|
HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use Depakote ER safely and effectively. See full prescribing information for Depakote ER.
Depakote ER (divalproex sodium) Tablet, Extended Release for Oral use
Initial U.S. Approval: 2000
|
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
-
Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the age of two years are at considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter(5.1)
-
Teratogenicity, including neural tube defects(5.2)
-
Pancreatitis, including fatal hemorrhagic cases(5.3)
|
|
RECENT MAJOR CHANGES
|
|
Warnings and Precautions (5.5) 4/2009
Warnings and Precautions (5.2) 11/2009
|
|
INDICATIONS AND USAGE
|
|
Depakote ER is indicated for:
-
Acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features (1.1)
-
Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2)
-
Prophylaxis of migraine headaches (1.3)
|
|
DOSAGE AND ADMINISTRATION
|
-
Depakote ER is intended for once-a-day oral administration. Depakote ER should be swallowed whole and should not be crushed or chewed.
-
Mania: - Initial dose is 25 mg/kg/day,increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2)
-
Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy(2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2)
-
Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2)
-
Migraine: The recommended starting dose is 500 mg/day for 1 week, thereafter increasing to 1000 mg/day (2.3)
|
|
DOSAGE FORMS AND STRENGTHS
|
|
Tablets: 250mg and 500mg (3)
|
|
CONTRAINDICATIONS
|
-
Hepatic disease or significant hepatic dysfunction (4, 5.1)
-
Known hypersensitivity to the drug (4, 5.10)
-
Urea cycle disorders (4, 5.4)
|
|
WARNINGS AND PRECAUTIONS
|
-
Hepatotoxicity; monitor liver function tests (5.1)
-
Teratogenic effects; weigh Depakote ER benefits of use during pregnancy against risk to the fetus (5.2)
-
Pancreatitis; Depakote ER should ordinarily be discontinued (5.3)
-
Suicidal behavior or ideation; Antiepileptic drugs, including Depakote ER, increase the risk of suicidal thoughts or behavior (5.5)
-
Thrombocytopenia; monitor platelet counts and coagulation tests (5.6)
-
Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.4, 5.7, 5.8)
-
Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.9)
-
Multi-organ hypersensitivity reaction; discontinue Depakote ER (5.10)
-
Somnolence in the elderly can occur. Depakote ER dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.12)
|
|
ADVERSE REACTIONS
|
-
Most common adverse reactions (reported >5%) reported in adult studies are nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain, alopecia, headache, fever, anorexia, constipation, diplopia, amblyopia/blurred, ataxia, nystagmus, emotional lability, thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4).
-
Most common, drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study are nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.
To report SUSPECTED ADVERSE REACTIONS, contact Abbott Laboratories at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
|
|
DRUG INTERACTIONS
|
-
Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
-
Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1)
-
Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2)
-
Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote ER (7.2)
-
Topiramate: Hyperammonemia and encephalopathy (5.8, 7.3)
|
|
USE IN SPECIFIC POPULATIONS
|
-
Pregnancy: Depakote ER can cause congenital malformations including neural tube defects (5.2, 8.1)
-
Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4)
-
Geriatric: reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.12, 8.5)
|
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling |
Revised: 06/2010 |
Back to Highlights and Tabs
|
FULL PRESCRIBING INFORMATION: CONTENTS* |
|
|
|
BOXED WARNING
RECENT MAJOR CHANGES
1 INDICATIONS AND USAGE
1.1 Mania
1.2 Epilepsy
1.3 Migraine
2 DOSAGE AND ADMINISTRATION
2.1 Mania
2.2 Epilepsy
2.3 Migraine
2.4 Conversion from Depakote to Depakote ER
2.5 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Teratogenicity/Usage in Pregnancy
5.3 Pancreatitis
5.4 Urea Cycle Disorders
5.5 Suicidal Behavior and Ideation
5.6 Thrombocytopenia
5.7 Hyperammonemia
5.8 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
5.9 Hypothermia
5.10 Multi-Organ Hypersensitivity Reactions
5.11 Interaction with Carbapenem Antibiotics
5.12 Somnolence in the Elderly
5.13 Monitoring: Drug Plasma Concentration
5.14 Effect on Ketone and Thyroid Function Tests
5.15 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Mania
6.2 Epilepsy
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Effect of Disease
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Mania
14.2 Epilepsy
14.3 Migraine
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Teratogenicity/Usage in Pregnancy
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS depression
17.7 Multi-organ Hypersensitivity Reaction
FDA–APPROVED PATIENT LABELING
|
FULL PRESCRIBING INFORMATION
BOXED WARNING
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote ER is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)].
Teratogenicity
Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). Accordingly, the use of Depakote ER in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine) is contemplated [see Warnings and Precautions(5.2)].
An information sheet describing the teratogenic potential of valproate is available for patients [see Patient Counseling Information(17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical eva luation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.3)].
1 INDICATIONS AND USAGE
1.1 Mania
Depakote ER is a valproate and is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).
The efficacy of Depakote ER is based in part on studies of Depakote (divalproex sodium delayed release tablets) in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania [see Clinical Studies (14.1)].
The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote ER for extended periods should continually reeva luate the long-term risk-benefits of the drug for the individual patient.
1.2 Epilepsy
Depakote ER is indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote ER is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
1.3 Migraine
Depakote ER is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote ER is useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, Depakote ER should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see Warnings and Precautions(5.2), Patient Counseling Information(17.3)].
2 DOSAGE AND ADMINISTRATION
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 Mania
Depakote 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 Epilepsy
Depakote 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 Migraine
Depakote 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 eva luated 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 pr
