DIVALPROEX SODIUM capsule, coated pellets

Šalis: Jungtinės Valstijos

kalba: anglų

Šaltinis: NLM (National Library of Medicine)

Veiklioji medžiaga:

DIVALPROEX SODIUM (UNII: 644VL95AO6) (VALPROIC ACID - UNII:614OI1Z5WI)

Prieinama:

AvPAK

INN (Tarptautinis Pavadinimas):

DIVALPROEX SODIUM

Sudėtis:

VALPROIC ACID 125 mg

Vartojimo būdas:

ORAL

Recepto tipas:

PRESCRIPTION DRUG

Terapinės indikacijos:

  Divalproex sodium delayed-release capsules (sprinkle) are 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. Divalproex sodium delayed-release capsules (sprinkle) are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.    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. Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4), USE IN SPECIFIC POPULATIONS (8.1), AND PATIENT COUNSELING INFORMATION (17)]. - Divalproex sodium delayed-release capsules (sprinkle) should not be administered to patients with hepatic disease or significant hepatic dysfunction [see WARNINGS AND PRECAUTIONS (5.1) ]. - Divalproex sodium delayed-release capsules (sprinkle) are contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see WARNINGS AND PRECAUTIONS (5.1) ]. - Divalproex sodium delayed-release capsules (sprinkle) are contraindicated in patients with known hypersensitivity to the drug [see WARNINGS AND PRECAUTIONS (5.12) ]. - Divalproex sodium delayed-release capsules (sprinkle) are contraindicated in patients with known urea cycle disorders [see WARNINGS AND PRECAUTIONS (5.6) ]. Pregnancy Category D for epilepsy [see WARNINGS AND PRECAUTIONS (5.2, 5.3) ]. Pregnancy Registry To collect information on the effects of in utero exposure to divalproex sodium, physicians should encourage pregnant patients taking divalproex sodium to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, 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, hypospadias, limb malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see WARNINGS AND PRECAUTIONS (5.3) ]. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see WARNINGS AND PRECAUTIONS (5.3) ]. An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7 to 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% to 7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5% to 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 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 to 2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). - 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). - Divalproex sodium delayed-release capsules (sprinkle) should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. - To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. - Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. - Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. - Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions ( 5.8)] . If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate. - Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions ( 5.1)] . Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. - Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. Data Human There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC's National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. The NAAED Pregnancy Registry has reported a major malformation rate of 9 to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data show up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and malformations of varying severity involving other body systems. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero . The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105 to110]), carbamazepine (105 [95% C.I. 102 to 108]) and phenytoin (108 [95% C.I. 104 to 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. 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 two 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 divalproex sodium is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. 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 valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. 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. Pediatric Clinical Trials Divalproex sodium was studied in seven pediatric clinical trials. Two of the pediatric studies were doubleblinded placebo-controlled trials to evaluate the efficacy of divalproex sodium extended-release tablets for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium extended-release tablets) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium extended-release tablets). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported > 5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. The remaining five trials were long term safety studies. Two six month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release tablets 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 divalproex sodium extended-release tablets for the indication of migraine (353 patients aged 12 to 17 years). One twelve month study was conducted to evaluate the safety of divalproex sodium delayed-release capsules (sprinkle) in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of divalproex sodium 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/m 2 basis. No patients above the age of 65 years were enrolled in doubleblind 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 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 (5.14) ]. 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 (2.2) ]. 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 years) [see CLINICAL PHARMACOLOGY (12.3) ]. Liver Disease Liver disease impairs the capacity to eliminate valproate [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Produkto santrauka:

Divalproex sodium delayed-release capsules, USP (sprinkle) equivalent to 125 mg of valproic acid are white to off-white free flowing pellets filled in size '0' hard gelatin capsules with blue colored cap  printed with "ZA66" in black ink and white body printed with "125mg" in black ink and are supplied as follows: NDC 50268-258-13     5 capsules per card, 6 cards per carton. Dispensed in Unit Dose Package. For Institutional Use Only. Storage : Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].  Dispense in a tight, light-resistant container.

Autorizacija statusas:

Abbreviated New Drug Application

Pakuotės lapelis

DIVALPROEX SODIUM- DIVALPROEX SODIUM CAPSULE, COATED PELLETS
AvPAK
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MEDICATION GUIDE
Divalproex Sodium
(dye val PRO ex sew dee uhm)
Delayed-release Capsules, USP (Sprinkle)
Read this Medication Guide before you start taking divalproex sodium
delayed-release capsules (sprinkle)
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.
What is the most important information I should know about divalproex
sodium delayed-release capsules
(sprinkle)?
Do not stop taking divalproex sodium delayed-release capsules
(sprinkle) without first talking to your
healthcare provider.
Stopping divalproex sodium delayed-release capsules (sprinkle)
suddenly can cause serious problems.
Divalproex sodium delayed-release capsules (sprinkle) can cause
serious side effects, including:
1.
Serious liver damage that can cause death, especially in children
younger than 2 years old.
The risk of getting this serious liver damage is more likely to happen
within the first 6 months of
treatment.
Call your healthcare provider right away if you get any of the
following symptoms:
•
nausea or vomiting that does not go away
•
loss of appetite
•
pain on the right side of your stomach (abdomen)
•
dark urine
•
swelling of your face
•
yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2 Divalproex sodium delayed-release capsules (sprinkle) may harm your
unborn baby.
•
If you take divalproex sodium delayed-release capsules (sprinkle)
during pregnancy for any
medical condition, your baby is at risk for serious birth defects that
affect the brain and spinal cord
and are called spina bifida or neural tube defects. These defects
occur in 1 to 2 out of every 100
babies born to mothers who use this medicine during pregnancy. These
defects can begin in the
first month, even before you know you are pregnant. Other birth
defects that affect the struct

Prekės savybės

DIVALPROEX SODIUM- DIVALPROEX SODIUM CAPSULE, COATED PELLETS
AVPAK
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HIGHLIGHTS OF PRESCRIBING INFORMATION
DIVALPROEX SODIUM DELAYED-RELEASE CAPSULES, USP
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
DIVALPROEX SODIUM
DELAYED-RELEASE CAPSULES (SPRINKLE) SAFELY AND EFFECTIVELY. SEE FULL
PRESCRIBING
INFORMATION FOR DIVALPROEX SODIUM DELAYED-RELEASE CAPSULES (SPRINKLE).
DIVALPROEX SODIUM DELAYED-RELEASE CAPSULES (SPRINKLE), FOR ORAL USE
INITIAL U.S. APPROVAL: 1989
WARNING: LIFE THREATENING ADVERSE REACTIONS
SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.
HEPATOTOXICITY, INCLUDING FATALITIES, USUALLY DURING THE FIRST 6
MONTHS OF TREATMENT.
CHILDREN UNDER THE AGE OF TWO YEARS AND PATIENTS WITH MITOCHONDRIAL
DISORDERS ARE
AT HIGHER RISK. MONITOR PATIENTS CLOSELY, AND PERFORM SERUM LIVER
TESTING PRIOR TO
THERAPY AND AT FREQUENT INTERVALS THEREAFTER (5.1)
FETAL RISK, PARTICULARLY NEURAL TUBE DEFECTS OTHER MAJOR
MALFORMATIONS, AND
DECREASED IQ (5.2, 5.3, 5.4)
PANCREATITIS, INCLUDING FATAL HEMORRHAGIC CASES (5.5)
INDICATIONS AND USAGE
Divalproex sodium delayed-release capsules (sprinkle) are
anti-epileptic drug indicated for:
Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence
seizures; adjunctive therapy in patients with multiple seizure types
that include absence seizures (1)
DOSAGE AND ADMINISTRATION
Divalproex sodium delayed-release capsules (sprinkle) may be swallowed
whole or the contents may be
sprinkled on soft food. The drug/food mixture should be swallowed
immediately (avoid chewing) (2.2)
Safety of doses above 60 mg/kg/day is not established (2.1), (2.2)
Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
week intervals by 5 to 10
mg/kg/day to achieve optimal clinical response; if response is not
satisfactory, check valproate plasma
level; see full prescribing information for conversion to monotherapy
(2.1)
Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week
intervals by 5 to 10 mg/kg/day until
seizu