Depakote (divalproex sodium)
Depakote® is a medication that is used to treat symptoms of seizure and bipolar disorders, as well as to prevent migraine headaches. Depakote should not be taken by pregnant women as it has been linked to serious birth defects including spina bifida, cleft palate, low intellectual functioning, and facial abnormalities. It is available by prescription in 125mg, 250mg, and 500mg tablets.
Loading...Depakote Recall
Get an alert when a recall is issued.
Questions & Answers
Side Effects & Adverse Reactions
The FDA has issued a black box warning (.pdf) (the strictest warning category) for Depakote, as it can cause pancreatitis in children and adults and can result in liver failure. Symptoms of liver problems include jaundice (yellowing of the skin and eyes), loss of appetite, stomach pain, and back pain. It is most likely to cause liver problems during the first six months of use.
In Children
Children less than two years of age with certain medical conditions (including congenital disorders, and severe seizure disorders) who are taking more than one medication for seizures are at increased risk of experiencing potentially dangerous side effects. Children with intellectual disabilities or any form of cognitive impairment (difficulty thinking or learning) should also not take divalproex sodium.
In Pregnant and Nursing Mothers
Depakote has been listed by the FDA as a Category D pregnancy risk for treating epilepsy and mania, and is known to cause serious birth defects when taken by pregnant women. The FDA has also categorized the drug as a Category X pregnancy risk (fda.gov) for the treatment of migraines, as the benefits of the medication do not outweigh the risks (valproic acid should not be taken by pregnant women for the treatment of migraine headaches). Some of the birth defects associated with divalproex sodium include polydactyly (extra fingers or toes), cleft palate, spinal cord malformations such as spina bifida (a condition where the bones of the spine don’t develop normally), skull abnormalities, facial deformations, low intellectual functioning (low IQ), congenital heart defects, such as a hole in the heart, and neural tube defects. Babies born to mothers that take valproic acid during their first 12 weeks of pregnancy have a 1 in 20 chance of being born with a neural tube defect. These infants are also four times more likely to be born with major malformations.
Despite being considered safe by The American Academy of Pediatrics and the World Health Organization (WHO), the FDA suggests women who are breastfeeding should consult their doctor before taking the drug as it can pass into breast milk (.pdf).
In People with Bipolar Disorder
The FDA has warned that people with bipolar disorder who take Depakote are at increased risk for depression and suicidal thoughts and behaviors.
Other Side Effects
Less severe side effects of Depakote include bruising easily, dizziness, joint weakness, abnormal bleeding, changes in menstrual periods, difficulty breathing, loss of consciousness, fever, hives, confusion, fatigue, nausea, and vomiting.
Legal Issues
Several lawsuits are linked to the drug’s manufacturer, Abbot Laboratories, due to illegal promotion for off-label uses. Lawsuits have also been filed with the makers of this medication as a result of birth defects from prenatal exposure to valproic acid, and for not providing sufficient warnings of the risks associated with fetal exposure, such as spina bifida and low intellectual functioning.
In 2015, a Saint Louis jury awarded the family of a young girl born with several birth defects, including spina bifida, $38 million. The jury decided that Abbot Laboratories did not provide sufficient warning of the elevated risk of birth defects in babies born to women that were taking Depakote while pregnant. In 2012, the manufacturer paid $1.6 billion in a settlement because it promoted valproate to nursing homes for unapproved uses, including for the treatment of agitation in elderly patients with dementia, schizophrenia, depression, and anxiety. In 2011, Abbot Laboratories was required to pay $1.6 billion to settle claims that it illegally marketed the drug for off-label purposes that have not been approved by the FDA (washingtonpost.com).
Abbot Laboratories and its subdivision Abbvie continue to deal with accusations of racketeering. In April 2015, the U.S. Court of Appeals in Chicago reversed a district court’s earlier dismissal of a putative class action lawsuit brought by Sidney Hillman Health Center of Rochester and others that claimed the manufacturers conducted a scheme to have them and other third-parties pay for Depakote prescriptions to treat non-FDA approved conditions in violation of the Racketeering and Corrupt Organizations Act (RICO) (dailyreportingsuite.com).
Regardless of the number of legal issues surrounding Depakote, valproic acid is included on the World Health Organization's List of Essential Medicines, a list of what the organization considers to be the most vital medications in the healthcare industry.
FDA Safety Alerts
On May 6, 2013, the FDA issued the Safety Communication linked below, warning that women should not take Depacon, Stavzor, Depakene, Depakote, Depakote ER, Depakote CP, or any of the generic forms of these drugs to treat migraine headaches, as these drugs can cause decreased IQ scores in children who were exposed prenatally. The risk category was changed from D, with the benefit outweighing the risk, to X, with the benefit clearly not. (fda.gov)
Manufacturer Warnings
In July, 2000, Abbot Laboratories issued the below “Important Drug Warning”, indicating that children and adults taking Depakote Tablets, Depakote ER Tablets, Depakon injections, Depakene Capsules and Syrup, and Depakote Sprinkle Capsules are at an increased risk for developing life-threatening pancreatitis. Symptoms can develop quickly after first use or over years of use, and include abdominal pain, nausea, vomiting, and trouble eating. (.pdf).
In June, 2002, Abbott also alerted healthcare professionals and their patients that there had been reports of hyperammonemic encephalopathy in people that took Depakote who also had a urea cycle disorder, particularly ornithine transcarbamylase deficiency (UCD is a group of rare genetic abnormalities). People with UCD have difficulty producing urea, a substance that controls levels of ammonia in the body. Signs of hyperammonemic encephalopathy include changes in mental status, loss of energy, and vomiting. Some of these cases were fatal. People with UCD and people who are suspected of having UCD should not take valproate. This warning includes Depakote Tablets, Depakote ER Tablets (divalproex sodium), Depakene Capsules and Syrup, Depakon injections (valproate sodium), and Depakote Sprinkle Capsules (.pdf).
FDA Labeling Changes
http://www.fda.gov/.../ucm360487.htm
As of March, 2015, the U.S. Food and Drug Administration has issued several labeling changes to Depakote packaging, which makes note of adverse reactions, precautions, and other warnings. These changes are summarized below:
March 2015
Depakote causes changes in hair and eye color, as well as changes in the endocrine system, including elevated testosterone and male patterns of body hair in women.
January 2015
Serious birth defects resulting from prenatal exposure to valproic acid have also been reported such as neural tube defects, skull abnormalities, heart defects, and limb defects. These babies were exposed to the drug because their mothers were taking Depakote while pregnant. During this time, the FDA also reported bleeding disorders such as dose-related thrombocytopenia, decreases in other cell lines and myelodysplasia, and issues with blood clotting.
A multiorgan hypersensitivity reaction, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), was included in this release of warnings for Depakote. Symptoms of DRESS include fever, rash, lymphadenopathy (a lymph-node disease), and hepatitis. These reactions are very serious and can be fatal.
June 2014
Depakote can also affect the musculoskeletal system. People taking Depakote are at risk for decreased bone mineral density, bone fractures, osteoporosis, and osteopenia (reduced bone mass- like a less severe form of osteoporosis).
July 2013
The FDA released a new Black Box Warning (the most serious category of warnings) as individuals that take Depakote who also have a mitochondrial disease are at increased risk of acute liver failure and death. This includes people taking valproate with hereditary neurometabolic syndromes resulting from DNA mutations involving the mitochondrial DNA Polymerase γ (POLG) gene (such as those with Alpers Huttenlocher Syndrome). People (especially children that are younger than two years old) should not take Depakote if they could have a mitochondrial disease, even if they haven't been officially diagnosed. Most of these fatalities have occurred in children and adolescents.
June 2013
Depakote shouldn’t be taken by women who plan to conceive unless not doing so would result in permanent injury or death, and should not be taken for epilepsy (a seizure disorder) by women who are pregnant or plan to become pregnant if their conditions may be treated with other medications. This labeling change was added after evidence was found of babies being born with birth defects, such as structural and cardiovascular abnormalities, including low IQ and spina bifida.
Uses
Depakote is used in the treatment of seizure disorders (including complex partial seizures and simple and complex absence seizures) and to prevent migraine headaches. It is also used to treat manic episodes related to bipolar disorder and is often combined with SSRI’s (selective serotonin reuptake inhibitors) to treat bipolar depression. It has been the most widely prescribed antiepileptic drug worldwide (jcs.biologists.org).
History
Valproic acid was developed by B.S. Burton in France in 1882 to be used as an organic solvent, and approved in France for the treatment of epilepsy in 1967. Also known as 2-Propylvaleric acid, and marketed under the trade name Depakote, it was first approved in the United States by the FDA in 1983 to treat epilepsy. In 1995, the drug was approved by the FDA to treat bipolar disorder, and in 1996 to prevent chronic migraines. Today, Depakote is still one of the most commonly prescribed medications for seizure disorders, bipolar disorder, and migraine headaches.
Other Information
How It Works
Depakote works to balance chemicals in the body by increasing the amount of GABA (gamma-aminobutyric acid), a neurotransmitter that helps to control the nervous system and is categorized as an anticonvulsant and a mood stabilizer. Other forms include Depakote CP and Depakote ER. The prescription comes in three doses: 125 mg, 250 mg, and 500 mg. Generic names include divalproex sodium, valproic acid, and valproate. Stavzor, Convulex, Epilim, Valparin, Depakene, Depacon, and Valproic are some of the other brand names for valproic acid. Once changed into a usable form in the body, valproic acid is called valproate.
Drugs That May Adversely React With Depakote & Related Drugs
According to the National Alliance for Mental Illness (NAMI), Depakote should not be taken in combination with certain antidepressants, such as phenelzine, nortriptyline, and amitriptyline. It is also noted that some antibiotics do not interact well with valproate, such as doripenem and imipenem, and that certain seizure medications are not safe to combine with Depakote. Phenobarbital (also used to treat epilepsy), phenytoin, and topiramate are some of these medications. Also mentioned is high-dose aspirin, which should not be taken with divalproex sodium. Antihistamines and alcohol can increase medication side effects, such as drowsiness, and should be avoided when taking Depakote (nami.org).
Sources
Depakote Manufacturers
-
Remedyrepack Inc.
![Depakote (Divalproex Sodium) Tablet, Delayed Release [Remedyrepack Inc. ]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Depakote | Remedyrepack Inc.
Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed.
Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months.
Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients.
Depakote is indicated for prophylaxis of migraine headaches in adults.
Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
-
Physicians Total Care, Inc.
Depakote | Physicians Total Care, Inc.
Depakote ER is an extended-release product intended for once-a-day oral administration. Depakote ER tablets should be swallowed whole and should not be crushed or chewed.
2.1 ManiaDepakote ER tablets are administered orally. The recommended initial dose is 25 mg/kg/day given once daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote ER treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote ER in such longer-term treatment (i.e., beyond 3 weeks).
2.2 EpilepsyDepakote ER (divalproex sodium) extended release tablets are administered orally, and must be swallowed whole. As Depakote ER dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote ER has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote ER therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote ER may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies(14.3)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions(7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology(12.3)].
As Depakote ER dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions(7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
2.3 MigraineDepakote ER is indicated for prophylaxis of migraine headaches in adults.
The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000 mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products, doses of Depakote ER should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with Depakote ER, Depakote should be used instead.
2.4 Conversion from Depakote to Depakote ERIn adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving Depakote, Depakote ER should be administered once-daily using a dose 8 to 20% higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily dose cannot be directly converted to Depakote ER, consideration may be given at the clinician’s discretion to increase the patient’s Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
Table 1. Dose Conversion Depakote Depakote ER Total Daily Dose (mg) (mg)* These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total daily dose of Depakote ER because the required dosing strengths of Depakote ER are not available. Consideration may be given at the clinician's discretion to increase the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
500* - 625 750 750* - 875 1000 1000*-1125 1250 1250-1375 1500 1500-1625 1750 1750 2000 1875-2000 2250 2125-2250 2500 2375 2750 2500-2750 3000 2875 3250 3000-3125 3500There is insufficient data to allow a conversion factor recommendation for patients with DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE ER on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL) [see Clinical Pharmacology(12.2)].
2.5 General Dosing AdviceDosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower than 250mg can only be achieved by the use of Depakote. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.12)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.6)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Compliance
Patients should be informed to take Depakote ER every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
-
Rebel Distributors Corp
Depakote | Rebel Distributors Corp
Depakote ER is an extended-release product intended for once-a-day oral administration. Depakote ER tablets should be swallowed whole and should not be crushed or chewed.
2.1 ManiaDepakote ER tablets are administered orally. The recommended initial dose is 25 mg/kg/day given once daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote ER treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote ER in such longer-term treatment (i.e., beyond 3 weeks).
2.2 EpilepsyDepakote ER (divalproex sodium) extended release tablets are administered orally, and must be swallowed whole. As Depakote ER dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote ER has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote ER therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote ER may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies(14.3)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions(7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology(12.3)].
As Depakote ER dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions(7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
2.3 MigraineDepakote ER is indicated for prophylaxis of migraine headaches in adults.
The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000 mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products, doses of Depakote ER should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with Depakote ER, Depakote should be used instead.
2.4 Conversion from Depakote to Depakote ERIn adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving Depakote, Depakote ER should be administered once-daily using a dose 8 to 20% higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily dose cannot be directly converted to Depakote ER, consideration may be given at the clinician’s discretion to increase the patient’s Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
Table 1. Dose Conversion Depakote Depakote ER Total Daily Dose (mg) (mg)* These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total daily dose of Depakote ER because the required dosing strengths of Depakote ER are not available. Consideration may be given at the clinician's discretion to increase the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
500* - 625 750 750* - 875 1000 1000*-1125 1250 1250-1375 1500 1500-1625 1750 1750 2000 1875-2000 2250 2125-2250 2500 2375 2750 2500-2750 3000 2875 3250 3000-3125 3500There is insufficient data to allow a conversion factor recommendation for patients with DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE ER on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL) [see Clinical Pharmacology(12.2)].
2.5 General Dosing AdviceDosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower than 250mg can only be achieved by the use of Depakote. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.12)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.6)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Compliance
Patients should be informed to take Depakote ER every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
-
Lake Erie Medical & Surgical Supply Dba Quality Care Products Llc
Depakote | Lake Erie Medical & Surgical Supply Dba Quality Care Products Llc
ManiaDEPAKOTE tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 µg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during DEPAKOTE treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the benefits of DEPAKOTE in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with DEPAKOTE, the safety of DEPAKOTE in long-term use is supported by data from record reviews involving approximately 360 patients treated with DEPAKOTE for greater than 3 months.
EpilepsyDEPAKOTE tablets are administered orally. DEPAKOTE is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the DEPAKOTE dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected (see PRECAUTIONS - Drug Interactions).
Complex Partial SeizuresFor adults and children 10 years of age or older.
Monotherapy (Initial Therapy)DEPAKOTE has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 µg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 µg/mL in females and 135 µg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to MonotherapyPatients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 µg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of DEPAKOTE therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive TherapyDEPAKOTE may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 µg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to DEPAKOTE, no adjustment of carbamazepine or phenytoin dosage was needed (see CLINICAL STUDIES). However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs (see Drug Interactions), periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy (see PRECAUTIONS - Drug Interactions).
Simple and Complex Absence SeizuresThe recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 µg/mL. Some patients may be controlled with lower or higher serum concentrations (see CLINICAL PHARMACOLOGY).
As the DEPAKOTE dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected (see PRECAUTIONS) .
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving DEPAKENE (valproic acid) therapy, DEPAKOTE tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on DEPAKOTE tablets, a dosing schedule of two or three times a day may be elected in selected patients.
MigraineDEPAKOTE tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.
General Dosing Advice Dosing in Elderly PatientsDue to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response (see WARNINGS).
Dose-Related Adverse EventsThe frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males) (see PRECAUTIONS). The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. IrritationPatients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
-
Cardinal Health
Depakote | Cardinal Health
Depakote ER is an extended-release product intended for once-a-day oral administration. Depakote ER tablets should be swallowed whole and should not be crushed or chewed.
2.1 ManiaDepakote ER tablets are administered orally. The recommended initial dose is 25 mg/kg/day given once daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote ER treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote ER in such longer-term treatment (i.e., beyond 3 weeks).
2.2 EpilepsyDepakote ER (divalproex sodium) extended release tablets are administered orally, and must be swallowed whole. As Depakote ER dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote ER has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote ER therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote ER may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies(14.3)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions(7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology(12.3)].
As Depakote ER dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions(7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
2.3 MigraineDepakote ER is indicated for prophylaxis of migraine headaches in adults.
The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000 mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products, doses of Depakote ER should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with Depakote ER, Depakote should be used instead.
2.4 Conversion from Depakote to Depakote ERIn adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving Depakote, Depakote ER should be administered once-daily using a dose 8 to 20% higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily dose cannot be directly converted to Depakote ER, consideration may be given at the clinician’s discretion to increase the patient’s Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
Table 1. Dose Conversion Depakote Depakote ER Total Daily Dose (mg) (mg)* These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total daily dose of Depakote ER because the required dosing strengths of Depakote ER are not available. Consideration may be given at the clinician's discretion to increase the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.
500* - 625 750 750* - 875 1000 1000*-1125 1250 1250-1375 1500 1500-1625 1750 1750 2000 1875-2000 2250 2125-2250 2500 2375 2750 2500-2750 3000 2875 3250 3000-3125 3500There is insufficient data to allow a conversion factor recommendation for patients with DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE ER on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL) [see Clinical Pharmacology(12.2)].
2.5 General Dosing AdviceDosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower than 250mg can only be achieved by the use of Depakote. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.12)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.6)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Compliance
Patients should be informed to take Depakote ER every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
-
Cardinal Health
Depakote | Cardinal Health
2.1 EpilepsyDepakote Sprinkle Capsules are administered orally. As Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to Depakote, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures are considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.2)].
As Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote Sprinkle Capsules should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote Sprinkle Capsules, a dosing schedule of two or three times a day may be elected in selected patients.
2.2 General Dosing AdviceDosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.12), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.6)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Administration of Sprinkle Capsules
Depakote Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft food such as applesauce or pudding. The drug/food mixture should be swallowed immediately (avoid chewing) and not stored for future use. Each capsule is oversized to allow ease of opening.
-
Remedyrepack Inc.
Depakote | Remedyrepack Inc.
Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed.
Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months.
Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients.
Depakote is indicated for prophylaxis of migraine headaches in adults.
Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.15), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.9)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
-
Abbvie Inc.
Depakote | Abbvie Inc.
Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed.
Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
2.1 ManiaDepakote tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months.
2.2 EpilepsyDepakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients.
2.3 MigraineDepakote is indicated for prophylaxis of migraine headaches in adults.
Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy.
2.4 General Dosing AdviceDosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
![Depakote (Divalproex Sodium) Tablet, Delayed Release [Remedyrepack Inc. ]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=acc183a0-4a81-4023-bd6b-fbe477846dca&name=MM6.jpg)
![Depakote (Divalproex Sodium) Tablet, Extended Release [Physicians Total Care, Inc.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=ded64147-7a43-4055-accc-2c011828079d&name=4959.jpg)
![Depakote (Divalproex Sodium) Tablet, Extended Release [Rebel Distributors Corp]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=bfbc2cfb-8e96-4cf2-81c7-d63a1b7365c4&name=bfbc2cfb-8e96-4cf2-81c7-d63a1b7365c4-05.jpg)
![Depakote (Divalproex Sodium) Tablet, Delayed Release [Lake Erie Medical & Surgical Supply Dba Quality Care Products Llc]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=349cd946-3fd9-4ea3-9140-daf5d7304a65&name=depakote250mgabbott.jpg)
![Depakote (Divalproex Sodium) Tablet, Extended Release [Cardinal Health]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=d3f7c414-db83-4a7a-a7aa-745c5606cdba&name=eb0bf16b-8747-4070-baaa-d32085cb029f-05.jpg)
![Depakote (Divalproex Sodium) Capsule [Cardinal Health]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=9869b6dd-03ed-4c6f-9c32-2c324e773b7d&name=422faa3e-5c25-438d-866b-791664be6d05-08.jpg)
![Depakote (Divalproex Sodium) Tablet, Delayed Release [Remedyrepack Inc. ]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=fbedc069-5735-4f4f-a2b2-85ff67786ca2&name=MM6.jpg)
![Depakote (Divalproex Sodium) Tablet, Delayed Release [Abbvie Inc.]](https://www.recallguide.org/wp-content/themes/bootstrap/assets/img/drug-image-placeholder.jpg)
Login To Your Free Account