Action And Clinical Pharmacology: Although not yet established, the mechanism of valproic acid’s anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA). The effect of the drug on the neuronal membrane is unknown.
Valproic acid is rapidly absorbed after oral administration, with peak serum levels occurring approximately 1 to 4 hours after a single oral dose. The half-life of valproic acid in serum is typically in the range of 7 to 16 hours. Usually patients taking other antiepileptic drugs have half-lives in the lower part of this range. When the drug is administered with meals, a slight delay in absorption occurs, but this does not affect the total absorption. Distribution of valproic acid throughout the body is rapid. The drug is strongly bound (95%) to human plasma proteins. Decreases in the extent of protein binding and variable changes in valproic acid clearance and elimination may result with increases in dose. The therapeutic plasma concentration is believed to range from 50 to 100 Âµg/mL. Occasionally, certain patients may be controlled by serum levels lower or higher than this. A good correlation between daily dose, serum levels and therapeutic effect has not been established.
Valproic acid is primarily metabolized to the glucuronide conjugate in the liver. Only very little unmetabolized parent drug is excreted in the urine. Valproic acid and its metabolites are principally eliminated in the urine, with minor amounts appearing in the feces and expired air.
See statement on fatal hepatic dysfunction in Warnings.
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 also may be used adjunctively in patients with multiple seizure types including either absence or tonic clonic seizures.
Simple absence is defined as a very brief loss of consciousness or clouding of the sensorium (lasting usually 2 to 15 seconds) accompanied by certain generalized epileptic discharges without other detectable clinical signs. When other signs are also present, complex absence is the term used.
Contra-Indications: Patients with hepatic disease or significant dysfunction and those hypersensitive to valproic acid.
Manufacturers’ Warnings In Clinical States: There have been fatalities due to hepatic failure in patients receiving valproic acid. Usually these incidences have occurred during the first 6 months of treatment with valproic acid.
Children under 2 years of age who received valproic acid as part of multiple anticonvulsant therapy were shown in a recent survey study of valproate use in the United States in nearly 400 000 patients between 1978 and 1984 to be at the greatest risk (nearly 20-fold increase) of developing fatal hepatotoxicity. In addition to severe seizure disorders, these patients typically had other medical conditions such as congenital metabolic disorders, mental retardation or organic brain disease. In patients receiving valproate as monotherapy, the risk in this age group decreased considerably. Patients aged 3 to 10 years were similarly at somewhat greater risk if they received multiple anticonvulsants than those who received only valproate. Generally, risk declined with increasing age. There have been no reports of death in patients over 10 years of age who received valproate alone.
Valproic acid should be used with extreme caution and as a sole agent if it is to be used in children 2 years old or younger. The benefits of control of seizures should be weighted against the risk.
Nonspecific symptoms such as loss of seizure control, malaise, weakness, lethargy, anorexia and vomiting may precede serious or fatal hepatotoxicity. Parents and patients should be instructed to report such symptoms. In patients who become unwell, other than through obvious cause, while taking valproic acid, hepatotoxicity should be suspected because of the nonspecific nature of some of the early signs.
Liver function tests should be performed prior to therapy and, especially during the first 6 months, at frequent intervals. Physicians should not rely totally on serum biochemistry however, since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Patients with a prior history of hepatic disease should be administered valproic acid with caution. At particular risk are those patients with various unusual congenital disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease.
It might also be useful in high risk patients to monitor serum fibrinogen and albumin for decrease in concentrations and serum ammonia for increases in concentration. Valproic acid should be discontinued if changes occur. Dosage should be maintained at the lowest dose found by titration to provide optimal seizure control.
In the presence of significant hepatic dysfunction, suspected or apparent, the drug should be discontinued immediately. Hepatic dysfunction has progressed in spite of discontinuation of the drug in some cases. With increasing doses the frequency of adverse effects, particularly elevated liver enzymes, may increase. Therefore, it is necessary to weigh the benefits gained by improved seizure control by increasing the dosage against the increasing incidence of adverse effects sometimes seen at higher dosages.
Pregnancy: Recent reports in the medical literature indicate that valproic acid may produce teratogenicity in the offspring of human females receiving the drug during pregnancy. The fetus of a mother receiving valproic acid during the first trimester of pregnancy may have an increased incidence of neural tube defects. Based upon a single report, the risk of valproic acid exposed women having children with spina bifida was estimated to be approximately 1.2%. This is similar to the risk which applies to nonepileptic women who have had children with neural tube defects (spina bifida and anencephaly). Teratogenicity has been demonstrated in animal studies, and placental transfer of the drug has been demonstrated in studies in human females.
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 has been indicated in multiple reports. The incidence in the general population of congenital malformations is regarded to be approximately 2%. In children of treated epileptic women, this incidence may be increased 2 to 3-fold. Specific defects, e.g., congenital malformations of the heart, cleft lip and/or palate and neural tube defects are largely responsible for this increase. Nevertheless, normal infants are delivered to the great majority of mothers receiving anticonvulsant medications.
With respect to phenytoin and phenobarbital, the most commonly prescribed anticonvulsants, data are more extensive. Some reports indicate that a similar association with the use of other antiepileptic drugs, including trimethadione, paramethadione and valproic acid, is possible. However, it is also possible 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.
Because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risks to both the mother and the unborn child, antiepileptic drugs should not be discontinued in patients to whom the drug is administered to prevent major seizures. It is necessary to weigh the risks of discontinuing drugs given for minor seizures prior to or during pregnancy 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. The onset of pregnancy should be reported promptly. Appropriate consultation might be indicated where the necessity for continued use of antiepileptic medication is in doubt.
Lactation: Valproic acid is secreted in breast milk in concentrations which have been reported to be 1 to 10% of serum concentrations. As a general rule, while a patient is receiving valproic acid, nursing should not be undertaken.
Fertility: Reduced spermatogenesis and testicular atrophy were demonstrated in chronic toxicity studies in juvenile and adult rats and dogs at doses greater than 200 mg/kg/day in rats and 90 mg/kg/day in dogs. Doses up to 350 mg/kg/day for 60 days have been shown to have no effect on fertility in segment 1 fertility studies in rats. In humans, the effect of valproic acid on the development of the testes and on sperm production and fertility is unknown.
A potential carcinogenic risk is indicated in long-term toxicity studies in rats and mice.
Precautions: Hepatic Dysfunction: See Contraindications and Warnings.
General: Platelet counts and bleeding time determination are recommended before instituting therapy and at periodic intervals because of reports of thrombocytopenia and inhibition of platelet aggregation. It is recommended that platelet counts be monitored prior to planned surgery. Pending investigation, clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of dosage or withdrawal of therapy.
Hyperammonemia with or without lethargy or coma has been reported and may be present in the absence of abnormal liver function tests. Valproic acid should be discontinued if elevation occurs.
Periodic serum level determinations of concurrently administered antiepileptics are recommended during the early part of therapy because valproic acid may interact with other antiepileptic drugs (see Drug Interactions). Breakthrough seizures have been reported to occur with the combination of valproic acid and phenytoin.
A false interpretation of the urine ketone test may result as valproic acid is partially eliminated in the urine as a ketone containing metabolite.
Although the clinical significance is unknown, there have been reports of altered thyroid function tests associated with valproic acid.
CNS depression may be produced by valproic acid, especially when combined with another CNS depressant such as alcohol.
Occupational Hazards: Until it is known that they do not become drowsy from the drug, patients should be advised not to engage in potentially hazardous occupations such as driving a car or operating dangerous machinery.
Drug Interactions: The CNS depressant action of alcohol may be potentiated by valproic acid.
There is evidence that valproic acid impairs nonrenal clearance, thereby increasing serum phenobarbital levels. Severe CNS depression may result. Without significantly elevating barbiturate or valproic acid serum levels, the combination of valproic acid and phenobarbital has also been reported to produce CNS depression. Patients should be closely monitored for neurological toxicity when receiving concomitant barbiturate therapy. If possible, serum barbiturate drug levels should be obtained and the barbiturate dosage decreased if indicated.
As primidone is metabolized into a barbiturate, it may also be involved in a similar or identical interaction.
Conflicting evidence regarding the interaction of valproic acid with phenytoin exists (see Precautions). It is not known if there is a change of unbound (free) phenytoin serum levels. Phenytoin dosage should be adjusted as required by the clinical situation.
Absence status may be produced with the concomitant use of valproic acid and clonazepam.
Caution is recommended when drugs affecting coagulation, e.g., ASA and warfarin, are administered with valproic acid (see Adverse Effects).
Adverse Reactions: Nausea, vomiting and indigestion are the most commonly reported adverse reactions. In most cases it may not be possible to determine whether the adverse reactions mentioned are due to valproic acid alone or to the combination of drugs since valproic acid has usually been used with other antiepileptics.
Gastrointestinal: At the initiation of therapy, nausea, vomiting and indigestion are the most commonly reported side effects. These effects are usually transient and rarely is discontinuation of therapy required. There are also reports of diarrhea, abdominal cramps and constipation. Increased appetite with some weight gain and anorexia with some weight loss have also been observed.
CNS: Sedative effects, although found most often in patients on combination therapy, have been noted in patients receiving valproic acid alone. Upon reduction of other antiepileptic medications, sedation usually disappears. There have been rare reports of ataxia, headache, nystagmus, diplopia, asterixis, “spots before the eyes”, tremor, dysarthria, dizziness and incoordination. In patients receiving valproic acid, alone or in conjunction with phenobarbital, there have been rare cases of coma.
Dermatologic: Hair loss has been observed to increase transiently. Rarely, skin rash and petechiae have been noted.
Endocrine: Patients receiving valproic acid have reported irregular menses and secondary amenorrhea.
There have been reports of abnormal thyroid function tests (see Precautions).
Psychiatric: emotional upset, depression, psychosis, aggression, hyperactivity and behavioral deterioration.
Musculoskeletal: There have been reports of weakness.
Hematopoietic: There have been reports of thrombocytopenia. The second phase of platelet aggregation is inhibited by valproic acid, and this may be reflected in altered bleeding time (see Precautions). There have been reports of bruising, hematoma formation and frank hemorrhage as well as leukopenia, eosinophilia, anemia and bone marrow suppression. Relative lymphocytosis and hypofibrinogenemia have been noted.
Hepatic: Transaminases (e.g., AST and ALT) and LDH frequently undergo mild elevations which appear to be dose related. Increases in serum bilirubin and abnormal changes in other liver function tests are occasionally shown in laboratory tests. These results may reflect potentially serious hepatotoxicity (see Warnings).
Metabolic: Hyperammonemia (see Precautions). Hyperglycinemia in a patient with pre-existing nonketotic hyperglycinemia has been associated with a fatal outcome.
Pancreatic: Valproic acid therapy has been associated with reports of acute pancreatitis.
Other: Edema of the extremities has been noted.
Symptoms And Treatment Of Overdose: Symptoms: A patient reportedly ingested 36 g of valproic acid in combination with phenobarbital and phenytoin. He presented in a deep coma. The diffuse slowing shown by an EEG recording was compatible with the state of consciousness. The patient recovered uneventfully.
Treatment: The CNS depressant effects of valproic acid overdose have reportedly been reversed with naloxone. However, naloxone should be used with caution as it could theoretically also reverse the antiepileptic effects of valproic acid.
Gastric lavage may be of limited value as valproic acid is absorbed very rapidly. General supportive measures are indicated with particular attention to the prevention of hypovolemia and the maintenance of adequate urinary output.
Dosage And Administration: Administered orally. An initial dose of 15 mg/kg/day orally is recommended, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dose is 60 mg/kg/day. When the total daily dose of 250 mg is exceeded, it should be given in a divided regimen. With increasing dose, the frequency of adverse effects (particularly elevated liver enzymes) may increase. It is therefore necessary to weigh the benefits gained by improved seizure control against the increased incidence of adverse effects.
Blood levels of phenobarbital and/or phenytoin may be affected as the valproic acid dosage is raised (see Precautions).
The administration of valproic acid with food or a progressive dosage increase from an initial low level may benefit patients who experience gastrointestinal irritation. To avoid local irritation of the mouth and throat, the capsules should be swallowed without chewing.
Availability And Storage: 250 mg: Each orange, oblong, soft gelatin capsule contains: valproic acid 250 mg as a clear, colorless liquid. Bottles of 100 and 500.
500 mg: Each pale, yellow-colored, oblong, soft gelatin, enteric coated capsule contains: valproic acid 500 mg as a clear, colorless liquid. Bottles of 100 and 500.
NOVO-VALPROIC Novopharm Valproic Acid Anticonvulsant