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Depacon (Valproate Sodium) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The adverse events that can result from DEPACON use include all of those associated with oral forms of valproate. The following describes experience specifically with DEPACON. DEPACON has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125 to 6000 mg (total daily dose). A total of 2% of patients discontinued treatment with DEPACON due to adverse events. The most common adverse events leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase. Other adverse events leading to discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate. The maximum rate of infusion studied was 200 mg/min.

Adverse events reported by at least 0.5% of all subjects/patients in clinical trials of DEPACON are summarized in Table 1.

Table 1. Adverse Events Reported During Studies of DEPACON
Body System/Event N = 463
Body as a Whole
     Chest Pain1.7%
     Headache4.3%
     Injection Site Inflammation0.6%
     Injection Site Pain2.6%
     Injection Site Reaction2.4%
     Pain (unspecified)1.3%
Cardiovascular
     Vasodilation0.9%
Dermatologic
     Sweating0.9%
Digestive System
     Abdominal Pain1.1%
     Diarrhea0.9%
     Nausea3.2%
     Vomiting1.3%
Nervous System
     Dizziness5.2%
     Euphoria0.9%
     Hypesthesia0.6%
     Nervousness0.9%
     Paresthesia0.9%
     Somnolence1.7%
     Tremor0.6%
Respiratory
     Pharyngitis0.6%
Special Senses
     Taste Perversion1.9%

In a separate clinical safety trial, 112 patients with epilepsy were given infusions of DEPACON (up to 15 mg/kg) over 5 to 10 minutes (1.5-3.0 mg/kg/min). The common adverse events (> 2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%), and headache (2.7%). While the incidence of these adverse events was generally higher than in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between the incidence of adverse events in the 2 cohorts cannot be made because of differences in patient populations and study designs.

Ammonia levels have not been systematically studied after IV valproate, so that an estimate of the incidence of hyperammonemia after IV DEPACON cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of DEPACON.

Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, DEPAKOTE (divalproex sodium) was generally well tolerated with most adverse events 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 2 lists treatment-emergent adverse events 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 events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.

Table 2. Adverse Events Reported by ≥ 5% of Patients Treated with DEPAKOTE 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 3 lists treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose DEPAKOTE 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 events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.

Table 3. Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of DEPAKOTE 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 events were reported by greater than 1% but less than 5% of the 358 patients treated with DEPAKOTE 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.

Other Patient Populations

Adverse events 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. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients using oral therapy.

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 – Urea Cycle Disorders 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 PRECAUTIONS - Drug Interactions).

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 PRECAUTIONS - General and Drug Interactions). 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 (e.g., 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).

Endocrine

Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests (see 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).

Metabolic

Hyperammonemia (see 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.

Mania

Although DEPACON has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of DEPAKOTE (DIVALPROEX SODIUM) tablets.

Body as a Whole

Chills, neck pain, neck rigidity.

Cardiovascular System

Hypotension, postural hypotension, vasodilation.

Digestive System

Fecal incontinence, gastroenteritis, glossitis.

Musculoskeletal System

Arthrosis.

Nervous System

Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.

Skin and Appendages

Furunculosis, maculopapular rash, seborrhea.

Special Senses

Conjunctivitis, dry eyes, eye pain.

Urogenital

Dysuria.

Migraine

Although DEPACON has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of DEPAKOTE (DIVALPROEX SODIUM) tablets.

Body as a Whole

Face edema.

Digestive System

Dry mouth, stomatitis.

Urogenital System

Cystitis, metrorrhagia, and vaginal hemorrhage.

Drug label data at the top of this Page last updated: 2009-02-25

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