ديفاكوت 500 مجم ممتد المفعول 20 قرص

12.1 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).

Divalproex sodium extended-release tablets are indicated for: • Acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features ( 1.1 ) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1.2 ) • Prophylaxis of migraine headaches ( 1.3 ) 1.1 Mania Divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. 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. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities). The efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania [see Clinical Studies (14.1) ] . The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use divalproex sodium extended-release tablets for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient. 1.2 Epilepsy Divalproex sodium extended-release tablets 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 extended-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures....

Divalproex sodium extended-release tablets are an extended-release product intended for once-a-day oral administration. Divalproex sodium extended-release tablets should be swallowed whole and should not be crushed or chewed. • Divalproex sodium extended-release tablets are intended for once-a-day oral administration. Divalproex sodium extended-release tablets should be swallowed whole and should not be crushed or chewed ( 2.1 , 2.2 ). • Mania: Initial dose is 25 mg/kg/day, increasing as rapidly as possible to achieve therapeutic response or desired plasma level ( 2.1 ). The maximum recommended dosage is 60 mg/kg/day ( 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 ( 2.2 ). The maximum recommended dosage is 60 mg/kg/day ( 2.1 , 2.2 ). • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects ( 2.2 ). The maximum recommended dosage is 60 mg/kg/day ( 2.1 , 2.2 ). • Migraine: The recommended starting dose is 500 mg/day for 1 week, thereafter increasing to 1,000 mg/day ( 2.3 ). 2.1 Mania Divalproex sodium extended-release tablets are administered orally. The recommended initial dose is 25 mg/kg/day given once daily. 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 a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. 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 divalproex sodium extended-release tablets 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 data to support the benefits of divalproex sodium extended-release tablets in such longer-term treatment (i.e., beyond 3 weeks). 2....

The following serious are described below and elsewhere in the labeling: • Hepatic Failure [see (5.1) ] • Birth Defects [see (5.2) ] • Decreased IQ and Neurodevelopmental Disorders following in utero exposure [see (5.3) ] • Pancreatitis [see (5.5) ] • Hyperammonemic Encephalopathy [see (5.6 , 5.9 , 5.10) ] • Suicidal Behavior and Ideation [see (5.7) ] • Bleeding and Other Hematopoietic Disorders [see (5.8) ] • Hypothermia [see (5.11) ] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see (5.12) ] • Serious Dermatologic Reactions [see (5.13) ] • Angioedema [see (5.14) ] • Somnolence in the Elderly [see (5.16) ] 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. Information on pediatric is presented in section 8. • Most common (reported ≥ 15% for any indication) are abdominal pain, alopecia, asthenia, diarrhea, diplopia, dizziness, dyspepsia, headache, infection, insomnia, nausea, somnolence, thrombocytopenia, tremor, vomiting ( 6.1 , 6.2 , 6.3 ). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4 ). To report SUSPECTED , contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of divalproex sodium extended-release tablets in the treatment of manic episodes associated with bipolar disorder. Table 3 summarizes those reported for patients in these trials where the incidence rate in the divalproex sodium extended-release tablets-treated group was greater than 5% and greater than the placebo incidence. Table 3....

Divalproex sodium extended-release tablets are contraindicated in patients: • with hepatic disease or significant hepatic dysfunction [see (5.1) ] . • 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 (5.1) ] . • with known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid. Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema [see (5.12 , 5.13 , 5.14) ] . • with known urea cycle disorders [see (5.6) ] . • being treated for prophylaxis of migraine headaches: who are pregnant or in women of childbearing potential who are not using effective contraception [see (5.2 , 5.3 , 5.4) and (8.1) ] . • Hepatic disease or significant hepatic dysfunction ( 4 , 5.1 ) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 ) • Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 ) • Known hypersensitivity to the drug ( 4 , 5.12 ) • Urea cycle disorders ( 4 , 5.6 ) • Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception ( 4 , 8.1 )