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.
* 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.
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.
| ||
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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