Valproic (Page 5 of 12)

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.

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 [ s ee Warnings and Precautions ( 5.3) ]
  • Pancreatitis [ see Warnings and Precautions ( 5.5) ]
  • Hyperammonemic encephalopathy [ see War nings and Precautions ( 5.6, 5.9, 5.10) ]
  • Suicidal behavior and ideation [ see Warning s and Precautions ( 5.7) ]
  • Bleeding and other hematopoietic disorders [ see Warnings and Precautions ( 5.8)]
  • Hypothermia [se e Warnings and Precautions ( 5.11)]
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [s ee 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 Epilepsy

The data described in the following section were obtained using divalproex sodium tablets.

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients.

Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive therapy for the 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 reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.

Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction Divalproex Sodium (%) (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 7
Abdominal 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 Lability 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 reactions which were reported by ≥ 5% of patients in the high dose divalproex sodium group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium 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 reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.

Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures1
Body System/Reaction 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
Abdominal Pain 12 9
Anorexia 11 4
Dyspepsia 11 10
Hemic/Lymphatic System
Thrombocytopenia 24 1
Ecchymosis 5 4
Metabolic/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 reaction 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 reactions were reported by greater than 1% but less than 5% of the 358 patients treated with divalproex sodium 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.

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