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Valproic Acid


Action And Clinical Pharmacology: Valproic acid exhibits anticonvulsant properties. While the exact mechanism of action is unknown, several investigators have proposed that the anticonvulsive effect of valproic acid can be related to increased gamma-amino-butyric acid (GABA) levels in the brain. The effect on the neuronal membrane is unknown. After oral administration, valproic acid is rapidly absorbed, reaching peak serum levels within 1 to 4 hours. Salts of valproate are converted into valproic acid in the digestive tract.

Valproate disappears from the blood in a biexponential manner indicating a 2-compartment pharmacokinetic model. The terminal serum half-life is about 6 to 16 hours. The shorter half-life is usually observed in epileptic patients receiving long-term therapy with some other antiepileptic drugs. A slight delay in the absorption of sodium valproate is observed if it is taken after ingestion of meals, but this does not affect the total absorption. Valproic acid (sodium valproate) is rapidly distributed throughout the body and is strongly bound (90%) to human plasma proteins. Dose increases may result in decreases in the extent of protein binding and variable changes in clearance and elimination of valproic acid. The therapeutic plasma concentration range is about 50 to 100 µg/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 level and therapeutic effect.

Elimination of valproic acid and its metabolites is principally by urinary excretion, with small amounts expelled in the feces and expired air. Only 1 to 3% of the administered dose is found as unchanged drug in the urine. Valproate is excreted in the urine after glucuronidation or beta oxidation to 2-propylene-2-pentanoic acid and 2-propyl-3-ketopentanoic acid in the liver. The principal metabolite formed in the liver is the glucuronide conjugate.

See Warnings regarding statement on fatal hepatic dysfunction.

Indications And Clinical Uses: Effective 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.

In accordance with the International Classification of 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. It is contraindicated in patients who have shown hypersensitivity to this drug or any of its components. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Hepatic failure resulting in fatalities has been reported in patients treated with valproic acid. These incidences usually have occurred during the first 6 months of treatment with valproic acid. A study of valproate use in the US in nearly 400 000 patients from 1978 through 1984, has shown that children under 2 years of age who received the drug as part of a 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 when valproic acid was used as monotherapy.

Similarly, patients aged 3 to 10 years were somewhat at greater risk if they receive multiple anticonvulsant therapy, than those who received valproic acid as monotherapy. Generally, the risk declines with increasing age. No deaths were reported in patients over 10 years old receiving valproic acid alone.

If valproic acid is to be used in children 2 years of age or younger, it should be used with extreme caution and as a sole agent. The clinician should watch such patients with particular care, especially in the early months of valproate therapy. The benefits of seizure control should be weighed against the risk.

Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as loss of seizure control, vomiting, lethargy, anorexia, malaise and weakness. Patients and parents should be instructed to report such symptoms. Because of the nonspecific nature of some of the early signs, during valproic acid treatment, hepatotoxicity should be suspected in patients who become unwell, other than through obvious causes.

Liver function tests should be performed prior to beginning therapy, 3 to 5 weeks after initiation of therapy, approximately monthly during the first 6 months of use and periodically thereafter. However, physicians should not rely totally on serum biochemistry since liver function tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. When administering valproic acid to patients with a prior history of hepatic disease, exercise caution. 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 may be useful to monitor serum fibrinogen and albumin for decreases in concentration and serum ammonia for increases in concentration. If changes occur, valproic acid should be discontinued. The dosage should be titrated to and maintained at the lowest dose that produces optimal seizure control.

In presence of significant hepatic dysfunction suspected or apparent, valproic acid should be discontinued immediately. In some cases, hepatic dysfunction has progressed in spite of discontinuation of the drug. The frequency of adverse reactions, particularly elevated liver enzymes, may increase with increasing dose. Therefore, the benefit gained by improved seizure control by increasing dosage must be weighed against the increasing incidence of adverse effects sometimes observed 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 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 a child with spina bifida is approximately 1.2%. This risk is similar to that which applies to nonepileptic women who have had children with neural tube defects (anencephaly and spina bifida).

Animal studies have demonstrated that valproic acid produced teratogenic effects. Human studies 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 approximately 2%, in children of women administered anticonvulsant medication during pregnancy, this incidence may be increased 2- to 3-fold. The increase is largely due to specific defects such as congenital malformations of the heart, cleft lip and/or palate and neural tube defects. Nevertheless, the great majority of mothers receiving anticonvulsant medications during pregnancy deliver normal infants.

Data are more extensive with respect to phenytoïn and phenobarbital, but these drugs are also the most commonly prescribed anticonvulsant. Some reports indicate a possible interaction with the use of other antiepileptic drugs, including trimethadione, paramethadione and valproic acid. However, the possibility also exists that other factors such as 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, taking into account the 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 is indicated.

Lactation: Valproic acid is secreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of maternal serum concentrations. As a general rule, nursing should not be undertaken while a patient is receiving valproic acid treatment.

Fertility: Chronic toxicity studies performed in juvenile and adult rats and dogs, demonstrated testicular atrophy and reduced spermatogenesis 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 have demonstrated a possible risk of carcinogenicity.

Precautions: Hepatic Dysfunction: See Contraindications and Warnings.

General: As valproic acid inhibits the secondary phase of platelet aggregation and produced thrombocytopenia, platelet counts and bleeding time determination are recommended before beginning treatment and at periodic intervals. It is recommended that patients receiving valproic acid be monitored for platelet count prior to any surgical intervention. Clinical evidence of hemorrhage, bruising or a disorder of homeostasis/coagulation is an indication for reduction of valproic acid dosage or withdrawal of therapy pending investigation.

Valproic acid should be discontinued if serum ammonia increases. Hyperammonemia with or without lethargy or coma has been reported and may be present in the absence of abnormal liver function tests.

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.

The alteration of thyroid function tests associated with valproic acid has been reported. The clinical significance of this is unknown.

Valproic acid may potentiate 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.

Phenobarbital: Valproic acid use may result in an increase in serum phenobarbital levels, by impairment of nonrenal 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: Primidone is metabolized into a barbiturate, and therefore, may also be involved in a similar or identical interaction.

Phenytoin: There is conflicting evidence regarding the interaction of valproic acid with phenytoin (see Precautions, General). It is not known if there is a change in unbound (free) phenytoin serum levels. Phenytoin dosage should be adjusted as required by the clinical situation.

Clonazepam: Absence status was observed with combination treatment of valproic acid and clonazepam.

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 gastrointestinal symptoms; nausea, vomiting and indigestion. Since valproic acid is generally used in conjunction 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. In general, these effects are usually transient, only rarely requiring 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 such as sedation have been noted in patients receiving valproic acid alone, but is most often reported during combination therapy. Sedation can generally be corrected 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.

Dermatological: Transient hair loss has 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, behavioral deterioration, aggression and hyperactivity 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 observed. 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: Adverse reactions such as edema of the extremities have been reported.

Symptoms And Treatment Of Overdose: Symptoms: One overdose case with valproic acid has been reported after ingestion of up to 36 g in combination with phenobarbital and phenytoin. The patient presented in deep coma (responding only to deeply painful stimuli). An EEG recording showed diffused slowing, compatible with the state of consciousness. The patient gradually became more alert and made an uneventful recovery. tag_Treatment

Treatment: Naloxone has been reported to reverse the CNS depressant effects in valproic acid overdose. Because naloxone could theoretically reverse the antiepileptic activity of valproic acid it should be used with caution in the treatment of valproic acid overdose.

Valproic acid is absorbed very rapidly, consequently gastric lavage may be of limited value. General supportive measures should be applied with particular attention to the prevention of hypovolemia and the maintenance of adequate urinary output.

Dosage And Administration: Administered orally. The recommended initial dosage is 15 mg/kg/day, increasing at 1-week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximal recommended dosage 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 reactions (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 reactions.

As the dosage of valproic acid is raised, blood level concentrations of phenobarbital and/or phenytoin may be affected (see Precautions).

Patients who experience gastrointestinal irritation may benefit from administration of the drug with food or by a progressive increase of the dose 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, imprinted with black ink, contains: valproic acid 250 mg. Nonmedicinal ingredients: corn oil, FD&C yellow #6, gelatin, glycerin, methylparaben, propylparaben, purified water, sorbitol and titanium dioxide. White, round, HDPE bottles of 100 and 500.

500 mg: Each pale yellow, oval, soft gelatin enteric-coated capsule contains: valproic acid 500 mg. Nonmedicinal ingredients: D&C yellow #10, FD&C yellow #6, gelatin, glycerin, hydroxypropylmethylcellulose, light mineral oil, methacrylic acid copolymer, purified water, simethicone, sodium hydroxide, talc, titanium dioxide and triethyl citrate. White, round, HDPE bottles of 100 and 500.

Syrup: Each 5 mL of red syrup contains: the equivalent of valproic acid 250 mg, as the sodium salt. Nonmedicinal ingredients: artificial flavoring, glycerin, methylparaben, propylparaben, purified water, sorbitol and sucrose. Bottles of 500 mL.

Store between 15 and 30°C. Preserve in tight container.

DEPROIC® Technilab Valproic Acid Anticonvulsant

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