Divalproex Sodium (Page 5 of 14)

5.11 Hypothermia

Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions

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 life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, 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.

5.13 Interaction with Carbapenem Antibiotics

Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)].

5.14 Somnolence in the Elderly

In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)].

5.15 Monitoring: Drug Plasma Concentration

Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)].

5.16 Effect on Ketone and Thyroid Function Tests

Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.

5.17 Effect on HIV and CMV Viruses Replication

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

5.18 Medication Residue in the Stool

There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Hepatic failure [see Warnings and Precautions (5.1)]
  • Birth defects [see Warnings and Precautions (5.2)]
  • Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
  • Pancreatitis [see Warnings and Precautions (5.5)]
  • Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9,5.10)]
  • Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
  • Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
  • Hypothermia [see Warnings and Precautions (5.11)]
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions (5.12)]
  • Somnolence in the elderly [see Warnings and Precautions (5.14)]

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.

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 delayed-release tablets in the treatment of manic episodes associated with bipolar disorder. The adverse reactions 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 2 summarizes those adverse reactions 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 reaction that was reported by significantly (p ≤ 0.05) more patients receiving divalproex sodium delayed-release tablets compared to placebo.

Table 2. Adverse Reactions Reported by > 5% of Divalproex Sodium Delayed-Release Tablets –Treated Patients During Placebo-Controlled Trials of Acute Mania1

1 The following adverse reactions occurred at an equal or greater incidence for placebo than for divalproex sodium delayed-release tablets: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.

Adverse Reaction Divalproex Sodium Delayed-Release Tablets (n = 89) % Placebo (n = 97) %
Nausea 22 15
Somnolence 19 12
Dizziness 12 4
Vomiting 12 3
Accidental Injury 11 5
Asthenia 10 7
Abdominal Pain 9 8
Dyspepsia 9 8
Rash 6 3

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 divalproex sodium delayed-release tablets -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 erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea.

Special Senses

Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.

Urogenital System

Dysmenorrhea, dysuria, urinary incontinence.

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