SIDE EFFECTS

Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of DEPAKOTE (divalproex sodium delayed release tablets) in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, DEPAKOTE (divalproex sodium delayed release tablets) , and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, DEPAKOTE (divalproex sodium delayed release tablets) , and lithium carbonate groups, respectively.

Table 2 summarizes those adverse events reported for patients in these trials where the incidence rate in the DEPAKOTE (divalproex sodium delayed release tablets) -treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the DEPAKOTE (divalproex sodium delayed release tablets) -treated group was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by significantly (p ≤ 0.05) more patients receiving DEPAKOTE (divalproex sodium delayed release tablets) compared to placebo.

Table 2. Adverse Events Reported by ≥ 5% of DEPAKOTE (divalproex sodium delayed release tablets) -Treated Patients During Placebo-Controlled Trials of Acute Mania¹

Adverse Event	DEPAKOTE (n = 89)	Placebo (n = 97)
Nausea	22%	15%
Somnolence	19%	12%
Dizziness	12%	4%
Vomiting	12%	3%
Asthenia	10%	7%
Abdominal pain	9%	8%
Dyspepsia	9%	8%
Rash	6%	3%
1. The following adverse events occurred at an equal or greater incidence for placebo than for DEPAKOTE: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.

The following additional adverse events were reported by greater than 1 % but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials:

Body as a Whole

Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.

Cardiovascular System

Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.

Digestive System

Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.

Hemic and Lymphatic System

Ecchymosis.

Metabolic and Nutritional Disorders

Edema, peripheral edema.

Musculoskeletal System

Arthralgia, arthrosis, leg cramps, twitching.

Nervous System

Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.

Respiratory System

Dyspnea, rhinitis.

Skin and Appendages

Alopecia, discoid lupus erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.

Special Senses

Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.

Urogenital System

Dysmenorrhea, dysuria, urinary incontinence.

Migraine

Based on two placebo-controlled clinical trials and their long term extension, DEPAKOTE (divalproex sodium delayed release tablets) was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to DEPAKOTE (divalproex sodium delayed release tablets) 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 events reported as the primary reason for discontinuation by ≥ 1 % of 248 DEPAKOTE (divalproex sodium delayed release tablets) -treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SCOT and/or SGPT (1%), and depression (1%).

Table 3 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the DEPAKOTE (divalproex sodium delayed release tablets) -treated group was greater than 5% and was greater than that for placebo patients.

Table 3. Adverse Events Reported by > 5% of DEPAKOTE (divalproex sodium delayed release tablets) -Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo¹

Body System Event	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 events occurred in at least 5% of DEPAKOTE-treated patients and at an equal or greater incidence for placebo than for DEPAKOTE: flu syndrome and pharyngitis.

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

Body as a Whole

Chest pain, chills, face edema, fever and malaise.

Cardiovascular System

Vasod ilatation.

Digestive System

Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.

Hemic and Lymphatic System

Ecchymosis.

Metabolic and Nutritional Disorders

Peripheral edema, SCOT increase, and SGPT increase.

Musculoskeletal System

Leg cramps and myalgia.

Nervous System

Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.

Respiratory System

Cough increased, dyspnea, rhinitis, and sinusitis.

Skin and Appendages

Pruritus and rash.

Special Senses

Conjunctivitis, ear disorder, taste perversion, and tinnitus.

Urogenital System

Cystitis, metrorrhagia, and vaginal hemorrhage.

Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, DEPAKOTE (divalproex sodium delayed release tablets) 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 (divalproex sodium delayed release tablets) -treated patients (6%), compared to 1% of placebo-treated patients.

Table 4 lists treatment-emergent adverse events which were reported by ≥ 5% of DEPAKOTE (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 events can be ascribed to DEPAKOTE (divalproex sodium delayed release tablets) alone, or the combination of DEPAKOTE (divalproex sodium delayed release tablets) and other antiepilepsy drugs.

Table 4. Adverse Events Reported by ≥ 5% of Patients Treated with DEPAKOTE (divalproex sodium delayed release tablets) 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 events which were reported by ≥ 5% of patients in the high dose DEPAKOTE (divalproex sodium delayed release tablets) group, and for which the incidence was greater than in the low dose group, in a controlled trial of DEPAKOTE (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 events can be ascribed to DEPAKOTE (divalproex sodium delayed release tablets) alone, or the combination of DEPAKOTE (divalproex sodium delayed release tablets) and other antiepilepsy drugs.

Table 5. Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of DEPAKOTE (divalproex sodium delayed release tablets) 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
omnolence	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 events were reported by greater than 1 % but less than 5% of the 358 patients treated with DEPAKOTE (divalproex sodium delayed release tablets) 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

SCOT 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.

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., SCOT 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.

Read the entire FDA prescribing information for Depakote (Divalproex Sodium Delayed Release Tablets) »