Divalproex Sodium Extended-Release

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Overview

What is Divalproex Sodium Extended-Release?

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. 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 extended-release tablets 250 and 500 mg tablets are for oral administration. Divalproex sodium extended-release tablets contain divalproex sodium in a once-a-day extended-release formulation equivalent to 250 and 500 mg of valproic acid.

Inactive Ingredients

Divalproex sodium extended-release tablets 250 and 500 mg tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin.

In addition, 500 mg tablets contain iron oxide and polydextrose.

Meets USP Dissolution Test 2.

What does Divalproex Sodium Extended-Release look like?

What are the available doses of Divalproex Sodium Extended-Release?

Tablets: 250 mg and 500 mg

What should I talk to my health care provider before I take Divalproex Sodium Extended-Release?

How should I use Divalproex Sodium Extended-Release?

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 are based in part on studies of divalproex sodium 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 .

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.

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.

What interacts with Divalproex Sodium Extended-Release?

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What are the warnings of Divalproex Sodium Extended-Release?

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What are the precautions of Divalproex Sodium Extended-Release?

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What are the side effects of Divalproex Sodium Extended-Release?

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What should I look out for while using Divalproex Sodium Extended-Release?

Hepatic disease or significant hepatic dysfunction ,

Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ,

Suspected POLG-related disorder in children under two years of age ,

Known hypersensitivity to the drug ,

Urea cycle disorders ,

Pregnant patients treated for prophylaxis of migraine headaches ,

Hepatotoxicity

Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When divalproex sodium extended-release tablets are 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Fetal Risk

Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following exposure.

Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine . Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable.

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). Women should use effective contraception while using valproate .

A Medication Guide describing the risks of valproate is available for patients .

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated .

What might happen if I take too much Divalproex Sodium Extended-Release?

Over dosage 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 mcg/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 over dosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

How should I store and handle Divalproex Sodium Extended-Release?

Divalproex sodium extended-release tablets 250 mg are available as white ovaloid tablets with the “a” logo and the code (HF). Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 250 mg of valproic acid.Divalproex sodium extended-release tablets 500 mg are available as gray ovaloid tablets with the “a” logo and the code HC. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 500 mg of valproic acid.They are supplied by as follows:Recommended StorageStore tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Divalproex sodium extended-release tablets 250 mg are available as white ovaloid tablets with the “a” logo and the code (HF). Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 250 mg of valproic acid.Divalproex sodium extended-release tablets 500 mg are available as gray ovaloid tablets with the “a” logo and the code HC. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 500 mg of valproic acid.They are supplied by as follows:Recommended StorageStore tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Divalproex sodium extended-release tablets 250 mg are available as white ovaloid tablets with the “a” logo and the code (HF). Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 250 mg of valproic acid.Divalproex sodium extended-release tablets 500 mg are available as gray ovaloid tablets with the “a” logo and the code HC. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 500 mg of valproic acid.They are supplied by as follows:Recommended StorageStore tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Divalproex sodium extended-release tablets 250 mg are available as white ovaloid tablets with the “a” logo and the code (HF). Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 250 mg of valproic acid.Divalproex sodium extended-release tablets 500 mg are available as gray ovaloid tablets with the “a” logo and the code HC. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 500 mg of valproic acid.They are supplied by as follows:Recommended StorageStore tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Divalproex sodium extended-release tablets 250 mg are available as white ovaloid tablets with the “a” logo and the code (HF). Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 250 mg of valproic acid.Divalproex sodium extended-release tablets 500 mg are available as gray ovaloid tablets with the “a” logo and the code HC. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 500 mg of valproic acid.They are supplied by as follows:Recommended StorageStore tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

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Clinical Information

Chemical Structure

No Image found

Clinical Pharmacology

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).

Non-Clinical Toxicology

Hepatic disease or significant hepatic dysfunction ,

Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ,

Suspected POLG-related disorder in children under two years of age ,

Known hypersensitivity to the drug ,

Urea cycle disorders ,

Pregnant patients treated for prophylaxis of migraine headaches ,

Hepatotoxicity

Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When divalproex sodium extended-release tablets are 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Fetal Risk

Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following exposure.

Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine . Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable.

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). Women should use effective contraception while using valproate .

A Medication Guide describing the risks of valproate is available for patients .

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated .

There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting carbamazepine suspension immediately followed by Thorazine* solution. Subsequent testing has shown that mixing carbamazepine suspension and chlorpromazine solution (both generic and brand name) as well as carbamazepine suspension and liquid Mellaril, resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, carbamazepine suspension should not be administered simultaneously with other liquid medicinal agents or diluents (See ).

Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not limited to) the following:

General Information on Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.

Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.”

Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium extended-release tablets are 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. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.

Patients with Known or Suspected Mitochondrial Disease

Divalproex sodium extended-release tablets are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder . Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium extended-release tablets should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium extended-release tablets for the development of acute liver injury with regular clinical assessments and serum liver test monitoring.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug .

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Hepatic failure

Birth defects

Decreased IQ following exposure

Pancreatitis

Thrombocytopenia

Hyperammonemic encephalopathy , ,

Multi-organ hypersensitivity reactions

Somnolence in the elderly

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 adverse reactions is presented in section 8.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

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