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Expected pharmacological effect
Causality assessment · Expected pharmacological effect
Valproate and Hyperammonaemia / encephalopathy: is the FAERS signal real?
A written Bradford Hill assessment of one drug–event pair. The grade is a judgement about the signal, not a statement that this drug causes this event in any one person; FAERS counts are reports, not rates.
Valproate ↔ Hyperammonaemia / encephalopathy
n=624 co-reports · PRR 95.6 · ROR 97.5
Valproate interferes with the urea cycle and the metabolism of ammonia, so it commonly raises blood ammonia, and in some patients this produces a lethargic encephalopathy even when liver tests and valproate levels are normal. The effect is dose-related and follows directly from the drug's known biochemistry, and it is the reason ammonia is checked when a patient on valproate becomes drowsy. The 624 co-reports (PRR 95.6) reflect a genuine, mechanistically understood metabolic effect.
Regulatory basis: valproate prescribing information (hyperammonaemia and encephalopathy warning). Established valproate-ammonia literature.
| Bradford Hill viewpoint | Status | Note |
|---|---|---|
| Temporality (necessary) | met | Ammonia rises during therapy and the encephalopathy resolves after withdrawal |
| Strength | met | PRR 96 — a very high relative signal, though partly because the term is valproate-specific |
| Consistency | met | Reproduced across case series and metabolic studies |
| Specificity | met | A characteristic valproate effect, rare with other drugs |
| Biological gradient | met | Dose-related and worse with enzyme inducers, carnitine deficiency, or urea-cycle defects |
| Plausibility | met | Inhibition of the urea cycle / ammonia detoxification is the mechanism |
| Coherence | met | Coheres with the labelled warning and the practice of checking ammonia if drowsy |
| Experiment | partial | Dechallenge (withdrawal, carnitine) reverses the encephalopathy; no randomized trial |
| Analogy | met | Analogous to hyperammonaemia from other mitochondrial or urea-cycle-toxic drugs |
This page's own qualitative read, not an automated/citation-gated assessment.
✗ No ClinicalTrials.gov results-posting trial in the top search hits for valproate captured hyperammonaemia as a coded event; the metabolic finding is managed through routine ammonia testing rather than a trial AE table.