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.
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. 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. 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. 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. 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. Nursing Mothers Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. Pediatric Use Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions 5.
When Depakote 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.
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 Depakote was studied in seven pediatric clinical trials. Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania patients aged 10 to 17 years, 76 of whom were on Depakote ER and migraine patients aged 12 to 17 years, of whom were on Depakote ER.
Efficacy was not established for either the treatment of migraine or the treatment of mania. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania patients aged 10 to 17 years.
Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine patients aged 12 to 17 years. One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures patients aged 3 to 10 years.
In these seven clinical trials, the safety and tolerability of Depakote 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. Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness.
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.
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. There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over Overdosage Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia.
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. Depakote Description Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1: Chemically it is designated as sodium hydrogen bis 2-propylpentanoate.
Divalproex sodium has the following structure: Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to mg, mg, or mg of valproic acid. Inactive Ingredients Depakote tablets: In addition, individual tablets contain: Depakote - Clinical Pharmacology Mechanism of Action Divalproex sodium 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. Pharmacodynamics 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. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Although the rate of valproate ion absorption may vary with the formulation administered liquid, solid, or sprinkle , conditions of use e. 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 a greater influence on the rate of absorption of the tablet increase in Tmax from 4 to 8 hours than on the absorption of the sprinkle capsules increase in Tmax from 3.
While the absorption rate from the G. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate 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 between valproate formulations 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 and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration 2. Nonetheless, 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.
Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs e. Conversely, valproate may displace certain protein-bound drugs e. Metabolism Valproate is metabolized almost entirely by the liver. 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. Elimination Mean plasma clearance and volume of distribution for total valproate are 0. Mean plasma clearance and volume of distribution for free valproate are 4.
Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of to 1, 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. Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults.
This is a result of reduced clearance perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination as well as increased volume of distribution in part due to decreased plasma protein binding. For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.
Children Pediatric patients i. Elderly The capacity of elderly patients age range: Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration 2.
Effect of Sex There are no differences in the body surface area adjusted unbound clearance between males and females 4. Effect of Race The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease Liver disease impairs the capacity to eliminate valproate. In that study, the half-life of valproate was increased from 12 to 18 hours.
Liver disease is also associated with decreased albumin concentrations and larger unbound fractions 2 to 2. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning , Contraindications 4 , and Warnings and Precautions 5.
Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
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. Mutagenesis 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. The effect of valproate on testicular development and on sperm parameters and fertility in humans is unknown.
The benefit of preventing seizures may outweigh any risks to the baby. Do not use Depakote to prevent migraine headaches if you are pregnant. Call your doctor at once if the person taking this medicine has signs of liver or pancreas problems, such as: Do not stop using this medicine without your doctor's advice.
Stopping suddenly may cause a serious, life-threatening type of seizure. Before taking this medicine You should not use Depakote if you are allergic to divalproex sodium, or if you have: Divalproex sodium can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by a genetic mitochondrial disorder. Tell your doctor if you have ever had: Some young people have thoughts about suicide when first taking Depakote.
Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms. If you take Depakote for seizures or manic episodes: This medicine can harm an unborn baby, and may affect cognitive ability reasoning, intelligence, problem-solving later in the child's life.
However, having a seizure during pregnancy could harm both the mother and the baby. Do not start or stop taking the medicine during pregnancy without your doctor's advice. Use effective birth control while using this medicine, and tell your doctor right away if you become pregnant. Tell your doctor if you start or stop using hormonal contraception that contains estrogen birth control pills , injections, implants, skin patches, and vaginal rings.
Estrogen can interact with this medicine and make it less effective in preventing seizures. Seizure control is very important during pregnancy. The benefit of preventing seizures may outweigh any risks posed by taking Depakote. There may be other seizure medications that can be more safely used during pregnancy. Follow your doctor's instructions about taking this medicine while you are pregnant.
It may not be safe to breast-feed while using this medicine. Ask your doctor about any risk. How should I take Depakote? Take Depakote exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed. Drink plenty of water while you are taking this medication.
Your dose may need to be changed if you do not get enough fluids each day. If you cannot swallow a sprinkle capsule whole, open it and sprinkle the medicine into a spoonful of pudding or applesauce.
Swallow the mixture right away. Do not save it for later use. Do not crush, chew, break, or open a delayed-release or extended-release tablet or capsule. You may need frequent blood tests. In case of emergency, wear or carry medical identification to let others know you use Depakote. If you need surgery, tell the surgeon ahead of time that you are using Depakote.
While the absorption rate from the G, depakote 500mg indica��o. Because of the 500mg of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: Report any new or worsening symptoms to your doctor, such as: Leg cramps and indica��o. Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P isozymes, epoxide hydrase, and glucuronosyltransferases. Depakote side effects Get emergency medical help if you have signs of an allergic reaction to Depakote hivesdifficult breathing, swelling in your face or throat or depakote severe skin reaction 500mg, sore throatburning eyes, skin pain, red or purple skin rash with blistering and peeling. This medicine can harm an unborn baby, and may affect cognitive ability reasoning, intelligence, problem-solving later in the child's life. Common Depakote side effects may include: Special Populations Effect of Age Neonates Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Cimetidine and Ranitidine Cimetidine and ranitidine do not indica��o the clearance of valproate. Tell your doctor about all your current medicines and any medicine you start or stop using. Metabolic and Nutritional Disorders:
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