What are the important side effects of sodium valproate?

Important Side Effects of Sodium Valproate

Sodium valproate carries several critical side effects that require vigilant monitoring, with the most serious being hepatotoxicity (particularly in high-risk groups), teratogenicity including neural tube defects, and polycystic ovary syndrome in women of reproductive age.

Life-Threatening and Severe Side Effects

Hepatotoxicity

• Fatal hepatotoxicity occurs with an overall incidence of 1 in 20,000, but increases dramatically to 1 in 600-800 in high-risk groups 1
• High-risk patients include infants below 2 years of age receiving anticonvulsant polytherapy 1
• Baseline and periodic monitoring (every 3-6 months) of liver function tests is mandatory 2
• Patients and families must be educated about presenting symptoms of liver dysfunction, as periodic monitoring alone does not ensure early detection 2

Teratogenicity

• Neural tube defects occur in 1-3% of pregnancies exposed to valproate 2, 1
• Valproate is contraindicated for migraine prevention in pregnant women or those who may become pregnant without effective contraception 3
• The drug should not be used in women with childbearing potential unless other treatments have failed 3

Pancreatitis

• Acute pancreatitis, including fatal cases, has been reported 2, 3
• This represents a medical emergency requiring immediate discontinuation 3

Hyperammonemic Encephalopathy

• Can develop with or without fever shortly after initiating valproate monotherapy 3
• May occur without hepatic dysfunction or elevated plasma valproate levels 3
• Fatalities have been reported, particularly in patients with underlying urea cycle disorders 3
• Average serum ammonia levels in affected patients can reach 219.15 μmol/L 4

Reproductive and Endocrine Effects in Women

Polycystic Ovary Syndrome (PCOS)

• In women on valproate monotherapy, 45% experienced menstrual irregularities, 60% developed polycystic ovaries, and 30% had elevated testosterone 2
• In one study, 64% of women on valproate monotherapy developed polycystic ovaries or hyperandrogenemia 2
• These effects are mediated through hyperinsulinemia, reduced insulin-like growth factor binding protein-1, and direct effects on ovarian steroidogenesis 2
• Discontinuation of valproate led to reversal of hyperinsulinemia, hyperandrogenism, dyslipidemia, and polycystic ovaries within one year 2
• Effects occur in both obese and lean women, though weight gain is a contributing factor 2

Other Endocrine Effects

• Irregular menses, secondary amenorrhea, breast enlargement, and galactorrhea 3
• Abnormal thyroid function tests 3

Hematologic Side Effects

Thrombocytopenia and Bleeding Disorders

• Thrombocytopenia occurred in 24% of high-dose patients versus 1% of low-dose patients 3
• Inhibition of secondary phase of platelet aggregation manifests as altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage 3
• Other hematologic effects include pancytopenia, aplastic anemia, agranulocytosis, and bone marrow suppression 3

Common and Dose-Related Side Effects

Gastrointestinal Effects

• Nausea (34-48%), vomiting (23-27%), and diarrhea (13-23%) are the most common initial side effects 3
• These are usually transient and rarely require discontinuation 3
• Delayed-release formulations may reduce gastrointestinal side effects 3

Neurological Effects

• Tremor is highly dose-dependent, occurring in 57% of high-dose versus 19% of low-dose patients 3
• Somnolence (27-30%), dizziness (18-25%), and ataxia (8%) are common 3
• Sedation occurs most often with combination therapy and usually abates with dose reduction of other antiepileptic medications 3
• Rare cases of coma, particularly when combined with phenobarbital 3

Metabolic Effects

• Weight gain occurs in 9% of patients and represents a significant concern 2, 3
• Weight gain reduces insulin sensitivity and promotes PCOS development in predisposed women 2
• Hyperammonemia can occur without encephalopathy 3, 4

Dermatologic Effects

• Hair loss (alopecia) occurs in 24% of high-dose versus 13% of low-dose patients 3
• This is typically transient 1, 5
• Rare but serious: Stevens-Johnson syndrome, toxic epidermal necrolysis (including fatal cases) 3

Monitoring Requirements

Baseline Assessment

• Complete blood count, liver function tests, pregnancy test in females of reproductive age 2
• Consider ammonia level if symptoms suggest hyperammonemia 4

Ongoing Monitoring

• Serum drug levels, hepatic and hematological indices every 3-6 months 2
• Body weight and metabolic parameters, particularly in women of reproductive age 2
• Clinical assessment for menstrual irregularities and signs of hyperandrogenism in women 2

Special Populations at Higher Risk

Contraindications and High-Risk Groups

• Patients with mitochondrial disorders (e.g., Alpers-Huttenlocher syndrome) should not receive valproate 3
• Infants under 2 years on polytherapy have dramatically increased hepatotoxicity risk 1
• Women of childbearing potential require careful counseling about teratogenic risks 3
• Patients with urea cycle disorders are at increased risk for fatal hyperammonemic encephalopathy 3

Drug Interactions Increasing Toxicity

• Valproate inhibits metabolism of phenobarbital, lamotrigine, and zidovudine, increasing their plasma concentrations 1
• Concomitant lamotrigine increases risk of serious skin reactions 3
• Use with atypical antipsychotics may increase hematologic toxicities 2