Depakote CP
Depakote CP - General Information
A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage dependent sodium channels. [PubChem]
Pharmacology of Depakote CP
Divalproex is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Divalproex is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat migraine headaches and schizophrenia. In epileptics, divalproex is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome. Divalproex is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain. Divalproex dissociates to the valproate ion in the gastrointestinal tract.
Depakote CP for patients
Important Information for Women Who Could Become Pregnant About the Use of DEPAKOTE (divalproex sodium) Tablets
Please read this leaflet carefully before you take DEPAKOTE (divalproex sodium) tablets. This leaflet provides a summary of important information about taking DEPAKOTE to women who could become pregnant. If you have any questions or concerns,or want more information about DEPAKOTE, contact your doctor or pharmacist.
Information For Women Who Could Become Pregnant
DEPAKOTE can be obtained only by prescription from your doctor. The decision to use DEPAKOTE is one that you and your doctor should make together, taking into account your individual needs and medical condition.
Before using DEPAKOTE, women who can become pregnant should consider the fact that DEPAKOTE has been associated with birth defects, in particular, with spina bifida and other defects related to failure of the spinal canal to close normally. Approximately 1 to 2% of children born to women with epilepsy taking DEPAKOTE in the first 12 weeks of pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency based in Atlanta). The incidence in the general population is 0.1 to 0.2%.
Information For Women Who Are Planning to Get Pregnant
ï Women taking DEPAKOTE who are planning to get pregnant should discuss the treatment options with their doctor.
Information For Women Who Become Pregnant While Taking DEPAKOTE
ï If you become pregnant while taking DEPAKOTE you should contact your doctor immediately.
Other Important Information About DEPAKOTE Tablets
ï DEPAKOTE tablets should be taken exactly as it is prescribed by your doctor to get the most benefits from DEPAKOTE and reduce the risk of side effects.
ï If you have taken more than the prescribed dose of DEPAKOTE, contact your hospital emergency room or local poison center immediately.
ï This medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
Facts About Birth Defects
It is important to know that birth defects may occur even in children of individuals not taking any medications or without any additional risk factors.
This summary provides important information about the use of DEPAKOTE to women who could become pregnant. If you would like more information about the other potential risks and benefits of DEPAKOTE, ask your doctor or pharmacist to let you read the professional labeling and then discuss it with them. If you have any questions or concerns about taking DEPAKOTE, you should discuss them with your doctor.
Depakote CP Interactions
Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving poly-therapy with antiepilepsy drugs.
In contrast,drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on val-proate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin - A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The ß-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.
Felbamate - A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 µg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 µg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Meropenem - Subtherapeutic valproic acid levels have been reported when meropenem was coadministered.
Rifampin - A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Antacids - A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine - A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving val-proate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine - Cimetidine and ranitidine do not affect the clearance of valproate.
Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
Clonazepam - The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam - Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosux-imide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, espe-cially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital - Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin - Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of val-proate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Tolbutamide - From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.
Warfarin - In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if DEPAKOTE therapy is instituted in patients taking anticoagulants.
Zidovudine - In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:
Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.
Clozapine - In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.
Lithium - Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam - Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50 µg)/levonorgestrel (250 µg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
Depakote CP Contraindications
DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION.
Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.
Divalproex sodium is contraindicated in patients with known urea cycle disorders.
Additional information about Depakote CP
Depakote CP Indication: For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache.
Mechanism Of Action: Divalproex binds to and inhibits GABA transaminase. The drug's anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Divalproex may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.
Drug Interactions: Amobarbital Valproic acid increases the effect of barbiturate
Aprobarbital Valproic acid increases the effect of barbiturate
Aspirin The salicylate increases the effect of valproic acid
Bismuth Subsalicylate The salicylate increases the effect of valproic acid
Butabarbital Valproic acid increases the effect of barbiturate
Butalbital Valproic acid increases the effect of barbiturate
Butethal Valproic acid increases the effect of barbiturate
Carbamazepine Carbamazepine decreases the effect of valproic acid
Cholestyramine Cholestyramine decreases the levels of valproate
Cisplatin Possible decrease of anticonvulsant levels
Dihydroquinidine barbiturate Valproic acid increases the effect of barbiturate
Erythromycin Erythromycin increases the effect of valproic acid
Ethotoin Valproate increases the effect of hydantoin
Felbamate Felbamate increases the effect of valproate
Fosphenytoin Valproate increases the effect of hydantoin
Heptabarbital Valproic acid increases the effect of barbiturate
Hexobarbital Valproic acid increases the effect of barbiturate
Josamycin Erythromycin increases the effect of valproic acid
Lamotrigine Valproic acid increases the effect of lamotrigine
Mephenytoin Valproate increases the effect of hydantoin
Meropenem Decreased plasma antiepileptic levels
Methohexital Valproic acid increases the effect of barbiturate
Methylphenobarbital Valproic acid increases the effect of barbiturate
Nimodipine Valproic acid increases the effect of nimodipine
Pentobarbital Valproic acid increases the effect of barbiturate
Phenobarbital Valproic acid increases the effect of barbiturate
Phenytoin Valproate increases the effect of hydantoin
Primidone Valproic acid increases the effect of barbiturate
Quinidine barbiturate Valproic acid increases the effect of barbiturate
Risperidone Risperidone increases the effect and toxicity of valproic acid
Ritonavir Possible decrease of valproate levels
Salicylate-magnesium The salicylate increases the effect of valproic acid
Salicylate-sodium The salicylate increases the effect of valproic acid
Salsalate The salicylate increases the effect of valproic acid
Trisalicylate-choline The salicylate increases the effect of valproic acid
Secobarbital Valproic acid increases the effect of barbiturate
Talbutal Valproic acid increases the effect of barbiturate
Food Interactions: Take with food to reduce irritation.
Food slows the rate of absorption but the extent of absorption is not affected.
Generic Name: Divalproex sodium
Synonyms: Divalproex sodium; Valproate semisodium
Drug Category: Antimanic Agents; GABA Agents; Anticonvulsants
Drug Type: Small Molecule; Approved
Other Brand Names containing Divalproex sodium: Depakote; Depakote CP; Depakote ER; Depakote Sprinkle; Epival;
Absorption: Rapid absorption from gastrointestinal tract.
Toxicity (Overdose): Overdosage with divalproex may result in somnolence,heart block,and deep coma. Fatalities have been reported; however patients have recovered from divalproex levels as high as 2120 µg/mL.
Protein Binding: 80-90%
Biotransformation: Divalproex is metabolized almost entirely by the liver. Mitochondrial ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose.
Half Life: 9-16 hours
Dosage Forms of Depakote CP: Tablet, delayed release Oral
Chemical IUPAC Name: sodium; 2-propylpentanoate; 2-propylpentanoic acid
Chemical Formula: C16H31NaO4
Divalproex sodium on Wikipedia: https://en.wikipedia.org/wiki/Divalproex_sodium
Organisms Affected: Humans and other mammals
