Prescription Drug Information: Divalproex Sodium (Page 5 of 12)

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 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-treated group was greater than 5% and greater than the placebo incidence.

Table 3. Adverse Reactions Reported by > 5% of Divalproex Sodium Delayed-Release-Treated Patients During Placebo-Controlled Trials of Acute Mania 1

Adverse Event

Divalproex Sodium Extended-Release (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 divalproex sodium extended-release: headache

The following additional adverse reactions were reported by greater than 1% of the divalproex sodium extended-release-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 was 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-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-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 alone, or the combination of divalproex sodium delayed-release 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 (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 divalproex sodium delayed-release 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 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 1

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.

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