Valproic Acid

Sun Pharmaceutical Industries Limited

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use valproic acid safely and effectively. See full prescribing information for valproic acid capsules. Valproic Acid Capsules, USPInitial U.S. Approval: 1978 RECENT MAJOR CHANGES5.25.3BOXED WARNINGWARNINGS: LIFE THREATENING ADVERSE REACTIONSSee full prescribing information for complete boxed warning Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the age of two years are a considerable higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function test 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) INDICATIONS AND USAGE Monotherapy and adjunctive therapy of complex partial seizures; sole and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1) DOSAGE AND ADMINISTRATION2.1 Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control or limiting side effects (2.1) Safety of doses above 60 mg/kg/day is not established (2.1, 2.2) 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 valproic acid capsules benefits of use during pregnancy against risk to the fetus (5.2) Birth Defects; valproic acid capsules can cause fetal harm when taken during pregnancy (5.3) Pancreatitis; valproic acid capsules should ordinarily be discontinued (5.4) Suicidal behavior or ideation; Antiepileptic drugs, including valproic acid, 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 (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 valproic acid capsules (5.11) Somnolence in the elderly can occur. Valproic acid dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.13) Side Effects6.1To report SUSPECTED ADVERSE REACTIONS, contact CARACO Pharmaceutical Laboratories Ltd. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatchDRUG INTERACTIONS Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, 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 dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is recommended (7.1) Coadministration 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 valproic acid (7.2) Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3) USE IN SPECIFIC POPULATIONS Pregnancy: Valproic acid capsules 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)

FULL PRESCRIBING INFORMATION: CONTENTS*

• BOXED WARNING
• 1 VALPROIC ACID INDICATIONS AND USAGE
• 2 VALPROIC ACID DOSAGE AND ADMINISTRATION
  • 2.1 Epilepsy
  • 2.2 General Dosing Advice
• 3 DOSAGE FORMS AND STRENGTHS
• 4 VALPROIC ACID 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 (UCD)
  • 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 VALPROIC ACID ADVERSE REACTIONS
  • 6.1 Epilepsy
  • 6.2 Mania
  • 6.3 Migraine
  • 6.4 Other Patient Populations
• 7 DRUG INTERACTIONS
  • 7.1 Effects of Coadministered 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 VALPROIC ACID DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Epilepsy
• 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
• Medication Guide
• PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Epilepsy

2.2 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 (UCD)

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 Epilepsy

Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial SeizuresHeadache was the only adverse reaction that occurred in ≥5% of patients in the high dose group and at an equal or greater incidence in the low dose group

Body System/Reaction	High Dose (%) (n = 131)	Low Dose (%) (n = 134)
Body as a Whole
Asthenia	21	10
Digestive System
Nausea	34	26
Diarrhea	23	19
Vomiting	23	15
Abdominal Pain	12	9
Anorexia	11	4
Dyspepsia	11	10
Hemic/Lymphatic System
Thrombocytopenia	24	1
Ecchymosis	5	4
Metabolic/Nutritional
Weight Gain	9	4
Peripheral Edema	8	3
Nervous System
Tremor	57	19
Somnolence	30	18
Dizziness	18	13
Insomnia	15	9
Nervousness	11	7
Amnesia	7	4
Nystagmus	7	1
Depression	5	4
Respiratory System
Infection	20	13
Pharyngitis	8	2
Dyspnea	5	1
Skin and Appendages
Alopecia	24	13
Special Senses
Amblyopia/Blurred Vision	8	4
Tinnitus	7	1

6.2 Mania

6.3 Migraine

6.4 Other Patient Populations

7 DRUG INTERACTIONS

7.1 Effects of Coadministered Drugs on Valproate Clearance

7.2 Effects of Valproate on Other Drugs

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. 

7.3 Topiramate

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

• Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1 to 2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births).
• To prevent major seizures, women with epilepsy should not discontinue valproic acid capsules abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.
• 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. It is not known whether the risk of neural tube defects in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. 

In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems.

There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy.

8.3 Nursing Mothers

8.4 Pediatric Use

Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning]. When valproic acid is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations. 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.

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Absorption/Bioavailability 

Equivalent oral doses of divalproex sodium products and 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. 

Distribution  

Protein Binding  

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/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 Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs.)

CNS Distribution  

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. 

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

Carcinogenesis  

14 CLINICAL STUDIES

14.1 Epilepsy

The efficacy of divalproex sodium 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, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.

Table 5: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

Add-on Treatment	Number of Patients	Baseline Incidence	Experimental Incidence
Divalproex Sodium	75	16	8.9Reduction from baseline statistically significantly greater for divalproex sodium than placebo at ≤0.05 level.
Placebo	69	14.5	11.5

The second study assessed the capacity of divalproex sodium 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 divalproex sodium. 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 divalproex sodium monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.

Table 6: Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment	Number of Patients	Baseline Incidence	Randomized Phase Incidence
High dose divalproex sodium	131	13.2	10.7Reduction from baseline statistically significantly greater for high dose than low dose at p≤0.05 level.
Low dose divalproex sodium	134	14.2	13.8

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

Medication Guide

• nausea or vomiting that does not go away
• loss of appetite
• pain on the right side of your stomach (abdomen)
• dark urine
• swelling of your face
• yellowing of your skin or the whites of your eyes

In some cases, liver damage may continue despite stopping the drug.

2. Valproic acid capsules may harm your unborn baby.

• If you take valproic acid capsules during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with valproic acid capsules affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen.
• Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
• Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect.
• If you take valproic acid capsules during pregnancy for any medical condition, your child is at risk for having a lower IQ.
• There may be other medicines to treat your condition that have a lower chance of birth defects. 
• All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of valproic acid capsules . If the decision is made to use valproic acid capsules , you should use effective birth control (contraception) unless you are planning to become pregnant.
• Tell your healthcare provider right away if you become pregnant while taking valproic acid capsules. You and your healthcare provider should decide if you will continue to take valproic acid capsules while you are pregnant.
• Pregnancy Registry: If you become pregnant while taking valproic acid capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. 

• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.

• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types

• have liver problems
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in
  valproic acid capsules. See the end of this leaflet for a complete list of ingredients in valproic acid capsules.
• have a genetic problem called urea cycle disorder

• drink alcohol
• are pregnant or breastfeeding. Valproic acid can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take valproic acid capsules.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions

• Take valproic acid capsules exactly as your healthcare provider tells you. Your healthcare provider
  will tell you how much valproic acid capsules to take and when to take it. 
• Your healthcare provider may change your dose.
• Do not change your dose of valproic acid capsules without talking to your healthcare provider.
• Do not stop taking valproic acid capsules without first talking to your healthcare provider. Stopping valproic acid capsules suddenly can cause serious problems.
• Swallow valproic acid capsules whole. Do not crush or chew valproic acid capsules. Tell your healthcare provider if you can not swallow valproic acid capsules whole. You may need a different medicine. 
• If you take too many valproic acid capsules, call your healthcare provider or local Poison Control Center right away.

• Valproic acid capsules can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking valproic acid capsules, until you talk with your doctor. Taking valproic acid capsules with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. 
• Do not drive a car or operate dangerous machinery until you know how valproic acid capsules affect you. Valproic acid capsules can slow your thinking and motor skills.

• See “What is the most important information I should know about valproic acid capsules?”

• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status. 
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma. 
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of valproic acid capsules.  Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of valproic acid capsules include:

• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination

• Store valproic acid capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).

PRINCIPAL DISPLAY PANEL