Label Changes for:

Stavzor (Valproic acid) Delayed Release Capsules

March 2014

Changes have been made to the BOXED WARNING, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

 

March 2014

BOXED WARNING

LIFE-THREATENING ADVERSE REACTIONS

Hepatotoxicity

General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. 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 [see Warning and Precautions (5.1)].

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 Stavzor 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome) Stavzor is 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 [see Contraindications (4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Stavzor should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Stavzor for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice. These incidents usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be preceded by nonspecific 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. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months

WARNINGS AND PRECAUTIONS

Hepatotoxicity

General Information on Hepatotoxicity

  • Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid . 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 function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first sixmonths. 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 valproic acid 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 Stavzor 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. In progressively

Patients with Known or Suspected Mitochondrial Disease

  • 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 then 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 testingshould 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. Stavzor is 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 [see Contraindications]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Stavzor should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Stavzor 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.

ADVERSE REACTIONS

Postmarketing Experiences
  • muscle weakness and panic attack

 

June 2013

 

BOXED WARNING

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 in utero 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.
 
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