STAVZOR - valproic acid capsule, delayed release
Noven Therapeutics, LLC
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use STAVZOR safely and effectively. See full prescribing information for STAVZOR.
STAVZOR (valproic acid) Delayed Release Capsules, for oral use Initial U.S. Approval: 2008
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
STAVZOR is indicated for:
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Delayed Release Capsules: 125 mg, 250 mg, 500 mg (3)
WARNINGS AND PRECAUTIONS
Most common adverse reactions (reported >5%) are nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain, alopecia, headache, fever, anorexia, constipation, diplopia, amblyopia/blurred vision, ataxia, nystagmus, emotional lability, thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4)
To report SUSPECTED ADVERSE REACTIONS, contact Noven Therapeutics, LLC at 1-800-455-8070 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable.
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)].
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.3)].
STAVZOR 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 valproate 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 valproate for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use STAVZOR for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.
STAVZOR is indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. STAVZOR 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.
STAVZOR is indicated for prophylaxis of migraine headaches. There is no evidence that STAVZOR is useful in the acute treatment of migraine headaches.
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)].
STAVZOR is contraindicated for prophylaxis of migraine headaches in women who are pregnant.
STAVZOR (valproic acid) delayed release capsules are administered orally, and must be swallowed whole. 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 STAVZOR 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 systematically obtained data to support the benefits of STAVZOR in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with STAVZOR, the safety of STAVZOR in long-term use is supported by data from record reviews involving approximately 360 patients treated with valproate for greater than 3 months.
STAVZOR (valproic acid) delayed release capsules are administered orally, and must be swallowed whole. As STAVZOR 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)
Valproate 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 STAVZOR 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.
STAVZOR 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 2 to 3 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 (14.3)]. 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)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at 1-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 2 to 3 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 are 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 STAVZOR 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, STAVZOR should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on STAVZOR, a dosing schedule of 2 or 3 times a day may be elected in selected patients.
STAVZOR (valproic acid) delayed release capsules are administered orally, and must be swallowed whole. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day. In clinical trials, there was no evidence that higher doses led to greater efficacy.
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)].
Dose-Related Adverse Reactions
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 ≥110 mcg/mL (females) or ≥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.
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 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.
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 studies1 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]). 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 causes 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.
Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), 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, valproate 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. 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 receiving valproate.
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, STAVZOR should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning].
STAVZOR 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 UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of STAVZOR 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 blood urea nitrogen (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 UCD [see Contraindications (4) and Warnings and Precautions (5.8),(5.9)].
Antiepileptic drugs (AEDs), including STAVZOR, 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 suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
|Indication||Placebo Patients with Events Per 1000 Patients||Drug Patients with Events Per 1000 Patients||Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients||Risk Difference: Additional Drug Patients with Events Per 1000 Patients|
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing STAVZOR or any other AED must balance the risk of suicidal thoughts and behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤75 × 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (eg, low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving STAVZOR be monitored for platelet count and coagulation parameters prior to planned surgery. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤75 × 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males). Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.10)].
If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.5)].
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)].
In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.8)].
Hypothermia, defined as an unintentional drop in body core temperature to < 35° C (95° F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. 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 Drug Interactions (7.1)].
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)].
Since valproic acid may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)].
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV-infected patients receiving valproate or when following CMV-infected patients clinically.
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.
The incidence of adverse reactions has been ascertained based on combined data from 2 placebo-controlled clinical trials of valproate 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, valproate, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, valproate, and lithium carbonate groups, respectively.
Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the valproate -treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the valproate -treated group was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by significantly (p≤ 0.05) more patients receiving valproate compared to placebo.
The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 valproate-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.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the valproate -treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥5% of valproate -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 valproate alone, or the combination of valproate and other antiepilepsy drugs.
|Body System/Event||Valproate (%)|
(n = 77)
(n = 70)
|Body as a Whole|
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 valproate 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 valproate alone, or the combination of valproate and other antiepilepsy drugs.
|Body System/Event||High Dose (%)|
(n = 131)
|Low Dose (%)
(n = 134)
|Body as a Whole|
|Skin and Appendages|
The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
Based on 2 placebo-controlled clinical trials and their long-term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long-term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).
Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the valproate-treated group was greater than 5% and was greater than that for placebo patients.
|Body System Event||Valproate|
The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 valproate-treated patients in the controlled clinical trials:
Body as a Whole: Chest pain, chills, face edema, fever and malaise.
Cardiovascular System: Vasodilatation.
Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.
Musculoskeletal System: Leg cramps and myalgia.
Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.
Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.
Skin and Appendages: Pruritus and rash.
Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
The following adverse reactions have been identified during post approval use of STAVZOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome.
Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.
Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, polycystic ovary disease, and parotid gland swelling, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, 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
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.
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 in 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 (5.12)].
A study involving the co-administration of 1200 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 2400 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.
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.
An in vitro study evaluating dissolution of valproic acid showed earlier dissolution in the presence of ethanol than in the absence of ethanol. This has not been studied in humans. However, there is a potential for an earlier Tmax and therefore a higher Cmax when valproic acid is given with alcohol. Caution is advised if valproic acid is taken with alcohol.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
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.
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.
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.
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
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.
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.
The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 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.
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 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.
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.
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.
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproic acid therapy is instituted in patients taking anticoagulants.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to 3 epileptic patients.
In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy [see Warnings and Precautions (5.5), (5.8), and (5.9)]. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8), (5.10)].
Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)].
To collect information on the effects of in utero exposure to STAVZOR, physicians should encourage pregnant patients taking STAVZOR 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, http://www.aedpregnancyregistry.org/.
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). 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.
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.
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%.
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. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy.
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 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 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 a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy.
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate.
Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman.
Experience has indicated that pediatric patients under the age of 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. 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.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
Valproate has not been established to be safe and effective for the treatment of partial seizures in children under the age of 10 years.
Pediatric Clinical Trials
Valproate was studied in seven pediatric clinical trials.
A double-blind placebo-controlled trial evaluated the efficacy of valproate for the treatment of mania in 150 patients aged 10 to 17 years, 76 of whom were on valproate. Efficacy was not established.
A double-blind placebo-controlled trial evaluated the efficacy of valproate for the treatment of migraine in 304 patients aged 12 to 17 years, 231 of whom were on valproate. Efficacy was not established. Based on the results of this study, it is not expected that valproate would be effective in patients with migraine below the age of 12.
The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of valproate for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of valproate for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of valproate in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis.
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter 2 events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)].
There is insufficient information available to discern the safety and effectiveness of valproic acid for the prophylaxis of migraines in patients over 65. The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26) [see Clinical Pharmacology (12.3)].
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.
Valproic acid is a carboxylic acid designated as 2–propylpentanoic acid. It is also known as dipropylacetic acid. Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic odor. It is slightly soluble in water (1.3 mg/ml) and very soluble in organic solvents. Valproic acid has the following structure:
STAVZOR (valproic acid) delayed release capsules are for oral administration and are provided as orange-colored, oval- shaped capsules in 3 dosage strengths: 125 mg, 250 mg, 500 mg of valproic acid.
STAVZOR (valproic acid) delayed release capsules also contain ammonium hydroxide, gelatin, glycerin, methacrylic acid copolymer, triethyl citrate, water, and FD&C Yellow No. 6 as the colorant. Each capsule is printed with Opacode WB as the black printing ink.
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
A single-dose randomized crossover study compared STAVZOR 500-mg strength capsules to 500-mg Depakote delayed-release tablets. These studies demonstrated that the 2 products had similar plasma concentration-time profiles under fasted conditions in terms of valproic acid, although the median Tmax occurre d earlier with STAVZOR (2.0 hrs versus 3.5 hrs). Co-administration with food increased the Tmax of STAVZOR (2.0 hrs without food and approximately 4.8 hours with food), and resulted in a 23% decrease in Cmax of valproic acid, although there was no change in systemic exposure (AUC).
Although the rate of valproate ion absorption may vary with the conditions of use (eg, fasting or postprandial), these differences should be of minor clinical importance under the steady-state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had an influence on the rate of absorption of the capsule (increase in Tmax from 2.3 to 6.1 hours). While the absorption rate from the GI tract and fluctuation in valproate plasma concentrations vary with dosing regimen, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to 4-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicates that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)].
An in vitro study evaluating dissolution of valproic acid showed earlier dissolution in the presence of ethanol than in the absence of ethanol. This has not been studied in humans. However, there is a potential for an earlier Tmax and therefore a higher Cmax when valproic acid is given with alcohol.
Any changes in dosage administration, or the addition or discontinuance of concomitant drugs, should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.
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 (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, and tolbutamide) [See Drug Interactions (7) for more detailed information on the pharmacokinetic interactions of valproate with other drugs].
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.
Effect of Age
Effect of Gender
There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Disease
Plasma Levels and Clinical Effect
The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)].
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum human dose on a mg/m2 basis) for 2 years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown.
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known.
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.
The effectiveness of valproate for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies.
The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Valproate was initiated at a dose of 250 mg TID and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean valproate doses for completers in this study were 1118, 1525, and 2402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carried-forward [LOCF]) analysis were as follows:
|YMRS Total Score|
|Group||Baseline*||BL to Wk3†||Difference‡|
|BPRS–A Total Score|
|Group||Baseline*||BL to Wk3†||Difference‡|
|Group||Baseline*||BL to Wk3†||Difference‡|
Valproate was statistically significantly superior to placebo on all three measures of outcome.
The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Valproate was initiated at a dose of 250 mg TID and adjusted within a dose range of 750-2500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean valproate doses for completers in this study were 1116, 1683, and 2006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1312, 1869, and 1984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for 2 subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (LOCF) analysis were as follows:
|MRS Total Score|
|Group||Baseline*||BL to Day 21†||Difference‡|
|MSS Total Score|
|Group||Baseline*||BL to Day 21†||Difference‡|
|BIS Total Score|
|Group||Baseline*||BL to Day 21†||Difference‡|
Valproate was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender.
A comparison of the percentage of patients showing ≥30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1.
Figure 1. Percentage of Patients Achieving ≥30% Reduction in Symptom Score From Baseline
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in 2 controlled trials.
In one, multiclinic, placebo-controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer 8 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 valproate or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.
|Add-On Treatment||Number of Patients||Baseline Incidence||Experimental Incidence|
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.
The second study assessed the capacity of valproate 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 (ie, phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a 2-week interval to valproate. 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 valproate monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low-dose and high-dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-randomization assessment.
|Treatment||Number of Patients||Baseline Incidence||Randomized Phase Incidence|
Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital, or primidone monotherapy to high-dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low-dose valproate.
The results of 2 multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of valproate in the prophylactic treatment of migraine headache.
Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to valproate or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, valproate to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250-mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on valproate doses ranged from 500 to 2500 mg a day. Doses over 500 mg were given in 3 divided doses (TID). The mean dose during the treatment phase was 1087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL.
The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the valproate group (see Figure 2). These rates were significantly different.
In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three valproate dose groups (500, 1000, or 1500 mg/day) or placebo. The treatments were given in 2 divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1000/1500 mg/day group and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the valproate 500, 1000, and 1500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the valproate 500, 1000, and 1500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined valproate 1000/1500 mg group were significantly lower than in the placebo group.
STAVZOR (valproic acid) delayed release capsules are supplied as:
Advised the patient to read the FDA-Approved patient labeling (Medication Guide).
Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly.
Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.4)].
Birth Defects and Decreased IQ
Prescribers should inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Prescribers should advise women to use effective contraception while using valproate. Prescribers should counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1)].
Suicidal Thinking and Behavior
Patients, their caregivers, and families should be counseled that AEDs, including STAVZOR, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8),(5.9)].
Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
Multi-organ Hypersensitivity Reaction
Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.11)].
Noven Therapeutics, LLC
Miami, FL 33186
Banner Pharmacaps, Inc.
High Point, NC 27265
STAVZOR® is a registered trademark of Noven Therapeutics, LLC.
Depakene® and Depakote® are registered trademarks of Abbott Laboratories.
STAVZOR® (STAV- ZOR)
Delayed Release Capsules
Read this Medication Guide before you start taking STAVZOR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
Do not stop taking STAVZOR without first talking to your healthcare provider.
Stopping STAVZOR suddenly can cause serious problems.
STAVZOR can cause serious side effects including:
What is STAVZOR?
STAVZOR is a prescription medicine used:
Who should not take STAVZOR?
Do not take STAVZOR if you:
What should I tell my healthcare provider before taking STAVZOR?
Before you take STAVZOR, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements, and medicines that you take for a short period of time.
Taking STAVZOR with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.
How should I take STAVZOR?
What should I avoid while taking STAVZOR?
What are the possible side effects of STAVZOR?
STAVZOR may cause other serious side effects including:
Call your healthcare provider right away, if you have any of the symptoms listed above.
The most common side effects of STAVZOR include:
These are not all of the possible side effects of STAVZOR. For more information, ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store STAVZOR?
Keep STAVZOR and all medicines out of the reach of children.
General Information about STAVZOR
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use STAVZOR for a condition for which it was not prescribed. Do not give STAVZOR to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about STAVZOR. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about STAVZOR that is written for health professionals.
For more information, go to www.STAVZOR.com or call 1-800-455-8070
What are the ingredients in STAVZOR?
Active ingredient: valproic acid
Inactive ingredient: ammonium hydroxide, gelatin, glycerin, methacrylic acid copolymer, triethyl citrate, water, and FD&C Yellow No. 6 as the colorant
Noven Therapeutics, LLC
Miami, FL 33186
Banner Pharmacaps, Inc.
High Point, NC 27265
This Medication Guide has been approved by the U.S. Food and Drug Administration.
PACKAGE LABEL. PRINCIPAL DISPLAY PANEL-125 mg-100 count
(valproic acid delayed release capsule)
PACKAGE LABEL. PRINCIPAL DISPLAY PANEL-250 mg-100 count
(valproic acid delayed release capsule)
valproic acid capsule, delayed release
valproic acid capsule, delayed release
valproic acid capsule, delayed release
|Labeler - Noven Therapeutics, LLC (166888268)|
|Registrant - Banner Pharmacaps (002193829)|
|Banner Pharmacaps||945494508||MANUFACTURE(68968-3125, 68968-3250, 68968-3500), ANALYSIS(68968-3125, 68968-3250, 68968-3500)|