits hydrolysis of active epoxide metabolite of carbamazepine.
  • It displaces phenytoin from protein binding site and decreases its metabolism which may invite phenytoin toxicity.
  • Foetal abnormalities are more common if valproate and carbamazepine are given concurrently.

5 Potential Side Effects

The toxicity of divalproex is relatively low. Anorexia, nausea, vomiting, loose motions and heart burn are common but mild. Pancreatitis is also reported in some individuals. 

Drowsiness, ataxia, and tremor are dose-related side effects. However, cognitive and behavioral effects are not prominent. Alopecia, curling of hair, weight gain and increased bleeding tendency have been observed. 

Rashes and thrombocytopenia are infrequent hypersensitivity phenomena. Asymptomatic rise in serum transaminase is often noted. Thus, monitoring of liver function is advised. 

A rare but serious adverse effect is fulminant hepatitis; occurs only in children ( especially below 3 years). Those with hepatic disease or who receive other anticonvulsant or hepatotoxic drug are at greater risk. 

Long-term use of valproate in young girls has been associated with higher incidence of irregular menstruation and polycystic ovarian disease. 

Used during pregnancy, it has produced spina bifida and other neural tube defects in the offspring. That’s why, divalproex is strictly avoided in pregnant women.

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