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Depakote ER (Divalproex Sodium) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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.

Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of Depakote ER in the treatment of manic episodes associated with bipolar disorder.

Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote ER-treated group was greater than 5% and greater than the placebo incidence.

Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania1
Adverse Event Depakote ER
(n=338)
Placebo
(n=263)
1. The following adverse reactions/event occurred at an equal or greater incidence for placebo than for Depakote ER: headache
Somnolence26%14%
Dyspepsia23%11%
Nausea19%13%
Vomiting13%5%
Diarrhea12%8%
Dizziness12%7%
Pain11%10%
Abdominal pain10%5%
Accidental injury6%5%
Asthenia6%5%
Pharyngitis6%5%

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the Depakote ER-treated patients in controlled clinical trials:

Body as a Whole: Back Pain, Flu Syndrome, Infection, Infection Fungal

Cardiovascular System: Hypertension

Digestive System: Constipation, Dry Mouth, Flatulence

Hemic and Lymphatic System: Ecchymosis

Metabolic and Nutritional Disorders Peripheral Edema

Musculoskeletal System: Myalgia

Nervous System: Abnormal Gait, Hypertonia, Tremor

Respiratory System: Rhinitis

Skin and Appendages: Pruritis, Rash

Special Senses: Conjunctivitis

Urogenital System: Urinary Tract Infection, Vaginitis

Epilepsy

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

Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-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 Depakote alone, or the combination of Depakote and other antiepilepsy drugs.

Table 3. Adverse Reactions Reported by > 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event Depakote (%)
(N=77)
Placebo (%)
(N=70)
Body as a Whole
     Headache3121
     Asthenia277
     Fever64
Gastrointestinal System
     Nausea4814
     Vomiting277
     Abdominal pain236
     Diarrhea136
     Anorexia120
     Dyspepsia84
     Constipation51
Nervous System
     Somnolence2711
     Tremor256
     Dizziness2513
     Diplopia169
     Amblyopia/Blurred Vision129
     Ataxia81
     Nystagmus81
     Emotional Lability64
     Thinking Abnormal60
     Amnesia51
Respiratory System
     Flu Syndrome129
     Infection126
     Bronchitis51
     Rhinitis54
Other
     Alopecia61
     Weight Loss60

Table 4 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 Depakote 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 Depakote alone, or the combination of valproate and other antiepilepsy drugs.

Table 4. Adverse Reactions Reported by >5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Event High Dose (%)
(n=131)
Low Dose (%)
(n=134)

1.   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 as a Whole
     Asthenia2110
Digestive System
     Nausea3426
     Diarrhea2319
     Vomiting2315
     Abdominal pain129
     Anorexia114
     Dyspepsia1110
Hemic/Lymphatic System
     Thrombocytopenia241
     Ecchymosis54
Metabolic/Nutritional
     Weight Gain94
     Peripheral Edema83
Nervous System
     Tremor5719
     Somnolence3018
     Dizziness1813
     Insomnia159
     Nervousness117
     Amnesia74
     Nystagmus71
     Depression54
Respiratory System
     Infection2013
     Pharyngitis82
     Dyspnea51
Skin and Appendages
     Alopecia2413
Special Senses
     Amblyopia/Blurred Vision84
     Tinnitus71

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.

Migraine

Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).

Table 5 includes those adverse reactions reported for patients in the placebo-controlled trial where the incidence rate in the Depakote ER-treated group was greater than 5% and was greater than that for placebo patients.

Table 5. Adverse Reactions Reported by >5% of Depakote ER-Treated Patients During the Migraine Placebo-controlled Trial with a Greater Incidence than Patients Taking Placebo1
Body System
Event
Depakote ER
(n=122)
Placebo
(n=115)

1.   The following adverse reactions occurred in greater than 5% of Depakote ER-treated patients and at a greater incidence for placebo than for Depakote ER: asthenia and flu syndrome.

Gastrointestinal System
     Nausea15%9%
     Dyspepsia7%4%
     Diarrhea7%3%
     Vomiting7%2%
     Abdominal Pain7%5%
Nervous System
     Somnolence7%2%
Other
     Infection15%14%

The following additional adverse reactions were reported by greater than 1% but not more than 5% of Depakote ER-treated patients and with a greater incidence than placebo in the placebo-controlled clinical trial for migraine prophylaxis:

Body as a Whole: Accidental injury, viral infection.

Digestive System: Increased appetite, tooth disorder.

Metabolic and Nutritional Disorders: Edema, weight gain.

Nervous System: Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo.

Respiratory System: Pharyngitis, rhinitis.

Skin and Appendages: Rash.

Special Senses: Tinnitus.

Table 6 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the valproate-treated group was greater than 5% and was greater than that for placebo patients.

Table 6. Adverse Reactions Reported by > 5% of Valproate-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence than Patients Taking Placebo1
Body System
Reaction
Depakote
(n=202)
Placebo
(n=81)

1.   The following adverse reactions occurred in greater than 5% of Depakote-treated patients and at a greater incidence for placebo than for Depakote: flu syndrome and pharyngitis.

Gastrointestinal System
     Nausea31%10%
     Dyspepsia13%9%
     Diarrhea12%7%
     Vomiting11%1%
     Abdominal pain9%4%
     Increased appetite6%4%
Nervous System
     Asthenia20%9%
     Somnolence17%5%
     Dizziness12%6%
     Tremor9%0%
Other
     Weight gain8%2%
     Back pain8%6%
     Alopecia7%1%

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 valproate-treated patients in the controlled clinical trials:

Body as a Whole: Chest pain.

Cardiovascular System: Vasodilatation.

Digestive System: Constipation, dry mouth, flatulence, and stomatitis.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema.

Musculoskeletal System: Leg cramps.

Nervous System: Abnormal dreams, confusion, paresthesia, speech disorder, and thinking abnormalities.

Respiratory System: Dyspnea, and sinusitis.

Skin and Appendages: Pruritus.

Urogenital System: Metrorrhagia.

Other Patient Populations

Mania

The following adverse reactions not listed previously were reported by greater than 1% of DEPAKOTE-treated patients and with a greater incidence than placebo in placebo-controlled trials of manic episodes associated with bipolar disorder:

Body as a Whole: Chills, chills and fever, drug level increased, neck rigidity.

Cardiovascular System: Arrhythmia, hypotension, postural hypotension.

Digestive System: Dysphagia, fecal incontinence, gastroenteritis, glossitis, gum hemorrhage, mouth ulceration.

Hemic and Lymphatic System: Anemia, bleeding time increased,leucopenia.

Metabolic and Nutritional Disorders: Hypoproteinemia.

Musculoskeletal System: Arthrosis.

Nervous System: Agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia, psychosis, reflexes increased, sleep disorder, tardive dyskinesia.

Respiratory System: Hiccup.

Skin and Appendages: Discoid lupus erythematosis, erythema nodosum, furunculosis, macularpapular rash, seborrhea, sweating, vesiculobullous rash.

Special Senses: Conjunctivitis, dry eyes, eye disorder, eye pain, photophobia, taste perversion.

Urogenital System: Cystitis, menstrual disorder.

Epilepsy

Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system.

Gastrointestinal

The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. In some patients, many of whom have functional or anatomic (including ileostomy or colostomy) gastrointestinal disorders with shortened GI transit times, there have been postmarketing reports of Depakote ER tablets in stool.

CNS Effects

Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions ].

Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.

Dermatologic

Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7) ].

Psychiatric

Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.

Musculoskeletal

Weakness.

Hematologic

Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions and Drug Interactions (7) ]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Hepatic

Minor elevations of transaminases (eg, SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions ].

Endocrine

Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions ].

There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.

Pancreatic

Acute pancreatitis including fatalities [see Warnings and Precautions ].

Metabolic

Hyperammonemia [see Warnings and Precautions ], hyponatremia, and inappropriate ADH secretion.

There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.

Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.

Genitourinary

Enuresis and urinary tract infection.

Special Senses

Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.

Other

Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.



REPORTS OF SUSPECTED DEPAKOTE ER SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Depakote ER. The information is not vetted and should not be considered as verified clinical evidence.

Possible Depakote ER side effects / adverse reactions in 62 year old male

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-03

Patient: 62 year old male weighing 87.5 kg (192.6 pounds)

Reactions: Weight Decreased, Migraine, Insomnia, Hypophagia, Visual Impairment, Gait Disturbance

Adverse event resulted in: life threatening event, hospitalization

Suspect drug(s):
Depakote ER

Other drugs received by patient: Topamax



Possible Depakote ER side effects / adverse reactions in 25 year old male

Reported by a health professional (non-physician/pharmacist) from United States on 2011-11-23

Patient: 25 year old male

Reactions: Convulsion

Suspect drug(s):
Amoxicillin

Depakote ER
    Indication: Product Used FOR Unknown Indication

Amoxicillin
    Indication: Product Used FOR Unknown Indication

Other drugs received by patient: Aplenzin; Lamictal; Zoloft; Temazepam



Possible Depakote ER side effects / adverse reactions in 59 year old female

Reported by a consumer/non-health professional from United States on 2011-12-20

Patient: 59 year old female weighing 61.2 kg (134.7 pounds)

Reactions: Balance Disorder, Dizziness, Fall

Suspect drug(s):
Depakote ER



See index of all Depakote ER side effect reports >>

Drug label data at the top of this Page last updated: 2008-04-07

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