Proval CR

Approved Medical Indications:

• Epilepsy (monotherapy or adjunct):
• Generalized seizures (tonic-clonic, myoclonic, absence)
• Partial seizures (simple and complex)
• Mixed seizure types
• Status Epilepticus (IV formulation):
• As alternative to benzodiazepines and phenytoin in refractory cases
• Bipolar Disorder (mania):
• Treatment of acute manic episodes in bipolar disorder (especially when lithium is not suitable)
• Migraine Prophylaxis:
• Preventive treatment for chronic or frequent migraine attacks

Clinically Accepted Off-label Uses:

• Schizoaffective disorder and schizophrenia (as adjunct):
  When mood symptoms or aggression are prominent
• Borderline personality disorder (BPD):
  For mood stabilization and aggression control
• Agitation and aggression in dementia patients:
  Used cautiously under specialist supervision
• Neuropathic pain and fibromyalgia:
  Occasionally used in resistant cases

Adults:

• Epilepsy:
  Initial: 600 mg/day orally in 1–2 divided doses
  Maintenance: 1000–2000 mg/day in divided doses
  Maximum: 2500–3000 mg/day (depending on formulation and tolerability)
• Acute Mania in Bipolar Disorder:
  Initial: 750 mg/day
  Adjust dose to clinical response; therapeutic range: 50–100 mcg/mL
• Migraine Prophylaxis:
  Initial: 400–600 mg/day
  Maintenance: 500–1000 mg/day

Pediatric:

• Epilepsy:
  Initial: 10–15 mg/kg/day
  Maintenance: 20–30 mg/kg/day (max 60 mg/kg/day)

Elderly:

• Start at lower dose (250–500 mg/day) and titrate cautiously
• Monitor plasma levels and hepatic function

Renal Impairment:

• No dose adjustment generally required
• Monitor for accumulation of valproate metabolites in severe impairment

Hepatic Impairment:

• Contraindicated in significant hepatic dysfunction
• Liver function must be assessed before and during therapy

Administration:

• Oral: Tablets, syrup, or modified-release (MR) formulations; take with food to reduce GI upset
• IV: Administer slowly (over 3–5 minutes for bolus or via infusion) in hospital settings

Sodium Valproate enhances gamma-aminobutyric acid (GABA) levels in the central nervous system, which exerts inhibitory effects on neuronal firing. It achieves this by inhibiting GABA transaminase (the enzyme that breaks down GABA) and possibly stimulating glutamic acid decarboxylase (which synthesizes GABA). It also blocks voltage-gated sodium channels and T-type calcium channels, stabilizing hyperexcitable neuronal membranes. These combined actions help suppress epileptogenic activity and stabilize mood in bipolar disorder.

• Absorption: Rapid and nearly complete after oral administration; peak levels in 1–4 hours (delayed in extended-release forms)
• Bioavailability: Approximately 90–100%
• Distribution: Widely distributed; 90–95% protein bound (albumin)
• Metabolism: Primarily hepatic via glucuronidation and mitochondrial β-oxidation
• Active Metabolite: Valproate semialdehyde and other minor metabolites
• Half-life:
• Adults: 8–17 hours
• Children: 6–10 hours
• Excretion: Mainly via urine as conjugated metabolites

• Pregnancy:
  Sodium Valproate is contraindicated in pregnancy for epilepsy or bipolar disorder unless no alternative is effective due to high risk of:
• Neural tube defects (e.g., spina bifida)
• Cognitive impairments and developmental delays
• Facial dysmorphism and congenital malformations
  Pregnancy Prevention Program (PPP) is mandatory in many countries.
• Lactation:
  Sodium Valproate is excreted in breast milk in low concentrations.
  Generally considered compatible with breastfeeding, though infants should be monitored for liver dysfunction or sedation.

• Class: Antiepileptic (Anticonvulsant)
• Subclass: Broad-spectrum AED
• Additional Role: Mood stabilizer (in psychiatric disorders)

• Known hypersensitivity to Sodium Valproate or valproic acid derivatives
• Active or significant hepatic disease or hepatic dysfunction
• Urea cycle disorders
• Pancreatitis (current or history of)
• Pregnancy (unless no alternative is effective)
• Mitochondrial disorders caused by POLG mutations (e.g., Alpers-Huttenlocher syndrome)
• Co-administration with St. John’s Wort or other enzyme inducers

• Hepatotoxicity: May occur within first 6 months; monitor liver enzymes regularly, especially in children <2 years or with metabolic disorders
• Pancreatitis: Can be life-threatening; discontinue if suspected
• Teratogenicity: High risk of congenital malformations and neurodevelopmental disorders; enforce strict contraception in women of childbearing potential
• Hyperammonemia & encephalopathy: Especially with concomitant topiramate or carnitine deficiency
• Suicidal ideation: Monitor patients closely for mood or behavioral changes
• Weight gain, metabolic changes, and PCOS risk: Especially in adolescent females
• Coagulopathies and thrombocytopenia: Monitor platelets and coagulation parameters

Common (≥10%):

• Neurologic: Tremor, sedation, dizziness, headache
• GI: Nausea, vomiting, abdominal pain, diarrhea
• General: Weight gain, lethargy
• Psychiatric: Behavioral changes, agitation (especially in children)

Less Common (1–10%):

• Hair thinning or temporary hair loss
• Increased appetite
• Menstrual irregularities
• Blurred vision
• Ataxia

Serious and Rare (<1%):

• Hepatic failure
• Acute pancreatitis
• Severe thrombocytopenia or aplastic anemia
• Stevens-Johnson syndrome
• Encephalopathy (with or without hyperammonemia)
• Suicidal ideation or behavior

Onset & Severity:

• Most side effects appear within 1–2 weeks of initiation
• Hepatic and hematologic events may have delayed onset
• Dose-related effects (e.g., tremor, sedation) are usually reversible on dose reduction

• Enzyme inducers (e.g., phenytoin, carbamazepine, rifampicin): May reduce valproate levels
• Lamotrigine: Increases lamotrigine levels — risk of rash; adjust doses
• Aspirin & salicylates: Increase free valproate — risk of toxicity
• Topiramate: Increased risk of encephalopathy
• Oral contraceptives: Valproate does not reduce efficacy, but alternative contraception is advised due to teratogenicity
• Alcohol: May enhance CNS depression
• CYP450 system: Valproate is not a significant inducer or inhibitor, but it may affect glucuronidation pathways

• EMA & MHRA (Europe): Reaffirmed strong restrictions for use in women of childbearing potential; introduced Pregnancy Prevention Program (PPP)
• NICE (UK): Valproate should only be prescribed by specialists when no alternatives are suitable for epilepsy or bipolar disorder in women of reproductive age
• Updated warning (2023–2024): Reinforced education materials for prescribers and patients about teratogenic risks
• New guidelines encourage switching to safer alternatives (e.g., lamotrigine, levetiracetam) where appropriate

• Temperature: Store below 25°C (77°F)
• Humidity: Store in a dry place, in original container
• Light protection: Protect from direct sunlight
• Handling Instructions:
• Do not freeze liquid formulations
• Shake oral suspensions well before use
• Keep out of reach of children
• Shelf Life: As per manufacturer labeling; discard after expiration date