Stavzor Side Effects

Generic Name: valproic acid

Please note - some side effects for Stavzor 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 Stavzor - for the Consumer

Stavzor Delayed-Release Capsules

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 Stavzor Delayed-Release Capsules:

Constipation; diarrhea; dizziness; drowsiness; headache; increased or decreased appetite; mild hair loss; nausea; sore throat; stomach pain or upset; trouble sleeping; vomiting; weakness; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Stavzor Delayed-Release Capsules:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; behavior changes; blurred vision or other vision changes; change in menstrual period; change in the amount of urine produced; chest pain; confusion; dark urine; fast or irregular heartbeat; fever, chills, or persistent sore throat; general feeling of being unwell; hallucinations; hearing loss; joint or muscle pain or weakness; 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); pale stools; red, swollen, peeling, or blistered skin; ringing in the ears; severe or persistent nausea, vomiting, or loss of appetite; severe or persistent stomach pain or cramps; shortness of breath; sluggishness; suicidal thoughts or actions; swelling of the arms or legs; swollen lymph nodes; tremor; trouble speaking or walking; uncontrolled muscle movements; unusual bleeding or bruising; unusual tiredness or 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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Stavzor Side Effects - for the Professional

Stavzor

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.

 6.1 Mania

The incidence of treatment-emergent events has been ascertained based on combined data from  2 placebo-controlled clinical trials of valproate 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, valproate, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, valproate , and lithium carbonate groups, respectively.

Table 2 summarizes those adverse events reported for patients in these trials where the incidence rate in the valproate -treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the valproate -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 valproate compared to placebo.

Table 2.Adverse Reactions Reported by > 5% of Valproate –Treated Patients During Placebo –Controlled Trials of Acute Maniaa

Adverse Event	Valproate (n=89)	Placebo (n=97)
a. The following adverse events occurred at an equal or greater incidence for placebo than for valproate: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
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%

The following additional adverse events were reported by greater than 1% but not more than 5% of the 89  valproate-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.

 6.2 Epilepsy

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

Table 3 lists treatment-emergent adverse events which were reported by ≥ 5% of valproate -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 valproate alone, or the combination of valproate and other antiepilepsy drugs.

Table 3. Adverse Reactions Reported by > 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures

Body System/Event	Valproate (%) (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 4 lists treatment-emergent adverse events 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 valproate 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 valproate alone, or the combination of valproate and other antiepilepsy drugs.

Table 4. Adverse Reactions Reported by > 5% of Patients in the High-Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizuresa

Body System/Event	High Dose (%) (n = 131)	Low Dose (%) (n = 134)
a. 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 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 2 placebo-controlled clinical trials and their long-term extension, valproate was generally well tolerated with most adverse events 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 events 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 5 includes those adverse events 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 5. Adverse Reactions Reported by > 5% of Valproate -Treated Patients During Migraine Placebo-Controlled Trials With a Greater Incidence Than Patients Taking Placeboa

Body System Event	Valproate (n=202)	Placebo (n=81)
a. The following adverse events occurred in at least 5% of valproate -treated patients and at an equal or greater incidence for placebo than for valproate: flu syndrome and pharyngitis.
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%

The following additional adverse events 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, chills, face edema, fever and malaise.

Cardiovascular System: Vasodilatation.

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

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema, SGOT 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.

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  valproic acid capsules 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 and Precautions (5.4)].

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 (7)].

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 (5.6) and Drug Interactions (7)]. 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 (eg, 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 (5.1)].

Endocrine

  Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.14)].

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 (5.3)].

Metabolic: Hyperammonemia [see Warnings and Precautions (5.7)], 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.

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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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