Depacon Side Effects

Generic Name: valproic acid

Please note - some side effects for Depacon may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Depacon - for the Consumer

Depacon

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Depacon:

Change in appetite; constipation; diarrhea; dizziness; drowsiness; hair loss; headache; indigestion; mild pain or redness at the injection site; nausea; stomach cramps or pain; trouble sleeping; vomiting; weakness; weight changes.

Seek medical attention right away if any of these SEVERE side effects occur when using Depacon:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; blurred vision or other vision changes; changes in behavior; change in menstrual period; chest pain; chills; confusion; dark urine; difficulty speaking; difficulty urinating or other urination problems; extreme tiredness; fast or irregular heartbeat; fever; general body discomfort; hallucinations; hearing loss; involuntary movements of the arms and legs; involuntary movements or chewing movements of the face, jaw, mouth, or tongue; joint or muscle pain or weakness; lack of energy; loss of appetite; loss of coordination; memory loss; new or worsening mental or mood changes (eg, aggressiveness, agitation, anxiety, depression, exaggerated feeling of well-being, hostility, impulsiveness, inability to sit still, irritability, panic attacks, restlessness); new or worsening seizures; nosebleed; pale stools; red, swollen, blistered, or peeling skin; ringing in the ears; severe or persistent nausea, vomiting, or stomach pain; severe or persistent pain; shortness of breath; sore throat; suicidal thoughts or actions; swelling of the arms or legs; swollen lymph nodes; tremor; trouble speaking or walking; unusual bleeding or bruising; unusual weakness; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Depacon Side Effects - for the Professional

Depacon

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 Pain	1.7%
Headache	4.3%
Injection Site Inflammation	0.6%
Injection Site Pain	2.6%
Injection Site Reaction	2.4%
Pain (unspecified)	1.3%
Cardiovascular
Vasodilation	0.9%
Dermatologic
Sweating	0.9%
Digestive System
Abdominal Pain	1.1%
Diarrhea	0.9%
Nausea	3.2%
Vomiting	1.3%
Nervous System
Dizziness	5.2%
Euphoria	0.9%
Hypesthesia	0.6%
Nervousness	0.9%
Paresthesia	0.9%
Somnolence	1.7%
Tremor	0.6%
Respiratory
Pharyngitis	0.6%
Special Senses
Taste Perversion	1.9%

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
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 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
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 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.

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.

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. 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.

Endocrine

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

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

Pancreatic

Acute pancreatitis including fatalities.

Metabolic

Hyperammonemia, 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.

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Side Effects by Body System - for Healthcare Professionals

Gastrointestinal

Gastrointestinal side effects have been reported frequently and include nausea, vomiting, and indigestion (in up to 16% of patients), especially with initiation of therapy and rapid increases in dose. Life threatening pancreatitis has been reported to occur anywhere from shortly after initial use to after several years of use. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Hyperamylasemia has occurred in up to 20% of patients and has rarely presented as clinical pancreatitis (usually one to six months after initiation of therapy).

Severe nausea, emesis, and anorexia may be due to valproate-induced hyperammonemia or hepatitis. Adverse gastrointestinal effects may be attenuated by administering doses with food. Increased appetite and weight gain occur in approximately one half of treated patients.

Hepatic

Hepatic side effects including transient dose-dependent elevations of serum transaminases, amylase, and ammonia have been reported in up to 44% of treated patients. Dose-related hepatitis and a case of nonalcoholic liver disease have also been reported.

Some clinicians recommend monitoring liver function tests at baseline, then monthly during the first 6 months of therapy and every 3 months thereafter. Prompt withdrawal of valproic acid is recommended if significant hepatic dysfunction occurs.

Risk factors for valproic acid-associated hepatitis are young age (particularly age less than 2 years old), poor nutritional status, mental retardation, underlying metabolic disease, and concomitant use of other anticonvulsant medications. Characteristic pathological features include microvesicular steatosis.

Mild elevations in transaminases and amylase may be managed by dose reductions.

Nervous system

Neurologic side effects including drowsiness, ataxia, and hand tremor have been reported. Cases of encephalopathy (manifested by stupor, coma, hallucinations or affective changes) and chorea have also been reported. Valproate may inhibit urea synthesis resulting in hyperammonemia, which has been associated with encephalopathy, delirium, and ataxia in rare cases. Reversible sensorineural hearing loss associated with valproic acid has been reported rarely. Two cases of extrapyramidal disorders have been reported in association with valproic acid therapy. A case of truncal weakness and respiratory failure has also been associated with valproic acid therapy.

A clinical observational study has reported that valproic acid is associated with cognitive decline in HIV-infected individuals.

Loss of seizure control may indicate associated hepatitis.

Hematologic

Hematologic side effects including rare cases of reversible thrombocytopenia associated with antiplatelet antibodies and bone marrow suppression have been reported.

Some clinicians recommend monitoring complete blood counts (including platelet counts) at baseline, then monthly for three months, and every three months thereafter.

Data from a study of 265 patients strongly suggests a causal relationship between rising plasma valproic acid levels and reduced platelet counts, with additional risk factors including female gender and lower baseline platelet counts.

Dermatologic

Valproic acid has been associated with stomatitis and cutaneous leukoclastic vasculitis. A case of psoriasiform eruption has been reported in a patient receiving valproic acid.

The mechanism of valproic acid induced alopecia is believed to be telogen shedding. This is believed to appear within three months of the initiation of valproic acid therapy. Alopecia does not appear to be dose related. Limited data have reported that supplements with a zinc and selenium-containing vitamin may be useful in the prevention of valproic acid associated alopecia.

Dermatologic side effects including transient alopecia (2.6% to 12%), thinning of the hair, hair color changes, hair texture changes, and rare rashes have been reported. Valproic acid has been implicated in producing Stevens-Johnson syndrome and toxic epidermal necrolysis.

Cardiovascular

Cardiovascular side effects including peripheral edema have been reported rarely.

Renal

Valproate-induced Fanconi's syndrome has been reported more often in children than in adults.

Renal side effects including several cases of Fanconi's syndrome have been reported.

Endocrine

Valproate therapy has been associated with polycystic ovaries, elevated serum testosterone concentrations and menstrual disturbances. One study has suggested that 80% of women treated with valproic acid before the age of 20 have polycystic ovaries or hyperandrogenism.

Endocrine side effects including a variety of adverse reproductive endocrine disorders have been reported in epileptic women taking valproic acid.

Respiratory

Respiratory side effects including a case of eosinophilic pleural effusion have been reported.

Immunologic

Immunologic side effects have been reported including a case of bone marrow suppression in a girl who received high dose valproic acid.

Other

Other side effects including a case of valproate-withdrawal induced migraine has been reported.

Musculoskeletal

Musculoskeletal side effects including decreased bone mass and increased bone turnover have been reported.

Hypersensitivity

Hypersensitivity side effects including a case of hypersensitivity syndrome have been reported.

General

General side effects including hypothermia have been reported.

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