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Indications
Divalproex sodium delayed release tablets are 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 )
1.1Mania
Divalproex sodium delayed release tablets are a valproate and are 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 divalproex sodium delayed release tablets were 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 divalproex sodium delayed release tablets for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use divalproex sodium delayed release tablets for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.
1.2Epilepsy
Divalproex sodium delayed release tablets are 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. Divalproex sodium delayed release tablets are 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.
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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.
1.3Migraine
Divalproex sodium delayed release tablets are indicated for prophylaxis of migraine headaches. There is no evidence that divalproex sodium delayed release tablets are useful in the acute treatment of migraine headaches.
1.4 Important Limitations Because of the risk to the fetus of decreased IQ, 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 [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ), Use in Specific Populations ( 8.1 ), and Patient Counseling Information ( 17 )].
Divalproex sodium delayed release tablets are contraindicated for prophylaxis of migraine headaches in women who are pregnant.
Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 )
Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 )
Known hypersensitivity to the drug ( 4 , 5.12 )
Urea cycle disorders ( 4 , 5.6 )
Pregnant patients treated for prophylaxis of migraine headaches ( 4 , 8.1 )
Divalproex sodium delayed release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions ( 5.1 )] .
Divalproex sodium delayed release tablets are contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions ( 5.1 )] .
Divalproex sodium delayed release tablets are contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions ( 5.12 )] .
Divalproex sodium delayed release tablets are contraindicated in patients with known urea cycle disorders [see Warnings and Precautions ( 5.6 )] .
Divalproex sodium delayed release tablets are contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.1 )] .
Warnings and precautions
Hepatotoxicity; evaluate high risk populations and monitor serum liver tests ( 5.1 )
Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential ( 5.2 , 5.3 , 5.4 )
Pancreatitis; Divalproex sodium should ordinarily be discontinued ( 5.5 )
Suicidal behavior or ideation; Antiepileptic drugs, including divalproex sodium, increase the risk of suicidal thoughts or behavior ( 5.7 )
Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests ( 5.8 )
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 ( 5.6 , 5.9 , 5.10 )
Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate ( 5.11 )
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue divalproex sodium ( 5.12 )
Somnolence in the elderly can occur. Divalproex sodium dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.14 )
5.1Hepatotoxicity General Information on 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 these symptoms.
Serum liver 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. See below, "Patients with Known or Suspected Mitochondrial Disease." 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 divalproex sodium 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. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Divalproex sodium is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications ( 4 )] .
Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura.
POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with divalproex sodium for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. 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 )] .
5.2Birth Defects
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, hypospadias, limb malformations). The rate of 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.
5.3Decreased IQ Following
in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies 1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]).
It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations ( 8.1 )] . Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable.
In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential Because of the risk to th
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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 )
Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose ( 7.2 )
Dosage adjustment of amitriptyline/nortriptyline, warfarin, and zidovudine may be necessary if used concomitantly with divalproex sodium ( 7.2 )
Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 )
7.1Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate.
Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control.
The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions ( 5.13 )] . Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone.
Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate.
Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine Cimetidine and ranitidine do not affect the clearance of valproate.
7.2Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline.
Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone.
Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 7
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Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category D
for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions ( 5.2 , 5.3 )] . Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications ( 4 )] . Pregnancy Registry To collect information on the effects of in utero exposure to divalproex sodium, physicians should encourage pregnant patients taking divalproex sodium to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, Error! Hyperlink reference not valid. . Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations).
The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. [see Warnings and Precautions ( 5.3 )].
Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions ( 5.3 )] . An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy.
The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
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 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births).
Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy.
Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, 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).
Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches.
Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling.
To prevent major seizures, women with epilepsy should not discontinue valproate 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 or decreased IQ 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.
Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions ( 5.8 )] . If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate.
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Adverse reactions
Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, amblyopia/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 ).
The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4 ). To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA), Inc. at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following serious adverse reactions are described below and elsewhere in the labeling:
Hepatic failure [see Warnings and Precautions ( 5.1 )]
Birth defects [see Warnings and Precautions ( 5.2 )]
Decreased IQ following in utero exposure [see Warnings and Precautions ( 5.3 )]
Pancreatitis [see Warnings and Precautions ( 5.5 )]
Suicidal behavior and ideation [see Warnings and Precautions ( 5.7 )]
Bleeding and other hematopoietic disorders [see Warnings and Precautions ( 5.8 )]
Hypothermia [see Warnings and Precautions ( 5.11 )]
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions ( 5.12 )]
Somnolence in the elderly [see Warnings and Precautions ( 5.14 )] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
6.1Mania
The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, divalproex sodium, and lithium carbonate.
A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the divalproex sodium-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the divalproex sodium-treated group was statistically significantly greater than the placebo group.
Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving divalproex sodium compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Divalproex Sodium-Treated Patients During Placebo-Controlled Trials of Acute Mania 1 1. The following adverse reactions occurred at an equal or greater incidence for placebo than for divalproex sodium: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
Adverse Reaction Divalproex sodium (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal Pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials: Body as a Whole : Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.
Cardiovascular System : Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. Digestive System : Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. Hemic and Lymphatic System : Ecchymosis. Metabolic and Nutritional Disorders : Edema, peripheral edema. Musculoskeletal System : Arthralgia, arthrosis, leg cramps, twitching. Nervous System : Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.
Respiratory System : Dyspnea, rhinitis. Skin and Appendages : Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses : Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Urogenital System : Dysmenorrhea, dysuria, urinary incontinence.
6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures.
Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Divalproex sodium (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium monotherapy treatment of complex partial seizures.
Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of valproate and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures 1 1.
Headache 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 Dyspn
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Composition
Active ingredients
DIVALPROEX SODIUM EQ 250MG VALPROIC ACID
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
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.
Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC's National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data show up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and malformations of varying severity involving other body systems. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ 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 (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatme
