Attention, chocolate lovers: You may not be able to help yourselves. Swiss and British scientists have linked the widespread love of chocolate to a chemical "signature" that may be programmed into our metabolic systems.
Read more health news
DEPAKOTE® Tablets
(divalproex sodium)
delayed-release
tablets
BOX WARNING
HEPATOTOXICITY
HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECEIVING VALPROIC ACID AND ITS DERIVATIVES. EXPERIENCE HAS INDICATED THAT 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 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. ABOVE THIS AGE GROUP, EXPERIENCE IN EPILEPSY HAS INDICATED THAT 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.
TERATOGENICITY
VALPROATE CAN PRODUCE TERATOGENIC EFFECTS SUCH AS NEURAL TUBE DEFECTS (E.G., SPINA BIFIDA). ACCORDINGLY, THE USE OF DEPAKOTE TABLETS 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, INFORMATION FOR PATIENTS.
AN INFORMATION SHEET DESCRIBING THE TERATOGENIC POTENTIAL OF VALPROATE IS AVAILABLE FOR PATIENTS.
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 EVALUATION. 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.)
DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure:
Divalproex sodium occurs as a white powder with a characteristic odor.
DEPAKOTE tablets are for oral administration. DEPAKOTE tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid.
Inactive Ingredients
DEPAKOTE tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
In addition, individual tablets contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40.
250 mg tablets: FD&C Yellow No. 6 and iron oxide.
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
Pharmacokinetics
Distribution
Special Populations
Plasma Levels and Clinical Effect
The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 µg/mL to 18.5% at 130 µg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Clinical Trials
Mania
The effectiveness of DEPAKOTE for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies.
(1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for Bipolar Disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. DEPAKOTE was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 µg/mL by day 7. Mean DEPAKOTE doses for completers in this study were 1118, 1525, and 2402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows:
| YMRS Total Score | |||
1. Mean score at baseline 2. Change from baseline to Week 3 (LOCF) 3. Difference in change from baseline to Week 3 endpoint (LOCF) between DEPAKOTE and placebo | |||
| Group | Baseline1 | BL to Wk 32 | Difference3 |
| Placebo | 28.8 | + 0.2 | |
| DEPAKOTE | 28.5 | - 9.5 | 9.7 |
| BPRS-A Total Score | |||
| Group | Baseline1 | BL to Wk 32 | Difference3 |
| Placebo | 76.2 | + 1.8 | |
| DEPAKOTE | 76.4 | -17.0 | 18.8 |
| GAS Score | |||
| Group | Baseline1 | BL to Wk 32 | Difference3 |
| Placebo | 31.8 | 0.0 | |
| DEPAKOTE | 30.3 | + 18.1 | 18.1 |
DEPAKOTE was statistically significantly superior to placebo on all three measures of outcome.
(2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. DEPAKOTE was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2500 mg/day to achieve serum valproate concentrations in a range of 40-150 µg/mL. Mean DEPAKOTE doses for completers in this study were 1116, 1683, and 2006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1312, 1869, and 1984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows:
| MRS Total Score | |||
1. Mean score at baseline 2. Change from baseline to Day 21 (LOCF) 3. Difference in change from baseline to Day 21 endpoint (LOCF) between DEPAKOTE and placebo and lithium and placebo | |||
| Group | Baseline1 | BL to Day 212 | Difference3 |
| Placebo | 38.9 | - 4.4 | |
| Lithium | 37.9 | -10.5 | 6.1 |
| DEPAKOTE | 38.1 | - 9.5 | 5.1 |
| MSS Total Score | |||
| Group | Baseline1 | BL to Day 212 | Difference3 |
| Placebo | 18.9 | - 2.5 | |
| Lithium | 18.5 | - 6.2 | 3.7 |
| DEPAKOTE | 18.9 | - 6.0 | 3.5 |
| BIS Total Score | |||
| Group | Baseline1 | BL to Day 212 | Difference3 |
| Placebo | 16.4 | - 1.4 | |
| Lithium | 16.0 | - 3.8 | 2.4 |
| DEPAKOTE | 15.7 | - 3.2 | 1.8 |
DEPAKOTE was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender.
A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1.
* p < 0.05
PBO = placebo, DVPX = DEPAKOTE
Migraine
The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of DEPAKOTE in the prophylactic treatment of migraine headache.
Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to DEPAKOTE or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, DEPAKOTE to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on DEPAKOTE doses ranged from 500 to 2500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1087 mg/day resulting in a mean trough total valproate level of 72.5 µg/mL, with a range of 31 to 133 µg/mL.
The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the DEPAKOTE group (see Figure 2). These rates were significantly different.
In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three DEPAKOTE dose groups (500, 1000, or 1500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1000/1500 mg/day group and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 µg/mL in the DEPAKOTE 500, 1000, and 1500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the DEPAKOTE 500, 1000, and 1500 mg/day groups, respectively, based on intent-to-treat results (see Figure 2). Migraine headache rates in the combined DEPAKOTE 1000/1500 mg group were significantly lower than in the placebo group.
1 Mean dose of DEPAKOTE was 1087 mg/day.
2 Dose of DEPAKOTE was 500 or 1000 mg/day.
Epilepsy
The efficacy of DEPAKOTE in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either DEPAKOTE or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.
| Add-on Treatment | Number of Patients | Baseline Incidence | Experimental Incidence |
* Reduction from baseline statistically significantly greater for DEPAKOTE than placebo at p ≤ 0.05 level. | |||
| DEPAKOTE | 75 | 16.0 | 8.9* |
| Placebo | 69 | 14.5 | 11.5 |
Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for DEPAKOTE than for placebo. For example, 45% of patients treated with DEPAKOTE had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.
The second study assessed the capacity of DEPAKOTE to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to DEPAKOTE. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to DEPAKOTE monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 µg/mL in the low dose and high dose groups, respectively.
The following table presents the findings for all patients randomized who had at least one post-randomization assessment.
| Treatment | Number of Patients | Baseline Incidence | Randomized Phase Incidence |
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. | |||
| High dose DEPAKOTE | 131 | 13.2 | 10.7* |
| Low dose DEPAKOTE | 134 | 14.2 | 13.8 |
Figure 4 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose DEPAKOTE than for low dose DEPAKOTE. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose DEPAKOTE monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose DEPAKOTE.
INDICATIONS AND USAGE
Mania
DEPAKOTE (divalproex sodium) is indicated for the treatment of the manic episodes associated with bipolar disorder. 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 judgement, aggressiveness, and possible hostility.
The efficacy of DEPAKOTE was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania (See Clinical Trials under CLINICAL PHARMACOLOGY).
The safety and effectiveness of DEPAKOTE for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use DEPAKOTE for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.
Epilepsy
DEPAKOTE (divalproex sodium) is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. DEPAKOTE (divalproex sodium) is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients 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.
Migraine
DEPAKOTE is indicated for prophylaxis of migraine headaches. There is no evidence that DEPAKOTE is useful in the acute treatment of migraine headaches. Because valproic acid may be a hazard to the fetus, DEPAKOTE 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 - Usage In Pregnancy, PRECAUTIONS - Information for Patients).
SEE WARNINGS FOR STATEMENT REGARDING FATAL HEPATIC DYSFUNCTION.
CONTRAINDICATIONS
DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION.
Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.
Divalproex sodium is contraindicated in patients with known urea cycle disorders (See WARNINGS).
WARNINGS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. 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. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering DEPAKOTE products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When DEPAKOTE 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. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug.
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 rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use.The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated (see BOXED WARNING).
Urea Cycle Disorders (UCD)
Divalproex sodium is contraindicated in patients with known urea cycle disorders. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see CONTRAINDICATIONSand PRECAUTIONS).
Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly 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 (see DOSAGE AND ADMINISTRATION).
Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia [see PRECAUTIONS]) may be dose-related. In a clinical trial of DEPAKOTE as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 µg/mL (females) or ≥ 135 µg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
Usage In Pregnancy
VALPROATE CAN PRODUCE TERATOGENIC EFFECTS. DATA SUGGEST THAT THERE IS AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS ASSOCIATED WITH THE USE OF VALPROATE BY WOMEN WITH SEIZURE DISORDERS DURING PREGNANCY WHEN COMPARED TO THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO DO NOT USE ANTIEPILEPTIC DRUGS DURING PREGNANCY, THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO USE OTHER ANTIEPILEPTIC DRUGS, AND THE BACKGROUND INCIDENCE FOR THE GENERAL POPULATION. THEREFORE, VALPROATE SHOULD BE CONSIDERED FOR WOMEN OF CHILDBEARING POTENTIAL ONLY AFTER THE RISKS HAVE BEEN THOROUGHLY DISCUSSED WITH THE PATIENT AND WEIGHED AGAINST THE POTENTIAL BENEFITS OF TREATMENT.
THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE THAT INDICATE THE USE OF ANTIEPILEPTIC DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS IN OFFSPRING. ANTIEPILEPTIC DRUGS, INCLUDING VALPROATE, SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR MEDICAL CONDITION.
Antiepileptic drugs should not be discontinued abruptly 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 individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.
Human Data
PRECAUTIONS
Hepatic Dysfunction
See BOXED WARNING, CONTRAINDICATIONS and WARNINGS.
Pancreatitis
See BOXED WARNING and WARNINGS.
Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders (see CONTRAINDICATIONS and WARNINGS – Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use).
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. (see CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia).
Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. (see CONTRAINDICATIONS and WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia)
General
Because of reports of thrombocytopenia (see WARNINGS), inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving DEPAKOTE be monitored for platelet count and coagulation parameters prior to planned surgery. In a clinical trial of DEPAKOTE as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110µg/mL (females) or ≥ 135 µg/mL (males). Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since DEPAKOTE may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy. (See PRECAUTIONS - Drug Interactions.)
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.
Suicidal ideation may be a manifestation of certain psychiatric disorders, and may persist until significant remission of symptoms occurs. Close supervision of high risk patients should accompany initial drug therapy.
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
Multi-organ Hypersensitivity Reaction
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
Information for Patients
Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.
Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy (see PRECAUTIONS– Hyperammonemia) and be told to inform the prescriber if any of these symptoms occur.
Since DEPAKOTE products may produce CNS depression, especially when combined with another CNS depressant (eg, alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
Since DEPAKOTE has been associated with certain types of birth defects, female patients of child-bearing age considering the use of DEPAKOTE should be advised of the risk and of alternative therapeutic options and to read the Patient Information Leaflet, which appears as the last section of the labeling. 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 considered.
Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately (see PRECAUTIONS - Multi-organ Hypersensitivity Reaction).
Drug Interactions
Drugs for which a potentially important interaction has been observed
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Drugs for which a potentially important valproate interaction has been observed
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Pregnancy Category D: See WARNINGS.
Nursing Mothers
Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of serum concentrations. It is not known what effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when divalproex sodium is administered to a nursing woman.
Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions (see BOXED WARNING). When DEPAKOTE 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. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
The safety and effectiveness of DEPAKOTE for the treatment of acute mania has not been studied in individuals below the age of 18 years.
The safety and effectiveness of DEPAKOTE for the prophylaxis of migraines has not been studied in individuals below the age of 16 years.
The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4-day old) and juvenile (14-day old) rats are similar to those seen in young adult rats. However, additional findings, including renal alterations in juvenile rats and renal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosage approximately equivalent to the human maximum recommended daily dose on a mg/m2 basis. They were not seen at 90 mg/kg, or 40% of the maximum human daily dose on a mg/m2 basis.
Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence (see WARNINGS–Somnolence in the Elderly). The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence (see DOSAGE AND ADMINISTRATION).
There is insufficient information available to discern the safety and effectiveness of DEPAKOTE for the prophylaxis of migraines in patients over 65.
ADVERSE REACTIONS
Mania
The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of DEPAKOTE in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, DEPAKOTE, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, DEPAKOTE, and lithium carbonate groups, respectively.
Table 1 summarizes those adverse events reported for patients in these trials where the incidence rate in the DEPAKOTE-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the DEPAKOTE-treated group was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by significantly (p ≤ 0.05) more patients receiving DEPAKOTE compared to placebo.
| Adverse Event | DEPAKOTE (n = 89) | Placebo (n = 97) |
1. The following adverse events occurred at an equal or greater incidence for placebo than for DEPAKOTE: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. | ||
| Nausea | 22% | 15% |
| Somnolence | 19% | 12% |
| Dizziness | 12% | 4% |
| Vomiting | 12% | 3% |
| Asthenia | 10% | 7% |
| Abdominal pain | 9% | 8% |
| Dyspepsia | 9% | 8% |
| Rash | 6% | 3% |
The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials:
Migraine
Based on two placebo-controlled clinical trials and their long term extension, DEPAKOTE was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to DEPAKOTE in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse events reported as the primary reason for discontinuation by ≥ 1% of 248 DEPAKOTE-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).
Table 2 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the DEPAKOTE-treated group was greater than 5% and was greater than that for placebo patients.
| Body System Event | Depakote (N = 202) | Placebo (N = 81) |
1. The following adverse events occurred in at least 5% of DEPAKOTE-treated patients and at an equal or greater incidence for placebo than for DEPAKOTE: flu syndrome and pharyngitis. | ||
| Gastrointestinal System | ||
| Nausea | 31% | 10% |
| Dyspepsia | 13% | 9% |
| Diarrhea | 12% | 7% |
| Vomiting | 11% | 1% |
| Abdominal pain | 9% | 4% |
| Increased appetite | 6% | 4% |
| Nervous System | ||
| Asthenia | 20% | 9% |
| Somnolence | 17% | 5% |
| Dizziness | 12% | 6% |
| Tremor | 9% | 0% |
| Other | ||
| Weight gain | 8% | 2% |
| Back pain | 8% | 6% |
| Alopecia | 7% | 1% |
The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-treated patients in the controlled clinical trials:
Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, DEPAKOTE was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the DEPAKOTE-treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 uls treatment-emergent adverse events which were reported by ≥ 5% of DEPAKOTE-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.
| Body System/Event | Depakote (%) (n = 77) | Placebo (%) (n = 70) |
| Body as a Whole | ||
| Headache | 31 | 21 |
| Asthenia | 27 | 7 |
| Fever | 6 | 4 |
| Gastrointestinal System | ||
| Nausea | 48 | 14 |
| Vomiting | 27 | 7 |
| Abdominal Pain | 23 | 6 |
| Diarrhea | 13 | 6 |
| Anorexia | 12 | 0 |
| Dyspepsia | 8 | 4 |
| Constipation | 5 | 1 |
| Nervous System | ||
| Somnolence | 27 | 11 |
| Tremor | 25 | 6 |
| Dizziness | 25 | 13 |
| Diplopia | 16 | 9 |
| Amblyopia/Blurred Vision | 12 | 9 |
| Ataxia | 8 | 1 |
| Nystagmus | 8 | 1 |
| Emotional Lability | 6 | 4 |
| Thinking Abnormal | 6 | 0 |
| Amnesia | 5 | 1 |
| Respiratory System | ||
| Flu Syndrome | 12 | 9 |
| Infection | 12 | 6 |
| Bronchitis | 5 | 1 |
| Rhinitis | 5 | 4 |
| Other | ||
| Alopecia | 6 | 1 |
| Weight Loss | 6 | 0 |
Table 4 uls treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose DEPAKOTE group, and for which the incidence was greater than in the low dose group, in a controlled trial of DEPAKOTE monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.
| Body System/Event | High Dose (%) (n = 131) | Low Dose (%) (n = 134) |
1. Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. | ||
| Body as a Whole | ||
| Asthenia | 21 | 10 |
| Digestive System | ||
| Nausea | 34 | 26 |
| Diarrhea | 23 | 19 |
| Vomiting | 23 | 15 |
| Abdominal Pain | 12 | 9 |
| Anorexia | 11 | 4 |
| Dyspepsia | 11 | 10 |
| Hemic/Lymphatic System | ||
| Thrombocytopenia | 24 | 1 |
| Ecchymosis | 5 | 4 |
| Metabolic/Nutritional | ||
| Weight Gain | 9 | 4 |
| Peripheral Edema | 8 | 3 |
| Nervous System | ||
| Tremor | 57 | 19 |
| Somnolence | 30 | 18 |
| Dizziness | 18 | 13 |
| Insomnia | 15 | 9 |
| Nervousness | 11 | 7 |
| Amnesia | 7 | 4 |
| Nystagmus | 7 | 1 |
| Depression | 5 | 4 |
| Respiratory System | ||
| Infection | 20 | 13 |
| Pharyngitis | 8 | 2 |
| Dyspnea | 5 | 1 |
| Skin and Appendages | ||
| Alopecia | 24 | 13 |
| Special Senses | ||
| Amblyopia/Blurred Vision | 8 | 4 |
| Tinnitus | 7 | 1 |
The following additional adverse events were reported by greater than 1% but less than 5% of the 358 patients treated with DEPAKOTE in the controlled trials of complex partial seizures:
Other Patient Populations
Adverse events that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are uled below by body system.
OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2120 µg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.
DOSAGE AND ADMINISTRATION
Mania
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 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.
Epilepsy
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 phenobarbital, carbamazepine, and/or phenytoin may be affected (see PRECAUTIONS - Drug Interactions).
Complex Partial Seizures
For adults and children 10 years of age or older.
Migraine
DEPAKOTE 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
HOW SUPPLIED
DEPAKOTE tablets (divalproex sodium delayed-release tablets) are supplied as:
125 mg salmon pink-colored tablets:
Bottles of 100………………………………………..(NDC 0074-6212-13)
Abbo-Pac® unit dose packages of 100………………(NDC 0074-6212-11).
250 mg peach-colored tablets:
Bottles of 100……………………………………….(NDC 0074-6214-13)
Bottles of 500……………………………………….(NDC 0074-6214-53)
Abbo-Pac® unit dose packages of 100………………(NDC 0074-6214-11).
500 mg lavender-colored tablets:
Bottles of 100……………………………………….(NDC 0074-6215-13)
Bottles of 500……………………………………….(NDC 0074-6215-53)
Abbo-Pac® unit dose packages of 100……………...(NDC 0074-6215-11).
Recommended storage
Store tablets below 86°F (30°C).
Patient Information Leaflet
Important Information for Women Who Could Become Pregnant About the Use of DEPAKOTE®, DEPAKOTE® ER, DEPAKOTE® Sprinkle Capsules, and DEPAKENE®.
Please read this leaflet carefully before you take any of these medications. This leaflet provides a summary of important information about taking these medications to women who could become pregnant. If you have any questions or concerns, or want more information about these medications, contact your doctor or pharmacist.
Information For Women Who Could Become Pregnant
These medications can be obtained only by prescription from your doctor. The decision to use any of these medications is one that you and your doctor should make together, taking into account your individual needs and medical condition.
Before using any of these medications, women who can become pregnant should consider the fact that these medications have been associated with birth defects, in particular, with spina bifida and other defects related to failure of the spinal canal to close normally. Approximately 1 to 2% of children born to women with epilepsy taking DEPAKOTE in the first 12 weeks of pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency based in Atlanta). The incidence in the general population is 0.1 to 0.2%.
These medications have also been associated with other birth defects such as defects of the heart, the bones, and other parts of the body. Information suggests that birth defects may be more likely to occur with these medications than some other drugs that treat your medical condition.
Information For Women Who Are Planning to Get Pregnant
- Women taking any of these medications who are planning to get pregnant should discuss the treatment options with their doctor.
Information For Women Who Become Pregnant
- If you become pregnant while taking any of these medications you should contact your doctor immediately.
Other Important Information
- Your medication should be taken exactly as prescribed by your doctor to get the most benefit from your medication and reduce the risk of side effects.
- If you have taken more than the prescribed dose of your medication, contact your hospital emergency room or local poison center immediately.
- Your medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
Facts About Birth Defects
It is important to know that birth defects may occur even in children of individuals not taking any medications or without any additional risk factors.
This summary provides important information about the use of DEPAKOTE®, DEPAKOTE® ER, DEPAKOTE® Sprinkle Capsules, and DEPAKENE® to women who could become pregnant. If you would like more information about the other potential risks and benefits of these medications, ask your doctor or pharmacist to let you read the professional labeling and then discuss it with them. If you have any questions or concerns about taking these medications, you should discuss them with your doctor.
Manufactured by Abbott Pharmaceuticals PR Ltd.
Barceloneta, PR 00617
for
Abbott Laboratories
North Chicago, IL 60064, U.S.A.