SIDE EFFECTS

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 three week placebo-controlled clinical trials of Depakote ER (divalproex sodium) 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 Depakote ER (divalproex sodium) -treated group was greater than 5% and greater than the placebo incidence.

Table 3. 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)
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%
1. The following adverse reactions/event occurred at an equal or greater incidence for placebo than for Depakote ER: headache

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the Depakote ER (divalproex sodium) -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: Pruritus, 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 4 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 4. 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
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 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 5. 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)
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
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.

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

Table 6. 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)
Gastrointestinal System
Nausea	15%	9%
Dyspepsia	7%	4%
Diarrhea	7%	3%
Vomiting	7%	2%
Abdominal Pain	7%	5%
Nervous System
Somnolence	7%	2%
Other
Infection	15%	14%
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.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of Depakote ER (divalproex sodium) -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 7 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 7. 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)
Gastrointestinal System
Nausea	31%	10%
Dyspepsia	13%	9%
Diarrhea	12%	7%
Vomiting	11%	1%
Abdominal pain	9%	4%
Increased appetite	6%	4%
Nervous System
Asthenia	20%	9%
Somnolence	17%	5%
Dizziness	12%	6%
Tremor	9%	0%
Other
Weight gain	8%	2%
Back pain	8%	6%
Alopecia	7%	1%
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.

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 erythematosus, erythema nodosum, furunculosis, maculopapular 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 (divalproex sodium) 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].

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]. 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 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.

Read the entire FDA prescribing information for Depakote ER (Divalproex Sodium) »