HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Depakote safely and effectively. See full prescribing information for
`Depakote.
`Depakote (divalproex sodium) Tablets for Oral use
`Initial U.S. Approval: 1983
`
`WARNINGS: LIFE THREATENING ADVERSE REACTIONS
`See full prescribing information for complete boxed warning.
`Hepatotoxicity, including fatalities, usually during the first 6 months
`of treatment. Children under the age of two years are at a
`considerably higher risk of fatal hepatotoxicity. Monitor patients
`closely, and perform liver function tests prior to therapy and at
`frequent intervals thereafter (5.1)
` Fetal Risk, particularly neural tube defects and other major
`malformations (5.2, 5.3)
`Pancreatitis, including fatal hemorrhagic cases (5.4)
`
`•
`
`•
`
`•
`
`-------RECENT MAJOR CHANGES-------
`
`Warnings and Precautions, Use in Women of Childbearing Potential (5.2)
`10/2011
`Warnings and Precautions, Birth Defects (5.3) 10/2011
`
`•
`
`•
`
`•
`
`•
`
`-------INDICATIONS AND USAGE-------
`Depakote is an anti-epileptic drug indicated for:
`•
`Treatment of manic episodes associated with bipolar disorder (1.1)
`• Monotherapy and adjunctive therapy of complex partial seizures and
`simple and complex absence seizures; adjunctive therapy in patients
`with multiple seizure types that include absence seizures (1.2)
`Prophylaxis of migraine headaches (1.3)
`-------DOSAGE AND ADMINISTRATION-------
`Depakote is administered orally in divided doses. Depakote should be
`swallowed whole and should not be crushed or chewed. (2.1, 2.2)
`• Mania: Initial dose is 750 mg daily increasing as rapidly as possible to
`achieve therapeutic response or desired plasma level (2.1). The
`maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2)
`Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
`week intervals by 5 to 10 mg/kg/day to achieve optimal clinical
`response; if response is not satisfactory, check valproate plasma level;
`see full prescribing information for conversion to monotherapy (2.2).
`The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2)
`Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week
`intervals by 5 to 10 mg/kg/day until seizure control or limiting side
`effects (2.2). The maximum recommended dosage is 60 mg/kg/day.
`(2.1, 2.2)
`• Migraine: The recommended starting dose is 250 mg twice daily,
`thereafter increasing to a maximum of 1000 mg/day as needed. (2.3)
`-------DOSAGE FORMS AND STRENGTHS-------
`Tablets: 125 mg, 250mg and 500mg (3)
`-------CONTRAINDICATIONS-------
`Hepatic disease or significant hepatic dysfunction (4, 5.1)
`Known hypersensitivity to the drug (4, 5.11)
`Urea cycle disorders (4, 5.5)
`-------WARNINGS AND PRECAUTIONS-------
`•
`Hepatotoxicity; monitor liver function tests (5.1)
`• Women of Childbearing Potential; weigh Depakote benefits of use
`during pregnancy against risk to the fetus (5.2)
`•
`Birth Defects; Depakote can cause fetal harm when taken during
`pregnancy (5.3)
`Pancreatitis; Depakote should ordinarily be discontinued (5.4)
`
`•
`•
`•
`
`•
`
`•
`
`•
`•
`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 1 of 57
`Suicidal behavior or ideation; Antiepileptic drugs, including
`Depakote, increase the risk of suicidal thoughts or behavior (5.6)
`Thrombocytopenia; monitor platelet counts and coagulation tests (5.7)
`Hyperammonemia and hyperammonemic encephalopathy; measure
`ammonia level if unexplained lethargy and vomiting or changes in
`mental status, and also with concomitant topiramate use; consider
`discontinuation of valproate therapy (5.5, 5.8, 5.9)
`Hypothermia; Hypothermia has been reported during valproate
`therapy with or without associated hyperammonemia. This adverse
`reaction can also occur in patients using concomitant topiramate
`(5.10)
`• Multi-organ hypersensitivity reaction; discontinue Depakote (5.11)
`•
`Somnolence in the elderly can occur. Depakote dosage should be
`increased slowly and with regular monitoring for fluid and nutritional
`intake (5.13)
`
`•
`
`-------ADVERSE REACTIONS-------
`• Most common adverse reactions (reported >5%) reported in patients
`are abdominal pain, accidental injury, alopecia, ambylopia/blurred
`vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis,
`constipation, depression, diarrhea, diplopia, dizziness, dyspepsia,
`dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
`headache, increased appetite, infection, insomnia, nausea,
`nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis,
`somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor,
`vomiting, weight gain, weight loss, (6.1, 6.2, 6.3).
`
`•
`
`To report SUSPECTED ADVERSE REACTIONS, contact Abbott
`Laboratories at 1-800-633-9110 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`-------DRUG INTERACTIONS-------
`Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
`primidone, phenobarbital, rifampin) can increase valproate clearance,
`while enzyme inhibitors (e.g., felbamate) can decrease valproate
`clearance. Therefore increased monitoring of valproate and
`concomitant drug concentrations and dose adjustment is indicated
`whenever enzyme-inducing or inhibiting drugs are introduced or
`withdrawn (7.1)
`Aspirin, carbapenem antibiotics: Monitoring of valproate
`concentrations are recommended (7.1)
`Co-administration of valproate can affect the pharmacokinetics of
`other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by
`inhibiting their metabolism or protein binding displacement (7.2)
`Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
`zidovudine may be necessary if used concomitantly with Depakote
`(7.2)
`Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3)
`-------USE IN SPECIFIC POPULATIONS-------
`Pregnancy: Depakote can cause congenital malformations including
`neural tube defects. Pregnancy registry available (5.2, 8.1)
`Pediatric: Children under the age of two years are at considerably
`higher risk of fatal hepatotoxicity (5.1, 8.4)
`Geriatric: reduce starting dose; increase dosage more slowly; monitor
`fluid and nutritional intake, and somnolence (5.13, 8.5)
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 10/2011
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`BOXED WARNING
`1 INDICATIONS AND USAGE
`1.1 Mania
`1.2 Epilepsy
`1.3 Migraine
`2 DOSAGE AND ADMINISTRATION
`2.1 Mania
`2.2 Epilepsy
`2.3 Migraine
`2.4 General Dosing Advice
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatotoxicity
`5.2 Use in Women of Childbearing Potential
`5.3 Birth Defects and Neurobehavioral Adverse Effects
`5.4 Pancreatitis
`5.5 Urea Cycle Disorders
`5.6 Suicidal Behavior and Ideation
`5.7 Thrombocytopenia
`5.8 Hyperammonemia
`5.9 Hyperammonemia and Encephalopathy associated with Concomitant
`Topiramate Use
`5.10 Hypothermia
`5.11 Multi-Organ Hypersensitivity Reactions
`5.12 Interaction with Carbapenem Antibiotics
`5.13 Somnolence in the Elderly
`5.14 Monitoring: Drug Plasma Concentration
`5.15 Effect on Ketone and Thyroid Function Tests
`5.16 Effect on HIV and CMV Viruses Replication
`6 ADVERSE REACTIONS
`6.1 Mania
`6.2 Epilepsy
`6.3 Migraine
`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 2 of 57
`
`6.4 Other Patient Populations
`7 DRUG INTERACTIONS
`7.1 Effects of Co-Administered Drugs on Valproate Clearance
`7.2 Effects of Valproate on Other Drugs
`7.3 Topiramate
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Mania
`14.2 Epilepsy
`14.3 Migraine
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Hepatotoxicity
`17.2 Pancreatitis
`17.3 Birth Defects and Neurobehavioral Development Adverse Effects
`17.4 Suicidal Thinking and Behavior
`17.5 Hyperammonemia
`17.6 CNS depression
`17.7 Multi-organ Hypersensitivity Reaction
`FDA-APPROVED MEDICATION GUIDE
`* Sections or subsections omitted from the full prescribing information are
`not listed
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 3 of 57
`
`FULL PRESCRIBING INFORMATION
`
`BOXED WARNING
`
`WARNING: LIFE THREATENING ADVERSE REACTIONS
`
`Hepatotoxicity
`
`Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children
`under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially
`those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure
`disorders accompanied by mental retardation, and those with organic brain disease. When Depakote is used in
`this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be
`weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older
`patient groups.
`
`These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
`may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and
`vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored
`closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at
`frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)].
`
`Fetal Risk
`
`Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).
`Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the
`management of her medical condition. This is especially important when valproate use is considered for a
`condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective
`contraception while using valproate [see Warnings and Precautions (5.2, 5.3)].
`
`A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling
`Information (17)].
`
`Pancreatitis
`
`Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
`of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases
`have been reported shortly after initial use as well as after several years of use. Patients and guardians should be
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 4 of 57
`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 (5.4)].
`
`1 INDICATIONS AND USAGE
`
`1.1 Mania
`
`Depakote (divalproex sodium) is a valproate and 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 judgment, 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 Studies (14.1)].
`
`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.
`
`1.2 Epilepsy
`
`Depakote 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 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.
`
`1.3 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 it 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 and Precautions (5.2) and
`Patient Counseling Information (17.3)].
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`2 DOSAGE AND ADMINISTRATION
`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 5 of 57
`
`Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should
`not be crushed or chewed.
`
`Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as
`soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double
`the next dose.
`
`2.1 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 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended
`dosage is 60 mg/kg/day.
`
`There is no body of evidence available from controlled trials to guide a clinician in the longer term
`management of a patient who improves during Depakote treatment of an acute manic episode. While it is
`generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for
`maintenance of the initial response and for prevention of new manic episodes, there are no data to support the
`benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically
`address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported
`by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3
`months.
`
`2.2 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 clonazepam,
`diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
`affected [see Drug Interactions (7.2)].
`
`Complex Partial Seizures
`
`For adults and children 10 years of age or older.
`
`Monotherapy (Initial Therapy)
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 6 of 57
`Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15
`mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
`Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
`response has not been achieved, plasma levels should be measured to determine whether or not they are in the
`usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate
`for use at doses above 60 mg/kg/day can be made.
`
`The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations
`above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher
`doses should be weighed against the possibility of a greater incidence of adverse reactions.
`
`Conversion to Monotherapy
`
`Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week
`to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
`mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to
`determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No
`recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
`
`Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.
`This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a
`concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
`concomitant AED can be highly variable, and patients should be monitored closely during this period for
`increased seizure frequency.
`
`Adjunctive Therapy
`
`Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be
`increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
`achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma
`levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50
`to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day
`can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
`
`In a study of adjunctive therapy for complex partial seizures in which patients were receiving either
`carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage
`was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or other
`concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of
`concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`Simple and Complex Absence Seizures
`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 7 of 57
`
`The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until
`seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60
`mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
`
`A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.
`However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to
`range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations
`[see Clinical Pharmacology (12.3)].
`
`As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be
`affected [see Drug Interactions (7.2)].
`
`Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to
`prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant
`hypoxia and threat to life.
`
`In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be
`initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a
`dosing schedule of two or three times a day may be elected in selected patients.
`
`2.3 Migraine
`
`Depakote is indicated for prophylaxis of migraine headaches in adults.
`
`Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some
`patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher
`doses led to greater efficacy.
`
`2.4 General Dosing Advice
`
`Dosing in Elderly Patients
`
`Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the
`elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and
`with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.
`Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid
`intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the
`basis of both tolerability and clinical response [see Warnings and Precautions (5.13)].
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`Dose-Related Adverse Reactions
`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 8 of 57
`
`The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-
`related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations
`of (cid:149) 110 mcg/mL (females) or (cid:149) 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of
`improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence
`of adverse reactions.
`
`G.I. Irritation
`
`Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly
`building up the dose from an initial low level.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Depakote tablets (divalproex sodium delayed-release tablets) are supplied as:
`
`125 mg salmon pink-colored tablets
`
`250 mg peach-colored tablets
`
`500 mg lavender-colored tablets
`
`4 CONTRAINDICATIONS
`
`Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction [see
`Warnings and Precautions (5.1)].
`
`Depakote is contraindicated in patients with known hypersensitivity to the drug [see Warnings and
`Precautions (5.11)].
`
`Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions
`(5.5)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hepatotoxicity
`
`Hepatic failure resulting in fatalities has occurred in patients receiving valproate. 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
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 9 of 57
`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.
`
`Caution should be observed when administering valproate 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 [see Boxed
`Warning and Contraindications (4)].
`
`5.2 Use in Women of Childbearing Potential
`
`Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may
`occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential
`unless the drug is essential to the management of her medical condition. This is especially important when
`valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
`migraine). Women should use effective contraception while using valproate. Women who are planning a
`pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy,
`and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in
`Specific Populations (8.1)].
`
`To prevent major seizures, Depakote should not be discontinued abruptly, as this can precipitate status
`epilepticus with resulting maternal and fetal hypoxia and threat to life.
`
`Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
`pregnancy decreases the risk for congenital neural tube defects in the general population.
`
`5.3 Birth Defects and Neurobehavioral Adverse Effects
`
`Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that
`maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial
`defects, cardiovascular malformations and malformations involving various body systems). The rate of
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 10 of 57
`congenital malformations among babies born to mothers using valproate is about four times higher than the
`rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that
`folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for
`congenital neural tube defects in the general population.
`
`Several published epidemiological studies have indicated that children exposed to valproate in utero have
`lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
`antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
`States and United Kingdom that found that children with prenatal exposure to valproate had lower Differential
`Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal exposure to the other
`antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98-104]), carbamazepine (98
`[95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which has a mean score of 100 (SD =
`15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The D.A.S. is a measure of
`neurobehavioral development performed when children are too young to undergo IQ testing and generally
`correlates with IQ scores later in childhood.
`
`Although all of the available studies have methodological limitations, the weight of the evidence supports the
`conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development.
`
`In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and
`demonstrated behavioral deficits [see Use in Specific Populations (8.1)].
`
`5.4 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 2,416 patients, representing 1,044 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, Depakote should ordinarily be discontinued.
`Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see
`Boxed Warning].
`
`5.5 Urea Cycle Disorders
`
`Depakote is contraindicated in patients with known urea cycle disorders (UCD). 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
`
`Reference ID: 3026475
`
`AMN1009
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`Depakote (divalproex sodium) Tablets for Oral use
`FDA Approved Labeling Text dated October 7, 2011
`Page 11 of 57
`deficiency. Prior to the initiation of Depakote 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 Contraindications (4) and Warnings and Precautions (5.9)].
`
`5.6 Suicidal Behavior and Ideation
`
`Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or behavior in patients
`taking these drugs for any indication. Patients treated with any AED for any indication should be monitored
`for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in
`mood or behavior.
`
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
`showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
`1.8, 95% CI:1.2, 2.7) of