DN1172V1 03-5472 Depakote ER
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`
`DEPAKOTE® ER
`(divalproex sodium)
`extended-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,
`
`ARGENTUM Exhibit 1197
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`00001
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`DN1172V1 03-5472 Depakote ER
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`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 ER 250 and 500 mg tablets are for oral administration. DEPAKOTE ER
`tablets contain divalproex sodium in a once-a-day extended-release formulation
`equivalent to 250 and 500 mg of valproic acid.
`
`Inactive Ingredients
`DEPAKOTE ER 250 and 500 mg tablets: FD&C Blue No. 1, hypromellose, lactose,
`microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
`dioxide, titanium dioxide, and triacetin.
`In addition, 500 mg tablets contain iron oxide and polydextrose.
`
`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
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`DN1172V1 03-5472 Depakote ER
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`has been suggested that its activity in epilepsy is related to increased brain concentrations
`of gamma-aminobutyric acid (GABA).
`
`Pharmacokinetics
`
`Absorption/Bioavailability
`The absolute bioavailability of DEPAKOTE ER tablets administered as a single dose after
`a meal was approximately 90% relative to intravenous infusion.
`When given in equal total daily doses, the bioavailability of DEPAKOTE ER is less than
`that of DEPAKOTE (divalproex sodium delayed-release tablets). In five multiple-dose
`studies in healthy subjects (N=82) and in subjects with epilepsy (N=86), when
`administered under fasting and nonfasting conditions, DEPAKOTE ER given once daily
`produced an average bioavailability of 89% relative to an equal total daily dose of
`DEPAKOTE given BID, TID, or QID. The median time to maximum plasma valproate
`concentrations (Cmax) after DEPAKOTE ER administration ranged from 4 to 17 hours.
`After multiple once-daily dosing of DEPAKOTE ER, the peak-to-trough fluctuation in
`plasma valproate concentrations was 10-20% lower than that of regular DEPAKOTE given
`BID, TID, or QID.
`
`Conversion from DEPAKOTE to DEPAKOTE ER
`When DEPAKOTE ER is given in doses 8 to 20% higher than the total daily dose of
`DEPAKOTE, the two formulations are bioequivalent. In two randomized, crossover
`studies, multiple daily doses of DEPAKOTE were compared to 8 to 20% higher once-daily
`doses of DEPAKOTE ER. In these two studies, DEPAKOTE ER and DEPAKOTE
`regimens were equivalent with respect to area under the curve (AUC; a measure of the
`extent of bioavailability). Additionally, valproate Cmax was lower, and Cmin was either higher
`or not different, for DEPAKOTE ER relative to DEPAKOTE regimens (see following table).
`Bioavailability of DEPAKOTE ER Tablets Relative to DEPAKOTE When DEPAKOTE ER Dose is 8 to
`20% Higher
`
`Study
`Population
`
`Healthy Volunteers (N=35)
`
`Patients with epilepsy on concomitant enzyme-inducing
`antiepilepsy drugs (N = 64)
`
`Regimens
`
`DEPAKOTE ER vs.
`DEPAKOTE
`1000 & 1500 mg
`DEPAKOTE ER vs.
`875 & 1250 mg
`DEPAKOTE
`1000 to 5000 mg
`DEPAKOTE ER vs.
`875 to 4250 mg
`DEPAKOTE
`
`Relative
`Bioavailability
`AUC24 Cmax Cmin
`
`1.059
`
`0.882 1.173
`
`1.008
`
`0.899 1.022
`
`Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin,
`and lamotrigine were evaluated) that induce the cytochrome P450 isozyme system did not
`significantly alter valproate bioavailability when converting between DEPAKOTE and
`DEPAKOTE ER.
`
`Distribution
`
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`
`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
`(cid:533)-oxidation is the other major metabolic pathway, typically accounting for over 40% of the
`dose. Usually, less than 15-20% of 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.
`
`Special Populations
`
`Effect of Age
`Pediatric
`The valproate pharmacokinetic profile following administration of DEPAKOTE ER was
`characterized in a multiple-dose, non-fasting, open-label, multi-center study in children
`and adolescents. DEPAKOTE ER once-daily doses ranged from 250 to 1750 mg. Once-
`daily administration of DEPAKOTE ER in pediatric patients (10-17 years) produced
`plasma VPA concentration-time profiles similar to those that have been observed in
`adults.
`Elderly
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`DN1172V1 03-5472 Depakote ER
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`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 years).
`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 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.
`
`Mania
`In a placebo-controlled clinical trial of acute mania, patients were dosed to clinical
`response with trough plasma concentrations between 85 and 125 μg/mL (See DOSAGE
`AND ADMINISTRATION ).
`
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`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.
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`DN1172V1 03-5472 Depakote ER
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`
`Clinical Trials
`
`Mania
`The effectiveness of DEPAKOTE ER for the treatment of acute mania is based in part on
`studies establishing the effectiveness of DEPAKOTE (divalproex sodium delayed release
`tablets) for this indication. DEPAKOTE ER’s effectiveness was confirmed in one
`randomized, double-blind, placebo-controlled, parallel group, 3-week, multicenter study.
`The study was designed to evaluate the safety and efficacy of DEPAKOTE ER in the
`treatment of bipolar I disorder, manic or mixed type, in adults. Adult male and female
`patients who had a current DSM-IV TR primary diagnosis of bipolar I disorder, manic or
`mixed type, and who were hospitalized for acute mania, were enrolled into this study.
`DEPAKOTE ER was initiated at a dose of 25 mg/kg/day given once daily, increased by
`500 mg/day on Day 3, then adjusted to achieve plasma valproate concentrations in the
`range of 85-125 μg/mL. Mean daily DEPAKOTE ER doses for observed cases were 2362
`mg (range: 500-4000), 2874 mg (range: 1500-4500), 2993 mg (range: 1500-4500), 3181
`mg (range: 1500-5000), and 3353 mg (range: 1500-5500) at Days 1, 5, 10, 15, and 21,
`respectively. Mean valproate concentrations were 96.5 μg/mL, 102.1 μg/mL, 98.5 μg/mL,
`89.5 μg/mL at Days 5, 10, 15 and 21, respectively. Patients were assessed on the Mania
`Rating Scale (MRS; score ranges from 0-52).
`DEPAKOTE ER was significantly more effective than placebo in reduction of the MRS
`total score.
`
`Migraine
`The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group
`clinical trial demonstrated the effectiveness of DEPAKOTE ER in the prophylactic
`treatment of migraine headache. This trial recruited patients with a history of migraine
`headaches with or without aura occurring on average twice or more a month for the
`preceding three months. Patients with cluster or chronic daily headaches were excluded.
`Women of childbearing potential were allowed in the trial if they were deemed to be
`practicing an effective method of contraception.
`Patients who experienced (cid:149) 2 migraine headaches in the 4-week baseline period were
`randomized in a 1:1 ratio to DEPAKOTE ER or placebo and treated for 12 weeks. Patients
`initiated treatment on 500 mg once daily for one week, and were then increased to 1000
`mg once daily with an option to permanently decrease the dose back to 500 mg once daily
`during the second week of treatment if intolerance occurred. Ninety-eight of 114
`DEPAKOTE ER-treated patients (86%) and 100 of 110 placebo-treated patients (91%)
`treated at least two weeks maintained the 1000 mg once daily dose for the duration of
`their treatment periods. Treatment outcome was assessed on the basis of reduction in 4-
`week migraine headache rate in the treatment period compared to the baseline period.
`Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with
`DEPAKOTE ER (N=122) or placebo (N=115). Four patients were below the age of 18 and
`3 were above the age of 65. Two hundred and two patients (101 in each treatment group)
`
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`DN1172V1 03-5472 Depakote ER
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`completed the treatment period. The mean reduction in 4-week migraine headache rate
`was 1.2 from a baseline mean of 4.4 in the DEPAKOTE ER group, versus 0.6 from a
`baseline mean of 4.2 in the placebo group. The treatment difference was statistically
`significant (see Figure 1).
`Figure 1. Mean Reduction In 4-Week Migraine Headache Rates
`
`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 using DEPAKOTE (divalproex sodium delayed-release tablets).
`In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive
`therapy) using DEPAKOTE, 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.
`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 (cid:148) 0.05 level.
`
`Figure 2 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
`
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`DN1172V1 03-5472 Depakote ER
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`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 (cid:149) 50%
`reduction in complex partial seizure rate compared to 23% of patients treated with
`placebo.
`Figure 2.
`
`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
`Number
`Baseline
`of Patients
`Incidence
`
`Randomized
`Phase Incidence
`
`Treatment
`
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`DN1172V1 03-5472 Depakote ER
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`10.7*
`13.2
`131
`High dose DEPAKOTE
`13.8
`14.2
`134
`Low dose DEPAKOTE
`* Reduction from baseline statistically significantly greater for high dose than low dose at p (cid:148) 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 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 3.
`
`INDICATIONS AND USAGE
`
`Mania
`DEPAKOTE ER (divalproex sodium extended-release) 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,
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`DN1172V1 03-5472 Depakote ER
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`motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgement,
`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 Trials under CLINICAL PHARMACOLOGY).
`The effectiveness of DEPAKOTE ER 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 ER for extended periods should continually reevaluate the
`long-term risk and benefits of the drug for the individual patient.
`
`Migraine
`DEPAKOTE ER is indicated for prophylaxis of migraine headaches in adults. There is no
`evidence that DEPAKOTE ER is useful in the acute treatment of migraine headaches.
`Because valproic acid 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 - Usage In Pregnancy, PRECAUTIONS - Information for Patients).
`
`Epilepsy
`DEPAKOTE ER is indicated as monotherapy and adjunctive therapy in the treatment of
`adults and children 10 years of age or older 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.
`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
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`
`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. 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. 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
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`DN1172V1 03-5472 Depakote ER
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`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 CONTRAINDICATIONS and
`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 (divalproex sodium) 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 (cid:148) 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
`(cid:149) 110 μg/mL (females) or (cid:149) 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 WTH THE PATIENT AND WEIGHED
`AGAINST THE POTENTIAL BENEFITS OF TREATMENT.
`
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`THE DATA DESCRIBED BELOW WERE GAINED ALMOST EXCLUSIVELY FROM
`WOMEN WHO RECEIVED VALPROATE TO TREAT EPILEPSY. 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
`
`Congenital Malformations
`The North American Antiepileptic Drug Pregnancy Registry reported 16 cases of
`congenital malformations among the offspring of 149 women with epilepsy who were
`exposed to valproic acid monotherapy during the first trimester of pregnancy at doses of
`approximately 1,000 mg per day, for a prevalence rate of 10.7% (95% CI 6.3%-16.9%).
`Three of the 149 offspring (2%) had neural tube defects and 6 of the 149 (4%) had less
`severe malformations. Among epileptic women who were exposed to other antiepileptic
`drug monotherapies during pregnancy (1,048 patients) the malformation rate was 2.9%
`(95% CI 2.0% to 4.1%). There was a 4-fold increase in congenital malformations among
`infants with valproic acid-exposed mothers compared with those treated with other
`antiepileptic monotherapies as a group (Odds Ratio 4.0; 95% CI 2.1 to 7.4). This
`increased risk does not reflect a comparison versus any specific antiepileptic drug, but the
`risk versus the heterogeneous group of all other antiepileptic drug monotherapies
`combined.