Divalproex Sodium Delayed-Release Tablets USP, 125 mg, 250 mg and 500 mg

/Divalproex Sodium Delayed-Release Tablets USP, 125 mg, 250 mg and 500 mg
Divalproex Sodium Delayed-Release Tablets USP, 125 mg, 250 mg and 500 mg2018-09-06T09:12:40+00:00

Prescription Drug Name:

Divalproex Sodium Delayed-Release Tablets USP, 125 mg, 250 mg and 500 mg

ID:

9b3db659-f64c-4c48-946a-6b4f1d800eba

Code:

34391-3

DESCRIPTION


id: aa5a0e7a-a765-46da-bec0-15dc99454fbb
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. 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. Divalproex sodium delayed-release tablets are for oral administration. Divalproex sodium delayed-release tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Divalproex sodium delayed-release tablets: antifoam DC, colloidal silicon dioxide, D&C Red No. 30, FD&C Blue No. 2, hydroxylpropyl cellulose, hypromellose, hypromellose phthalate, iron oxides, lecithin, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, pregelatinised starch, shellac, talc, titanium dioxide, triethyl citrate.

INDICATIONS AND USAGE


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displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Mania Divalproex sodium delayed-release tablets are 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 judgement, aggressiveness, and possible hostility. The efficacy of divalproex sodium delayed-release tablets was established in 3-week trials with patients meeting DSMIII-R criteria for bipolar disorder who were hospitalized for acute mania (See Clinical Trials under CLINICAL PHARMACOLOGY  ). The safety and effectiveness of divalproex sodium delayed-release tablets 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 divalproex sodium delayed-release tablets for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. Epilepsy Divalproex sodium delayed-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium delayed-release tablets 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. Migraine Divalproex sodium delayed-release tablets are indicated for prophylaxis of migraine headaches. There is no evidence that Divalproex sodium delayed-release tablets are useful in the acute treatment of migraine headaches. Because valproic acid may be a hazard to the fetus, divalproex sodium delayed-release tablets should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment (see WARNINGSUsage In Pregnancy, PRECAUTIONSInformation for Patients ). SEE WARNINGS   FOR STATEMENT REGARDING FATAL HEPATIC DYSFUNCTION.

CONTRAINDICATIONS


id: d8ba1651-12f1-4a8b-9241-547d217b9c13
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION. Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug. Divalproex sodium is contraindicated in patients with known urea cycle disorders (See WARNINGS).

ADVERSE REACTIONS


id: 41b6eb89-3176-4a07-b398-17e184a95062
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Mania The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of divalproex sodium delayed-release tablets in the treatment of manic episodes associated with bipolar disorder. The adverse events 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, divalproex sodium delayed-release tablets, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium delayed-release tablets, and lithium carbonate groups, respectively. Table 1 summarizes those adverse events reported for patients in these trials where the incidence rate in the divalproex sodium delayed-release tablets-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the divalproex sodium delayed-release tablets-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 divalproex sodium delayed-release tablets compared to placebo.

Table 1. Adverse Events Reported by > 5% of Divalproex Sodium Delayed-Release Tablets-Treated Patients During Placebo- Controlled Trials of Acute Mania1
Adverse Event Divalproex Sodium Delayed-Release Tablets Placebo
(n=89) (n=97)
Nausea 22% 15%
Somnolence 19% 12%
Dizziness 12% 4%
Vomiting 12% 3%
Asthenia 10% 7%
Abnormal pain 9% 8%
Dyspepsia 9% 8%
Rash 6% 3%
1. The following adverse events occurred at an equal or greater incidence for placebo than for Divalproex Sodium Delayed-Release Tablets: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-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 erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea. Special Senses Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. Urogenital System Dysmenorrhea, dysuria, urinary incontinence. Migraine Based on two placebo-controlled clinical trials and their long term extension, divalproex sodium delayed-release tablets were generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to divalproex sodium delayed-release tablets 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 events reported as the primary reason for discontinuation by ≥1 % of 248 divalproex sodium delayed-release tablets-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 2 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the divalproex sodium delayed-release tablets-treated group was greater than 5% and was greater than that for placebo patients.
Table 2. Adverse Events Reported by > 5% of Divalproex Sodium Delayed-Release Tablets-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1
Body system Event Divalproex Sodium Delayed-Release Tablets
(n=202)
Placebo
(n=81)
Gastrointestinal System
     Nausea 31% 10%
     Dyspepsia 13% 9%
     Diarrhea 12% 7%
     Vomiting 11% 1%
     Abnormal Pain 9% 4%
     Increased appetite 6% 4%
Nervous System
     Asthenia 20% 9%
     Somnolence 17% 5%
     Dizziness 12% 6%
     Tremor 9% 0%
Other
     Weight gain 8% 2%
     Back Pain 8% 6%
     Alopecia 7% 1%
1. The following adverse events occurred in at least 5% of Divalproex Sodium Delayed-Release Tablets-treated patients and at an equal or greater incidence for placebo than for Divalproex Sodium Delayed-Release Tablets: flu syndrome and pharyngitis.
The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-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. Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium delayed-release tablets were generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium delayed-release tablets-treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse events which were reported by ≥5% of divalproex sodium delayed-release tablets-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 events can be ascribed to divalproex sodium delayed-release tablets alone, or the combination of divalproex sodium delayed-release tablets and other antiepilepsy drugs.
Table 3. Adverse Events Reported by ≥5% of Patients Treated with Divalproex Sodium Delayed-Release Tablets During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event Divalproex Sodium Delayed-Release Tablets (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
    Headache 31 21
    Asthenia 27 7
    Fever 6 4
Gastrointestinal System
    Nausea 48 14 
   Vomiting 27
   Abnormal Pain 23 6
    Diarrhea 13 6
    Anorexia 12 0
    Dyspepsia 8 4
    Constipation 5 1
Nervous System
    Somnolence 27 11
    Tremor 25 6
    Dizziness 25 13
    Diplopia 16 9
    Amblyopia/Blurred Vision 12 9
    Ataxia 8 1
    Nystagmus 8 1
    Emotional Liability 6 4
    Thinking abnormal 6 0
    Amnesia 5 1
Respiratory System
    Flu Syndrome 12 9
    Infection 12 6
    Bronchitis 5 1
    Rhinitis 5 4
Other
    Alopecia 6 1
    Weight Loss 6 0
Table 4 lists treatment-emergent adverse events which were reported by ≥5% of patients in the high dose divalproex sodium delayed-release tablets group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium delayed-release tablets 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 events can be ascribed to divalproex sodium delayed- release tablets alone, or the combination of divalproex sodium delayed-release tablets and other antiepilepsy drugs.
Table 4. Adverse Events Reported by ≥5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Delayed-Release Tablets Monotherapy for Complex Partial Seizures1
Body System/Event High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21 10
Digestive system
    Nausea 34 26
    Diarrhea 23 19
    Vomiting 23 15
    Abnormal Pain 12 9
    Anorexia 11 4
    Dyspepsia 11 10
Hemic/Lymphatic/System
    Therbocytopenia 24 1
    Ecchymosis 5 4
Metaboli/Nutritional
    Weight Gain 9 4
    Peripheral Edema 8 3
Nervous System
    Tremor 57 19
    Somnolence 30 18
    Dizziness 18 13
    Insomnia 15 9
    Nervousness 11 7
    Amnesia 7 4
    Nystagmus 7 1
    Depression 5 4
Respiratory System
    Infection 20 13
    Pharyngitis 8 2
    Dyspnea 5 1
Skin and Appendages Alopecia 24 13
Special Senses
    Amblyopia/ Blurred Vision 8 4
    Tinnitus 7 1
1. Headache was the only adverse event that occurred in ≥5% of patients in the high dose group and at an equal or greater incidence in the low dose group.
The following additional adverse events were reported by greater than 1 % but less than 5% of the 358 patients treated with divalproex sodium delayed-release tablets 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. Other Patient Populations Adverse events that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. CNS Effects Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, “spots before eyes”, dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders (see WARNINGS Urea Cycle Disorders and PRECAUTIONS ). Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate (see PRECAUTIONSDrug Interactions ). Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage (see PRECAUTIONSGeneral and Drug Interactions). 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. Hepatic Minor elevations of transaminases (eg, SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity (see WARNINGS ). Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests (see PRECAUTIONS ). There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities (see WARNINGS ). Metabolic Hyperammonemia (see PRECAUTIONS ) , hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi’s syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary Enuresis and urinary tract infection. Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.

OVERDOSAGE


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displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

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 μg/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.

DOSAGE AND ADMINISTRATION


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displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Mania Divalproex sodium delayed-release tablets are administered orally. 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 μg/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 divalproex sodium delayed-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 systematically obtained data to support the benefits of divalproex sodium delayed-release tablets in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with divalproex sodium delayed-release tablets, the safety of divalproex sodium delayed-release tablets in long-term use is supported by data from record reviews involving approximately 360 patients treated with divalproex sodium delayed-release tablets for greater than 3 months. Epilepsy Divalproex sodium delayed-release tablets are administered orally. Divalproex sodium delayed- release tablets are indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the divalproex sodium delayed-release tablets dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected (see PRECAUTIONSDrug Interactions ).
Complex Partial Seizures
For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Divalproex sodium delayed-release tablets have 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 μg/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 μg/mL in females and 135 μg/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 μg/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 divalproex sodium delayed-release tablets 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. Adjunctive Therapy Divalproex sodium delayed-release tablets 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 μg/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 divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium delayed-release tablets, no adjustment of carbamazepine or phenytoin dosage was needed (see CLINICAL STUDIES ). However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs (see Drug Interactions ), periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy (see PRECAUTIONSDrug Interactions ).
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one 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 divided 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 is considered to range from 50 to 100 μg/mL. Some patients may be controlled with lower or higher serum concentrations (see CLINICAL PHARMACOLOGY ). As the divalproex sodium delayed-release tablets dosage is titrated upward, blood concentrations of Phenobarbital and/or phenytoin may be affected (see PRECAUTIONS ). 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 valproic acid therapy, divalproex sodium delayed-release tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on divalproex sodium delayed-release tablets, a dosing schedule of two or three times a day may be elected in selected patients. Migraine Divalproex sodium delayed-release tablets are administered orally. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. General Dosing Advice
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 events. 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 ).
Dose-Related Adverse Events
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 ≥1 10 μg/mL (females) or ≥135 μg/mL (males) (see PRECAUTIONS ). The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

HOW SUPPLIED


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displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Divalproex sodium delayed-release tablets are supplied as: 250 mg lavender colored, oval shaped, biconvex, enteric coated tablets imprinted with “L006” (Black ink) on one side and plain on the other side. 60 DR Tabs NDC 21695-818-60 500 mg lavender colored, oval shaped, biconvex, enteric coated tablets imprinted with “L007” (Black ink) on one side and plain on the other side. 60 DR Tabs NDC 21695-819-60 90 DR Tabs NDC 21695-818-90

PATIENT INFORMATION LEAFLET


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displayName: SPL PATIENT PACKAGE INSERT SECTION
FDA Article Code: 42230-3

Divalproex Sodium Delayed-Release Tablets USP
125 mg, 250 mg and 500 mg
Rx only Important Information for Women Who Could Become Pregnant About the Use of Divalproex Sodium Delayed-Release Tablets Please read this leaflet carefully before you take any of these medications. This leaflet provides a summary of important information about taking these medications to women who could become pregnant. If you have any questions or concerns, or want more information about these medications, contact your doctor or pharmacist. Information For Women Who Could Become Pregnant These medications can be obtained only by prescription from your doctor. The decision to use any of these medications is one that you and your doctor should make together, taking into account your individual needs and medical condition. Before using any of these medications, women who can become pregnant should consider the fact that these medications have been associated with birth defects, in particular, with spina bifida and other defects related to failure of the spinal canal to close normally. Approximately 1 to 2% of children born to women with epilepsy taking divalproex sodium delayed-release tablets in the first 12 weeks of pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency based in Atlanta). The incidence in the general population is 0.1 to 0.2%. These medications have also been associated with other birth defects such as defects of the heart, the bones, and other parts of the body. Information suggests that birth defects may be more likely to occur with these medications than some other drugs that treat your medical condition. Information For Women Who Are Planning to Get Pregnant Women taking any of these medications who are planning to get pregnant should discuss the treatment options with their doctor. Information For Women Who Become Pregnant If you become pregnant while taking any of these medications you should contact your doctor immediately. Other Important Information Your medication should be taken exactly as prescribed by your doctor to get the most benefit from your medication and reduce the risk of side effects.
If you have taken more than the prescribed dose of your medication, contact your hospital emergency room or local poison center immediately.
Your medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
Swallow the tablets whole and not to crush or chew the delayed-release tablets.
Facts About Birth Defects It is important to know that birth defects may occur even in children of individuals not taking any medications or without any additional risk factors. This summary provides important information about the use of divalproex sodium delayed-release tablets to women who could become pregnant. If you would like more information about the other potential risks and benefits of these medications, ask your doctor or pharmacist to let you read the professional labeling and then discuss it with them. If you have any questions or concerns about taking these medications, you should discuss them with your doctor. Manufactured for: Lupin Pharmaceuticals, Inc.
Baltimore, Maryland 21202
United States
Manufactured by:
Lupin Limited
Mumbai 400 098
INDIA
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320

PRINCIPAL DISPLAY PANELS


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displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

Principal Display Panels


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displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

Principal Display Panel


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displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4