Divalproex Sodium (Page 6 of 14)

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.

Information on pediatric adverse reactions is presented in section 8.

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 extended-release tablets in the treatment of manic episodes associated with bipolar disorder.

Table 3 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the divalproex sodium extended-release tablets-treated group was greater than 5% and greater than the placebo incidence.

Table 3 Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-Release Tablets -Treated Patients During Placebo-Controlled Trials of Acute Mania*

* The following adverse reactions/event occurred at an equal or greater incidence for placebo than for divalproex sodium extended-release tablets: headache

Adverse Event Divalproex Sodium Extended-Release Tablets (n=338) Placebo (n=263)
% %
Somnolence 26 14
Dyspepsia 23 11
Nausea 19 13
Vomiting 13 5
Diarrhea 12 8
Dizziness 12 7
Pain 11 10
Abdominal pain 10 5
Accidental injury 6 5
Asthenia 6 5
Pharyngitis 6 5

The following additional adverse reactions were reported by greater than 1 % of the divalproex sodium extended-release tablets-treated patients in controlled clinical trials:

Body as a Whole

Back Pain, Chills, Chills and Fever, Drug Level Increased, Flu Syndrome, Infection, Infection Fungal, Neck Rigidity.

Cardiovascular System

Arrhythmia, Hypertension, Hypotension, Postural Hypotension.

Digestive System

Constipation, Dry Mouth, Dysphagia, Fecal Incontinence, Flatulence, Gastroenteritis, Glossitis, Gum Hemorrhage, Mouth Ulceration.

Hemic and Lymphatic System

Anemia, Bleeding Time Increased, Ecchymosis, Leucopenia.

Metabolic and Nutritional Disorders

Hypoproteinemia, Peripheral Edema.

Musculoskeletal System

Arthrosis, Myalgia.

Nervous System

Abnormal Gait, Agitation, Catatonic Reaction, Dysarthria, Hallucinations, Hypertonia, Hypokinesia, Psychosis, Reflexes Increased, Sleep Disorder, Tardive Dyskinesia, Tremor.

Respiratory System

Hiccup, Rhinitis.

Skin and Appendages

Discoid Lupus Erythematosus, Erythema Nodosum, Furunculosis, Maculopapular Rash, Pruritus, Rash, Seborrhea, Sweating, Vesiculobullous Rash.

Special Senses

Conjunctivitis, Dry Eyes, Eye Disorder, Eye Pain, Photophobia, Taste Perversion.

Urogenital System

Cystitis, Urinary Tract Infection, Menstrual Disorder, Vaginitis.

6.2 Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium delayed-release tablets were 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 delayed-release tablets-treated patients (6%), compared to 1% of placebo-treated patients.

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium delayed-release tablets-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for 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 delayed-release tablets alone, or the combination of divalproex sodium delayed-release tablets and other antiepilepsy drugs.

Table 4 Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Header$ Body System/Event Divalproex Sodium Delayed-Release Tablets Placebo
(n = 77) (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 5 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium delayed-release tablets 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 delayed-release tablets alone, or the combination of valproate and other antiepilepsy drugs.

Table 5 Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures *
*
Headache was the only adverse event that occurred in ≥5% of patients in the high dose group and at an equal or greater incidence in the low dose group.
Body System/Event High Dose Low Dose
(n = 131) (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

The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate 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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