Valproic acid capsule delayed release use in specific populations
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Use In Specific Populations
8.1 Pregnancy
Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.3 and 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 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)]
In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neuro behavioral 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.
Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)] . A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
Patients taking valproate may develop hepatic failure [see Warnings and Boxed Warnings]. Fatal hepatic failures, in a newborn and in an infant, have been reported following the maternal use of 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%.
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 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.
Animal
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.
8.3 Nursing Mothers
Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of serum concentrations. Because of the potential for adverse reactions in a nursing infant, a decision should be made whether to discontinue nursing or drug taking into account the importance of the drug to the mother.
8.4 Pediatric Use
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, Warning 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.
8.5 Geriatric Use
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 two 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)].[1]
References
Adapted from the FDA Package Insert.