VALPROIC ACID (Valproic Acid)

Australia TGA / PBS / State Schemes

Classified as S4 under the Therapeutic Goods Administration (TGA).

WorkSafe Victoria Drugs of Dependence Guidelines require monitoring for all S8 opioids. WorkCover QLD Pain Intervention Guidelines recommend multimodal pain management with opioids as a last resort.

United Kingdom NICE / MHRA / FPM

NICE NG193 (Chronic Pain) recommends against initiating opioids for chronic primary pain. The Faculty of Pain Medicine (FPM) Opioids Aware resource recommends structured opioid prescribing with regular review, dose limits, and documented tapering plans.

For personal injury claims in the UK, opioid prescribing duration and dose should be reviewed against NICE and FPM guidelines. Costs may be recoverable as a disbursement in high-value PI claims.

UK drug driving laws (Section 5A Road Traffic Act 2006) set specific limits for prescription drugs that cause impairment. Employers and occupational health advisors should assess fitness to work.

United States FDA / CDC / State WC

FDA approved for use in the United States.

FDA Boxed Warning: BOXED WARNING Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions ( 5.1 )] . Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When valproic acid products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproic acid is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications ( 4 )] . In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, valproic acid should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with valproic acid for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions ( 5.1 )] . Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure. Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant women and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )] . Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )] . A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information ( 17 )] . Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions ( 5.5 )] . See full prescribing information for complete boxed warning. Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter ( 5.1 ) Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ ( 5.2 , 5.3 , 5.4 ) Pancreatitis, including fatal hemorrhagic cases ( 5.5 )

The CDC Clinical Practice Guideline for Prescribing Opioids (2022) recommends non-opioid therapies as first-line treatment for pain. When opioids are prescribed, the lowest effective dose should be used for the shortest duration needed.

For workers compensation claims, many states require prior authorization for opioids beyond initial acute prescribing. State drug formularies (e.g. California MTUS, Texas, New York) may restrict or require step therapy before opioid approval.

New Zealand ACC / BPAC NZ / Medsafe

BPAC NZ recommends reassessing opioid therapy at regular intervals and limiting duration. The NZ Opioid Prescribing B-QuiCK Guide provides structured prescribing and tapering protocols.

ACC (Accident Compensation Corporation) covers treatment-related medications for accepted claims. Opioid prescribing beyond guidelines may require ACC clinical review and approval.