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Label Changes for:

Depakene (valproic acid) Capsules and Oral SolutionDepakote (divalproex sodium) Delayed ReleaseDepakote ER (Extended Release) TabletsDepakote Sprinkle Capsules (divalproex sodium coated particles in capsules)Depacon (valproate sodium) Injection

January 2015

Changes have been made to the WARNINGS and PRECAUTIONS sections of the safety label.

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

January 2015

WARNINGS AND PRECAUTIONS

Birth defects
  • Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities(e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations).
Bleeding and other hematopoietic disorders
  • Valproate is associated with dose-related thrombocytopenia… Valproate use has also been associated with decreases in other cell lines and myelodysplasia… Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease), measurements of complete blood counts and coagulation tests are recommended before initiating therapy and at periodic intervals.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or lifethreatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis,nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established.
     

 

 June 2014

ADVERSE REACTIONS
 

Post-Marketing Experience
 
  • Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis

July 2013

BOXED WARNING

Hepatotoxicity
  • 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). Valproate 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, ...

CONTRAINDICATIONS

  • Valproate is contraindicated in patients 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

WARNINGS AND PRECAUTIONS

Hepatotoxicity

Patients with Known or Suspected Mitochondrial Disease

  • Valproate 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)]. 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...

 

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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