Valproate

Valproic acid (2-propyl pentanoic acid, 2-propyl valeric acid) is a short-chain branched fatty acid. Prior to the serendipitous discovery of its anti-epileptic activity in 1963, valproic acid was used as an organic solvent.

UK-SmPC: In the treatment of generalized, partial or other epilepsy.

FDA-PI: (1) 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 and (2) use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

Valproate sodium injection is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible.

Valproate is one of the most effective broad-spectrum AEDs for all types of seizures and epilepsies. It has superior efficacy in all types of generalised seizures (idiopathic and symptomatic), all syndromes of IGE and photosensitive epilepsy compared with any other drug so far, with the probable exception of levetiracetam. The efficacy of valproate has been well documented in long-term and worldwide clinical practice and controlled studies.

However, valproate is (1) far inferior to carbamazepine and some newer AEDs in the treatment of focal epilepsies and (2) has serious ADRs in women of child-bearing age and in patients of early childhood.

Unlike many other AEDs, valproate appears to have a very low potential to aggravate seizures[reference needed].When seizure aggravation occurs with valproate, it is in a specific clinical context, such as overdose, encephalopathy, or hepatic or metabolic disorders.

Dosage and titration Adults: start treatment with 200 mg/day in two equally divided doses for 3 days. Titrate in increments of 200 mg/day every 3 days to a maintenance dose of usually 1000–1500 mg/day (maximum 3000 mg/day) given in two equally divided doses. Higher initial dosage and faster titration rates are usually well tolerated.

Children: start with 10 mg/kg/day. Titrate in increments of 10 mg/kg/day every 3 days. The typical maintenance dose in childhood is 20–30 mg/kg/day in two equally divided doses.

Combined therapy: it may be necessary to increase the dose by 30–50% when used in combination with enzymeinducing AEDs, such as phenytoin, phenobarbital and carbamazepine. On withdrawal of these AEDs, it may be possible to reduce the dose of valproate.

Dosing: twice or three-times daily, and once daily for slow-release formulations.

TDM: often not useful, because of poor correlation between valproate dose and plasma levels. However, because of significant drug interactions, monitoring of valproate and AEDs given concomitantly may be helpful when enzyme-inducing drugs are added or withdrawn.

Reference range (measures valproic acid): 50–100 mg/l (300–700 μmol/l).

Main ADRs Valproate is associated with serious ADRs, particularly in children and women. Acute liver necrosis and acute pancreatitis, which may be fatal, are rare and more likely to occur in children receiving polypharmacy. An estimated 1–2% risk of neural tube defects, predominantly spina bifida aperta, in babies of women on valproate is well established,288,289 and the overall risk of major teratogenic effects with valproate is two to three-times higher than the background prevalence of major non-syndromic congenital anomalies (Table 7.15).16 This together with polycystic ovary syndrome290 and other endocrine ADRs,291 makes the use of valproate in some women undesirable.

CNS-related ADRs: in contrast with other older AEDs, valproate is not usually associated with drowsiness and fatigability or significant dose-related effects on cognition or behaviour. Valproate encephalopathy is exceptional.

Tremor is the more troublesome CNS adverse effect of valproate. There is great individual susceptibility to the development of tremor, which is usually mild, but may become very intense, socially embarrassing and disabling. It is reversible and declines when the dose is lowered.

Systemic: the most serious are fatal hepatotoxicity and acute haemorrhagic pancreatitis.

Hepatic failure resulting in fatalities is primarily age-dependent and occurs mainly in children receiving polypharmacy and with organic brain disease. The risk is 1/600 before the age of 3 years. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups (range 1/8000–1/10,000 between 3 and 20 years of age) and in monotherapy with valproate. Hepatic failure has usually occurred during the first 6 months of treatment. The diagnosis is based on clinical criteria with non-specific symptoms, such as malaise, weakness, lethargy, facial oedema, anorexia, vomiting and loss of seizure control. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. However, this may not be helpful because:

benign elevation of liver enzymes is common during valproate treatment severe hepatotoxicity is not preceded by progressive elevation of liver enzymes. Raised liver enzymes are common during treatment with valproate, particularly if used in conjunction with other AEDs. These are usually transient or respond to dose reduction. Patients with such biochemical abnormalities should be reassessed clinically and liver function tests should be performed more frequently. An abnormally low prothrombin level, particularly in association with other relevant abnormalities, requires withdrawal of valproate. Any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway.

Acute haemorrhagic pancreatitis with markedly increased amylase and lipase levels is another rare, but serious, adverse effect of valproate treatment. It develops within the first 3 months of treatment, is more prevalent in children and with polytherapy.

Hyperammonaemic encephalopathy, which is sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders. When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment with valproate.

Thrombocytopenia and other haematological abnormalities:292 it is recommended that platelet counts and coagulation tests are performed before initiating therapy and at periodic intervals, because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters. Evidence of haemorrhage, bruising or a disorder of haemostasis/coagulation is an indication for reduction or withdrawal of valproate.

Weight gain occurs in 20% of patients and is some-times marked; women are more vulnerable. This is usually reversible if valproate is withdrawn early.

Hair loss and changes in hair texture or colour are relatively rare; they usually occur in the early months of valproate treatment and may resolve spontaneously despite continuation of the drug.

Other ADRs concern the gastrointestinal system (e.g. anorexia, constipation, dry mouth, stomatitis) and urogenital system (e.g. urinary incontinence, vaginitis, dysmenorrhoea, amenorrhoea and urinary frequency).

FDA warning: All patients who are currently taking or starting on valproate for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression (see page xxx).

Considerations in women Valproate treatment in women raises many issues, as has been detailed on many occassion in this book.

Pregnancy: category D.288,289,293 Valproate is teratogenic. It crosses the placenta and causes a spectrum of congenital anomalies, such as neural tube defects, craniofacial malformations and skeletal defects. The incidence of these anomalies is much higher when valproate is given as co-medication with other AEDs (Table 7.15).

Breastfeeding: There appears to be no contraindication to breast feeding; excretion in breast milk is low and with no clinical effects.

Interaction with hormonal contraception: none.

Other issues: see endocrine abnormalities.

Main mechanisms of action The main mechanism of action is unknown and a combination of several mechanisms may be responsible:

reduction of sustained, repetitive, high-frequency firing by inhibiting voltage-sensitive sodium channels, activating calcium-dependent potassium conductance and possibly by direct action on other ion channels valproate has a GABAergic effect through elevation of brain GABA by various mechanisms, such as inhibiting GABA-transaminase (GABA-T), enhancing GABA-synthesising enzymes, increasing GABA release and inhibiting GABA uptake. However, this GABAergic action is observed only at high valproate levels and may explain its efficacy in other, but not absence, seizures. GABAergic drugs that affect GABAB receptors have a pro-absence action because they potentiate absences (see useful note on page XXX). Another explanation for the effect of valproate on absence seizures is that this drug, like ethosuximide, reduces a low threshold (T-type) calcium-channel current,294 but this effect has not been supported by other studies.295 Pharmacokinetics Oral bioavailability: almost complete. Absorption of valproate varies according to the formulation used. Absorption is rapid and peak levels are reached within 2 hours after oral administration of syrup or uncoated tablets. This is longer (3–8 hours) with enteric-coated tablets.

Protein binding: valproate is highly protein bound (about 90%). However, if the plasma level of valproic acid rises above 120 mg/l or if the serum albumin concentration is lowered, the binding sites may become saturated, causing the amount of free drug to rise rapidly, out of proportion to any increase in dosage. Valproate may displace phenobarbital or phenytoin from plasma protein-binding sites.

Metabolism: hepatic. Valproate has a complex metabolism. It is rapidly and nearly totally eliminated by hepatic metabolism with numerous metabolites that contribute to its efficacy and toxicity. Two metabolites of valproate, 2-ene-valproic acid and 4-ene-valproic, are among the most pharmacologically active and have a similar potency to the parent drug. They are both produced by the action of CYP enzymes induced by other AEDs. They are eliminated primarily in the urine.

The major elimination pathway is via glucuronidation (40–60%). The remainder is largely metabolised via oxidation pathways, β-oxidation accounting for 30–40% and ω-oxidation, which is CYP dependent. Only 1–3% of the ingested dose is excreted unchanged in the urine.

Elimination half-life: this is variable, but generally appears to be 8–12 hours (range 4–16 hours). It is shorter in patients receiving enzyme-modifying AEDs or in long-term valproate treatment of children and adults. Many antipsychotic and antidepres sant drugs result in competitive metabolism or enzyme inhibition when given as a co-medication with valproate.

Drug interactions There are numerous drug interactions with valproate because:

its metabolism is sensitive to enzymatic induction it inhibits the metabolism of other drugs it has a high affinity for serum proteins; it may be displaced or displace other drugs. Effect of other AEDs on valproate: enzyme inducers, particularly those that elevate levels of UGTs, such as phenobarbital, phenytoin and carbamazepine, may increase the clearance of valproate, thus reducing plasma valproate levels by 30–50%.

The addition of ethosuximide may reduce the plasma concentration of valproate.

Effects of valproate on other AEDs: valproate does not interact with most of the newer AEDs. A notable exception is lamotrigine.296 Valproate is a potent inhibitor of UGT-dependent metabolism of lamotrigine, and doubles251 or triples76 its plasma half-life.

The addition of valproate to ethosuximide or phenobarbital may double the plasma concentration of these AEDs with concomitant toxicity.

There is evidence of severe CNS depression, with or without significant elevations of barbiturate or valproate plasma concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Plasma barbiturate concentrations should be measured, if possible, and the barbiturate dosage decreased, if appropriate.

Plasma levels of carbamazepine decrease to around 17%, while those of carbamazepine-10,11-epoxide increase by 45% on co-administration with valproate.

Valproate displaces phenytoin from its plasma albumin-binding sites and inhibits its hepatic metabolism. Valproate significantly increases the free fraction of phenytoin and reduces its total plasma concentration.

Valproate does not interact with hormonal contraception.

Main disadvantages The superior efficacy of valproate in generalised seizures is hindered by serious acute and chronic ADRs. It is particularly unsuitable for:

women, because of hormonal changes, weight gain and teratogenicity; it is virtually impossible to prescribe valproate to young women today. There are increasing numbers of litigations against physicians and health authorities by parents of children with foetal valproate syndrome (even if the risks were appropriately explained to them) on a scale characterised by the media as ‘bigger than thalidomide’. young children, particularly those Valproate is the superior AED for generalised epilepsies, but its use in focal epilepsies is of very limited value, because:

the doses of valproate required to be effective are much higher in focal than generalised epilepsies ADRs , particularly in some women, make its use undesirable there are other, more effective and safer drugs for focal seizures (see Chapter 15).