DIVALPROEX SODIUM tablet, film coated, extended release (2024)

The following serious adverse reactions are described below and elsewhere in the labeling:

Hepatic failure [see Warnings and Precautions (5.1)]
Birth defects [see Warnings and Precautions (5.2)]
Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
Pancreatitis [see Warnings and Precautions (5.5)]
Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
Hypothermia [see Warnings and Precautions (5.11)]
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions (5.12)]
Somnolence in the elderly [see Warnings and Precautions (5.14)]

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.

6.1 Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of divalproex sodium extended-release tablets 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 divalproex sodium extended-release tablets-treated group was greater than 5% and greater than the placebo incidence.

Table 3. Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-Release Tablets-Treated Patients During Placebo-Controlled Trials of Acute Mania*
*
bThe following adverse reactions/event occurred at an equal or greater incidence for placebo than for divalproex sodium extended-release tablets: headache

Adverse Event

Divalproex Sodium Extended-Release Tablets
(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

The following additional adverse reactions were reported by greater than 1% of the divalproex sodium extended-release tablets-treated patients in controlled clinical trials:

Body as a Whole: Back Pain, Chills, Chills and Fever, Drug Level Increased, Flu Syndrome, Infection, Infection Fungal, Neck Rigidity.

Cardiovascular System: Arrhythmia, Hypertension, Hypotension, Postural Hypotension.

Digestive System: Constipation, Dry Mouth, Dysphagia, Fecal Incontinence, Flatulence, Gastroenteritis, Glossitis, Gum Hemorrhage, Mouth Ulceration.

Hemic and Lymphatic System: Anemia, Bleeding Time Increased, Ecchymosis, Leucopenia.

Metabolic and Nutritional Disorders: Hypoproteinemia, Peripheral Edema.

Musculoskeletal System: Arthrosis, Myalgia.

Nervous System: Abnormal Gait, Agitation, Catatonic Reaction, Dysarthria, Hallucinations, Hypertonia, Hypokinesia, Psychosis, Reflexes Increased, Sleep Disorder, Tardive Dyskinesia, Tremor.

Respiratory System: Hiccup, Rhinitis.

Skin and Appendages: Discoid Lupus Erythematosus, Erythema Nodosum, Furunculosis, Maculopapular Rash, Pruritus, Rash, Seborrhea, Sweating, Vesiculobullous Rash.

Special Senses: Conjunctivitis, Dry Eyes, Eye Disorder, Eye Pain, Photophobia, Taste Perversion.

Urogenital System: Cystitis, Urinary Tract Infection, Menstrual Disorder, Vaginitis.

6.2 Epilepsy

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

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of 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 reactions can be ascribed to divalproex sodium delayed-release tablets alone, or the combination of divalproex sodium delayed-release tablets 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

Divalproex Sodium Delayed-
Release Tablets
(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

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

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

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 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 reactions can be ascribed to divalproex sodium delayed-release tablets 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 Seizures*
*
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 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

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.

6.3 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 divalproex sodium extended-release tablets-treated group was greater than 5% and was greater than that for placebo patients.

Table 6. Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-Release Tablets-Treated Patients During the Migraine Placebo-Controlled Trial with a Greater Incidence than Patients Taking Placebo*
*
The following adverse reactions occurred in greater than 5% of divalproex sodium extended-release tablets-treated patients and at a greater incidence for placebo than for divalproex sodium extended-release tablets: asthenia and flu syndrome.

Body System Event

Divalproex Sodium Extended-Release Tablets
(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

The following additional adverse reactions were reported by greater than 1% but not more than 5% of divalproex sodium extended-release tablets-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 Placebo*
*
The following adverse reactions occurred in greater than 5% of divalproex sodium delayed-release tablets-treated patients and at a greater incidence for placebo than for divalproex sodium delayed-release tablets: flu syndrome and pharyngitis.

Body System Reaction

Divalproex Sodium
Delayed-Release Tablets
(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

Other

Weight Gain

8

2

Back Pain

8

6

Alopecia

7

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.

6.4Postmarketing Experience

The following adverse reactions have been identified during post approval use of divalproex sodium delayed-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic:Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

Psychiatric:Emotional upset, psychosis, aggression, psychom*otor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.

Neurologic:Paradoxical convulsion, parkinsonism

There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.

There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or fully after valproate discontinuation.

Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Hematologic: Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.

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

Metabolism and nutrition: Weight gain.

Reproductive:Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.

Genitourinary: Enuresis, urinary tract infection, and tubulointerstitial nephritis.

Special Senses: Hearing loss.

Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.

DIVALPROEX SODIUM tablet, film coated, extended release (2024)
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