Action And Clinical Pharmacology: Although valproic acid’s mechanism of action has not yet been established, the drug’s anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA). The effect on the neuronal membrane is unknown.
Valproic acid is rapidly absorbed after oral administration. Peak serum levels occur approximately 1 to 4 hours after a single oral dose. The serum half-life of valproic acid is typically in the range of 6 to 16 hours. Half-lives in the lower part of the above range are usually found in patients taking other antiepileptic drugs. A slight delay in absorption occurs when the drug is administered with meals but this does not affect the total absorption. Valproic acid is rapidly distributed throughout the body and the drug is strongly bound (90%) to human plasma proteins. Increases in dose may result in decreases in the extent of protein binding and variable changes in valproic acid clearance and elimination. The therapeutic plasma concentration range is believed to be from 50 to 100 g/mL. Occasional patients may be controlled with serum levels lower or higher than this range. A good correlation has not been established between daily dose, serum levels and therapeutic effect.
Valproic acid is primarily metabolized in the liver to the glucuronide conjugate. Very little unmetabolized parent drug is excreted in the urine. Elimination of valproic acid and its metabolites occurs principally in the urine, with minor amounts in the feces and expired air.
See Warnings regarding statement on fatal hepatic dysfunction.
Indications And Clinical Uses: As sole or adjunctive therapy in the treatment of simple or complex absence seizures, including petit mal, and is useful in primary generalized seizures with tonic-clonic manifestations. Valproic acid may also be used adjunctively in patients with multiple seizure types which include either absence or tonic-clonic seizures.
Simple absence is defined as a very brief clouding of the sensorium or loss of consciousness (lasting usually 2 to 15 seconds) accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
Contra-Indications: Patients with hepatic disease or significant dysfunction. Hypersensitivity to valproic acid.
Manufacturers’ Warnings In Clinical States: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidences usually have occurred during the first 6 months of treatment with valproic acid.
A recent survey study of valproate use in the United States in nearly 400 000 patients between 1978 and 1984, has shown that children under 2 years of age who received the drug as part of multiple anticonvulsant therapy were at greatest risk (nearly 20 fold increase) of developing fatal hepatotoxicity. These patients typically had other medical conditions such as congenital metabolic disorders, mental retardation or organic brain disease, in addition to severe seizure disorders. The risk in this age group decreased considerably in patients receiving valproate as monotherapy. Similarly, patients aged 3 to 10 years were at somewhat greater risk if they received multiple anticonvulsants than those who received only valproate. Risk generally declined with increasing age. No deaths have been reported in patients over 10 years of age who received valproate alone.
If valproic acid is to be used in children 2 years old or younger, it should be used with extreme caution and as a sole agent. The benefits of seizure control should be weighed against the risk.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as loss of seizure control, malaise, weakness, lethargy, anorexia and vomiting. Patients and parents should be instructed to report such symptoms. Because of the non-specific nature of some of the early signs, hepatotoxicity should be suspected in patients who become unwell, other than through obvious cause, while taking valproic acid.
Liver function tests should be performed prior to therapy and at frequent intervals thereafter especially during the first 6 months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproic acid to patients with a prior history of hepatic disease. Patients with various unusual congenital disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.
In high-risk patients, it might also be useful to monitor serum fibrinogen and albumin for decrease in concentrations and serum ammonia for increases in concentration. If changes occur, valproic acid should be discontinued. Dosage should be titrated to and maintained at the lowest dose consistent with optimal seizure control.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of the drug. The frequency of adverse effects, particularly elevated liver enzymes, may increase with increasing doses. Therefore, the benefit gained by improved seizure control by increasing the dosage must be weighed against the increasing incidence of adverse effects sometimes seen at higher dosages.
Pregnancy: According to recent reports in the medical literature, valproic acid may produce teratogenicity in the offspring of human females receiving the drug during pregnancy. The incidence of neural tube defects in the fetus may be increased in the mothers receiving valproic acid during the first trimester of pregnancy. Based upon a single report, it was estimated that the risk of valproic acid exposed women having children with spina bifida is approximately 1.2%. This risk is similar to that which applies to non-epileptic women who have had children with neural tube defects (anencephaly and spina bifida). Animal studies have demonstrated teratogenicity, and studies in human females have demonstrated placental transfer of the drug.
Multiple reports indicate an association between the use of antiepileptic drugs and an elevated incidence of birth defects in children born to epileptic women taking such medication during pregnancy. The incidence of congenital malformations in the general population is regarded to be approximately 2%, in children of treated epileptic women, this incidence may be increased 2 to 3-fold. The increase is largely due to specific defects, e.g., congenital malformations of the heart, cleft lip and/or palate and neural tube defects. Nevertheless, the great majority of mothers receiving anticonvulsant medications deliver normal infants.
Data are more extensive with respect to phenytoin and phenobarbital, the most commonly prescribed anticonvulsants. Some reports indicate a possible similar association with the use of other antiepileptic drugs, including trimethadione, paramethadione and valproic acid. However, the possibility also exists that other factors, e.g., genetic predisposition or the epileptic condition itself, may contribute to, or may be mainly responsible for the higher incidence of birth defects.
Antiepileptic drugs should not be discontinued in patients to whom the drug is administered to prevent major seizures, because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risks to both the mother and the unborn child. The risks of discontinuing drugs given for minor seizures prior to or during pregnancy should be weighed against the risk of congenital defects in the particular case and with the particular family history.
Epileptic women of childbearing age should be encouraged to seek the counsel of their physician and should report promptly to him the onset of pregnancy. Where the necessity for continued use of antiepileptic medication is in doubt, appropriate consultation might be indicated.
Lactation: Valproic acid is secreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentrations. As a general rule, nursing should not be undertaken while a patient is receiving valproic acid.
Fertility: Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at doses greater than 200 mg/kg/day in rats and 90 mg/kg/day in dogs. Segment I fertility studies in rats have shown that doses up to 350 mg/kg/day for 60 days have no effect on fertility. The effect of valproic acid on the development of the testes and on sperm production and fertility in humans is unknown.
Long-term toxicity studies in rats and mice indicate a potential carcinogenic risk.
Precautions: Hepatic dysfunction: See Contraindications and Warnings.
General: Because of reports of thrombocytopenia and inhibition of platelet aggregation, platelet counts and bleeding time determination are recommended before instituting therapy and at periodic intervals. It is recommended that patients be monitored for platelet count prior to planned surgery. Clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of dosage or withdrawal of therapy pending investigation.
Hyperammonemia with or without lethargy or coma has been reported and may be present in the absence of abnormal liver function tests; if elevation occurs the valproic acid should be discontinued.
Because valproic acid may interact with other antiepileptic drugs, periodic serum level determinations of concurrently administered antiepileptics are recommended during the early part of therapy (see Drug Interactions). There have been reports of breakthrough seizures occurring with the combination of valproic acid and phenytoin.
Valproic acid is partially eliminated in the urine as a ketone-containing metabolite which may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproic acid: the clinical significance of these is unknown.
Valproic acid may produce CNS depression, especially when combined with another CNS depressant such as alcohol.
Occupational Hazards: Patients should be advised not to engage in potentially hazardous occupations such as driving a car or operating dangerous machinery until it is known that they do not become drowsy from the drug.
Drug Interactions: Valproic acid may potentiate the CNS depressant action of alcohol.
There is evidence that valproic acid may cause an increase in serum phenobarbital levels by impairment of non-renal clearance. This phenomenon can result in severe CNS depression. The combination of valproic acid and phenobarbital has also been reported to produce CNS depression without significant elevations of barbiturate or valproic acid serum levels. Patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate drug levels should be obtained, if possible, and the barbiturate dosage decreased, if indicated.
Primidone is metabolized into a barbiturate, and therefore, may also be involved in a similar or identical interaction.
There is conflicting evidence regarding the interaction of valproic acid with phenytoin (see Precautions). It is not known if there is a change in unbound (free) phenytoin serum levels. The dose of phenytoin should be adjusted as required by the clinical situation.
The concomitant use of valproic acid and clonazepam may produce absence status.
Caution is recommended when valproic acid is administered with drugs affecting coagulation, e.g., ASA and warfarin (see Adverse Effects).
Adverse Reactions: The most commonly reported adverse reactions are nausea, vomiting and indigestion. Since valproic acid has usually been used with other antiepileptics, in most cases it is not possible to determine whether the adverse reactions mentioned are due to valproic acid alone or to the combination of drugs.
Gastrointestinal: Nausea, vomiting and indigestion are the most commonly reported side effects at the initiation of therapy. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps and constipation have also been reported. Anorexia with some weight loss and increased appetite with some weight gain have also been observed.
CNS Effects: Sedative effects have been noted in patients receiving valproic acid alone, but are found most often in patients on combination therapy. Sedation usually disappears upon reduction of other antiepileptic medication. Ataxia, headache, nystagmus, diplopia, asterixis, “spots before the eyes”, tremor, dysarthria, dizziness and incoordination have been noted rarely. Rare cases of coma have been reported in patients receiving valproic acid alone or in conjunction with phenobarbital.
Dermatologic: Transient increases in hair loss have been observed. Skin rash and petechiae have rarely been noted.
Endocrine: There have been reports of irregular menses and secondary amenorrhea in patients receiving valproic acid.
Abnormal thyroid function tests have been reported (see Precautions).
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity and behavioural deterioration have been reported.
Musculoskeletal: Weakness has been reported.
Hematopoietic: Thrombocytopenia has been reported. Valproic acid inhibits the second phase of platelet aggregation (see Precautions). This may be reflected in altered bleeding time. Bruising, hematoma formation and frank hemorrhage have been reported. Relative lymphocytosis and hypofibrinogenemia have been noted. Leukopenia and eosinophilia have also been reported. Anemia and bone marrow suppression have been reported.
Hepatic: Minor elevations of transaminases [(e.g. AST and ALT] and LDH are frequent and appear to be dose related. Occasionally, laboratory tests also show increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity (see Warnings).
Metabolic: Hyperammonemia (see Precautions). Hyperglycinemia has been reported and associated with a fatal outcome in a patient with pre-existing nonketotic hyperglycinemia.
Pancreatic: There have been reports of acute pancreatitis occurring in association with valproic acid therapy.
Other: Edema of the extremities has been reported.
Symptoms And Treatment Of Overdose: Symptoms: In a reported case of ingestion of 36 g of valproic acid in combination with phenobarbital and phenytoin, the patient presented in deep coma. An EEG recorded diffuse slowing, compatible with the state of consciousness. The patient made an uneventful recovery.
Treatment: Naloxone has been reported to reverse the CNS depressant effects of valproic acid overdose. Because naloxone could theoretically also reverse the antiepileptic effects of valproic acid it should be used with caution.
As valproic acid is absorbed very rapidly, gastric lavage may be of limited value. Apply general supportive measures with particular attention to the prevention of hypovolemia and the maintenance of adequate urinary output.
Dosage And Administration: Administered orally. The recommended initial dose is 15 mg/kg/day orally, increasing at 1-week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. Maximum recommended dose is 60 mg/kg/day. When the total daily dose exceeds 250 mg, it should be given in a divided regimen (see Table I). A 500 mg enteric-coated capsule may be substituted for two 250 mg capsules. The frequency of adverse effects (particularly elevated liver enzymes) may increase with increasing dose. Therefore, the benefit gained by improved seizure control must be weighed against the increased incidence of adverse effects.
As the valproic acid dosage is raised, blood levels of phenobarbital and/or phenytoin may be affected (see Precautions).
Patients who experience gastrointestinal irritation may benefit from administration of valproic acid with food or by a progressive dosage increase from an initial low level. The capsules should be swallowed without chewing to avoid local irritation of the mouth and throat.
Availability And Storage: Capsules: 250 mg: Each orange-colored, soft gelatin capsule contains: valproic acid 250 mg. Nonmedicinal ingredients: corn oil, ethyl vanillin, FD&C yellow no. 6, gelatin, glycerin, methylparaben, propylparaben and titanium dioxide. Alcohol-, gluten-, lactose-, sucrose-, sulfite- and tartrazine-free. Bottles of 100 and 500.
500 mg: Each pale yellow, oval, soft gelatin enteric coated capsule contains: valproic acid 500 mg. Nonmedicinal ingredients: cellulose acetate phtalate, dextrose, diethyl phtalate, ethyl acetate, gelatin, glycerin, methylparaben, propylparaben, tartrazine and titanium dioxide. Alcohol-, gluten-, lactose-, sucrose- and sulfite-free. Bottles of 100 and 500.
Syrup: Each 5 mL of red syrup contains: the equivalent of 250 mg valproic acid, as the sodium salt. Nonmedicinal ingredients: artificial flavor, glycerin, hydrochloric acid, methylparaben, propylparaben, Red Amaranth Canadian Certified Food Color, sodium hydroxide, sorbitol, sucrose and vanillin. Energy: 74.08 kJ (17.70 kcal)/5 mL. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Bottles of 450 mL.
DEPAKENE® Abbott Valproic Acid Anticonvulsant