Depakote Tablets (divalproex sodium) Tablet
`[Abbott Laboratories]
`
`
`
` 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.
`
`ARGENTUM Exhibit 1142
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`A PATIENT INFORMATION LEAFLET 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.
`
`
`
`Page 00002
`
`

`
`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
`
`Absorption/Bioavailability
`
`Equivalent oral doses of DEPAKOTE (divalproex sodium) products and DEPAKENE (valproic acid)
`capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion
`absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use
`(e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the
`capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor
`clinical importance under the steady state conditions achieved in chronic use in the treatment of
`epilepsy.
`
`However, it is possible that differences among the various valproate products in Tmax and Cmax could
`be important upon initiation of treatment. For example, in single dose studies, the effect of feeding
`had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than
`on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
`
`Page 00003
`
`

`
`While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary
`with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is
`unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day,
`as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily
`systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that
`
`differences in the ratios of plasma peak to trough concentrations between valproate formulations are
`inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the
`efficacy of valproate as an antimanic or antimigraine agent is unknown.
`
`Co-administration of oral valproate products with food and substitution among the various
`DEPAKOTE and DEPAKENE formulations should cause no clinical problems in the management of
`patients with epilepsy (see DOSAGE AND ADMINISTRATION). Nonetheless, any changes in dosage
`administration, or the addition or discontinuance of concomitant drugs should ordinarily be
`accompanied by close monitoring of clinical status and valproate plasma concentrations.
`
`
`Distribution
`
`Protein Binding
`
`The plasma protein binding of valproate is concentration dependent and the free fraction increases
`from approximately 10% at 40 µg/mL to 18.5% at 130 µg/mL. Protein binding of valproate is reduced
`in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the
`presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound
`drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See PRECAUTIONS - Drug
`Interactions for more detailed information on the pharmacokinetic interactions of valproate with other
`drugs.)
`
`CNS Distribution
`
`Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma
`(about 10% of total concentration).
`
`
`
` Metabolism
`
`Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an
`administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other
`major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of
`
`Page 00004
`
`

`
`the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is
`excreted unchanged in urine.
`
`The relationship between dose and total valproate concentration is nonlinear; concentration does not
`increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma
`protein binding. The kinetics of unbound drug are linear.
`
`
`Elimination
`
`Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11
`L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6
` L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16
`
`hours following oral dosing regimens of 250 to 1000 mg.
`
`The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
`metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
`(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these
`changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified
`whenever concomitant antiepileptics are introduced or withdrawn.
`
`Special Populations
`
`Effect of Age
`
`Neonates
`
`Children within the first two months of life have a markedly decreased ability to eliminate valproate
`compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in
`development of glucuronosyltransferase and other enzyme systems involved in valproate elimination)
`as well as increased volume of distribution (in part due to decreased plasma protein binding). For
`example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to
`a range of 7 to 13 hours in children greater than 2 months.
`
`Children
`
`Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on
`weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
`parameters that approximate those of adults.
`
`Elderly
`
`Page 00005
`
`

`
`The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to
`be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%;
`the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly
`
` (See DOSAGE AND ADMINISTRATION).
`
`Effect of Gender
`
`There are no differences in the body surface area adjusted unbound clearance between males and
`females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
`
`Effect of Race
`
`The effects of race on the kinetics of valproate have not been studied.
`
`Effect of Disease
`
`Liver Disease
`
`(See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS). Liver disease impairs the
`
`capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50%
`in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy
`subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is
`also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold
`increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free
`concentrations may be substantially elevated in patients with hepatic disease whereas total
`concentrations may appear to be normal.
`
`Renal Disease
`
`A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with
`renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces
`valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in
`patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring
`total concentrations may be misleading.
`
`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
`
`Page 00006
`
`

`
`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.
`
`Epilepsy
`
` The therapeutic range in epilepsy is commonly considered to be 50 to 100 µg/mL of total valproate,
`
`although some patients may be controlled with lower or higher plasma concentrations.
`
`Mania
`
`In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with
`trough plasma concentrations between 50 and 125 µg/mL (See DOSAGE AND ADMINISTRATION).
`
`
`
` 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:
`
`
` Study 1
`
` YMRS Total Score
`
`
`
`Group
`
`
`Placebo
`DEPAKOTE
`
`Baseline1
`
`28.8
`28.5
`
`BL to Wk 32
`
`+ 0.2
`- 9.5
`
`Difference3
`
`
`9.7
`
`Page 00007
`
`

`
`
`
`BPRS-A Total Score
`
`BL to Wk 32
`Baseline1
`76.2
`+ 1.8
`76.4
`-17.0
`
`
`
`
`
`Difference3
`
`18.8
`
`GAS Score
`
`
`
`
`
`Baseline1
`31.8
`30.3
`
`
`
`BL to Wk 32
`0.0
`+ 18.1
`
`
`
`Difference3
`
`18.1
`
`
`
` Group
`
`Placebo
`DEPAKOTE
`
`Group
`
`
`
`
`Placebo
`DEPAKOTE
`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
`
`
`
`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:
`
`Group
`
`
`Placebo
`Lithium
`DEPAKOTE
`
`
`Group
`
`Placebo
`Lithium
`DEPAKOTE
`
` Study 2
`
` MRS Total Score
`
`
`
`
`
`Baseline1
`38.9
`37.9
`38.1
`
`
`
`Baseline1
`18.9
`18.5
`18.9
`
`
`
`BL to Day 212
`- 4.4
`-10.5
`- 9.5
`
`
`MSS Total Score
`BL to Day 212
`- 2.5
`- 6.2
`- 6.0
`
`
`
`
`
`Difference3
`
`6.1
`5.1
`
`
`
`Difference3
`
`3.7
`3.5
`
`Page 00008
`
`

`
` BIS Total Score
`
`BL to Day 212
`
`- 1.4
`- 3.8
`- 3.2
`
`
` Baseline1
`16.4
`16.0
`15.7
`
`Difference3
`
`
`2.4
`1.8
`
`
`
` Group
`
`
`
`Placebo
`Lithium
`DEPAKOTE
`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
`
`
`
`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.
`
`
`Figure 1. Percentage of Patients Achieving ≥ 30% Reduction in Symptom Score From Baseline
`
`
`
` * p < 0.05
`
`PBO = placebo, DVPX = DEPAKOTE
`
`
`
`Page 00009
`
`

`
`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.
`
`Page 00010
`
`

`
`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.
`
`
`Figure 2. Mean 4-week Migraine Rates
`
`
`
`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
`
`Page 00011
`
`

`
`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.
`
`Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
`
`Number
`Baseline
`Experimental
`Add-on
`
`of Patients
`
`Incidence
` Incidence
` Treatment
`
`75
`16.0
`8.9*
`DEPAKOTE
`69
`14.5
`11.5
`Placebo
`
`* Reduction from baseline statistically significantly greater for DEPAKOTE than placebo at p ≤ 0.05 level.
`
`
`
`
`
`
`
`
`
`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.
`
`
`
` Figure 3.
`
`
`
`Page 00012
`
`

`
`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.
`
`Monotherapy Study Median Incidence of CPS per 8 Weeks
`Randomized
`
`Number of
`Baseline
` Phase Incidence
`
`
` Patients
`Incidence
`10.7*
`
`131
`13.2
`High dose DEPAKOTE
`13.8
`
`134
`14.2
`Low dose DEPAKOTE
`
`* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
`
`
`
`
`
` Treatment
`
`
`
`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.
`
`
`
` Figure 4.
`
`Page 00013
`
`

`
`
`
`
`
` 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, healthcare providers 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
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`
`
` 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,
`healthcare providers 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.
`
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`
`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)
`
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`
`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 CONTRAINDICATIONS and PRECAUTIONS).
`
`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 pos