Antiepileptic barbiturate, enzyme inducer
Phenobarbital is an antiepileptic and sedative medicine (barbiturate) used to control seizures. It is effective, but can cause habituation and dependence, and stopping must always be gradual. It interacts with many medicines because it speeds up their elimination.
Also known as: Gardenal, Luminal
Combining Phenytoin with Phenobarbital may increase or decrease Phenytoin concentrations, requiring monitoring.
Phenobarbital is a potent inducer of hepatic enzymes (CYP2C9/2C19 — the same ones that metabolise phenytoin) and may reduce phenytoin levels, but competition for the same pathways and the saturable kinetics of phenytoin make the net effect variable: the phenytoin label includes phenobarbital among the "antiepileptics that may either increase or decrease phenytoin serum levels" and states that "the effect of phenytoin on phenobarbital serum levels... is unpredictable". Conversely, phenytoin may raise or lower phenobarbital levels. Both drugs have narrow therapeutic windows and additive CNS-depressant effects. Monitor serum levels of both during initiation/withdrawal, adjust doses based on levels and clinical symptoms, and watch for sedation, nystagmus and ataxia.
Phenytoin + phenobarbital: unpredictable bidirectional interaction (enzyme induction and competition for shared pathways). Monitor serum levels of both.
Phenobarbital, an enzyme inducer, and Phenytoin compete and induce shared metabolic pathways; the net effect is variable (increase or decrease in Phenytoin levels).
Monitor serum Phenytoin levels and clinical signs of toxicity.
Toxicity or loss of seizure control require dose reassessment.
Monitor serum Phenytoin and, if possible, Phenobarbital levels at start and dose adjustments.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenobarbital with Valproate increases Phenobarbital concentrations, with a risk of sedation and toxicity.
The phenobarbital label explicitly states that "valproate and valproic acid increase the phenobarbital serum levels; therefore, phenobarbital blood levels should be closely monitored and appropriate dosage adjustments made as clinically indicated". The valproate label confirms that "valproate inhibits the metabolism of phenobarbital". Raised phenobarbital levels potentiate CNS depression (sedation, somnolence, ataxia, respiratory compromise at high doses), mainly in the elderly. When starting valproate in patients stabilised on phenobarbital, monitor phenobarbital levels and clinical toxicity signs, reducing the phenobarbital dose if needed (usually 20–30%).
Phenobarbital + valproate: valproate inhibits phenobarbital metabolism and raises its levels (sedation up). Monitor levels and CNS depression.
Valproate inhibits Phenobarbital metabolism, raising its serum levels and potentiating its depressant effect.
Monitor sedation and, if available, Phenobarbital levels.
Excessive sedation or respiratory depression require discontinuation and evaluation.
Monitor signs of sedation and, if available, Phenobarbital levels; consider reducing the dose.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4 ; approved Valproic acid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenobarbital with Warfarin reduces the anticoagulant effect of Warfarin, posing a risk of thrombotic events.
Phenobarbital is a potent inducer of CYP2C9, CYP2C19 and CYP3A4, the enzymes that metabolise warfarin, and accelerates its elimination — the anticoagulant effect decreases and the INR falls, with thromboembolism risk if the dose is not adjusted. The inducing effect takes 1–3 weeks to fully develop and persists for several weeks after phenobarbital is stopped, when the INR can rise sharply. The INR should be monitored frequently when starting, during and after phenobarbital, increasing the warfarin dose as needed and re-adjusting it during the withdrawal phase.
Phenobarbital strongly induces CYP2C9/CYP3A4 and can markedly REDUCE the effect of warfarin. The warfarin dose may need to be increased with close monitoring; re-adjust after stopping.
As an enzyme inducer, Phenobarbital accelerates Warfarin metabolism, reducing its anticoagulant effect.
Frequent INR at start and dose changes.
A suboptimal INR or thrombotic events require anticoagulant adjustment.
Monitor the INR and adjust the Warfarin dose during co-administration.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Alcohol potentiates the central nervous system depression of phenobarbital and has additive effects on sedation and respiratory depression.
Avoid alcohol intake during treatment.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4
Phenobarbital can be administered with or without food, with no relevant change in absorption.
Take at the same time every day, with or without food.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4
Phenobarbital is contraindicated in porphyria, as it induces porphyrin synthesis and precipitates acute attacks.
Do not use in patients with porphyria; consider an alternative.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4
Phenobarbital depresses the central nervous system and the respiratory centre, with an increased risk in severe lung disease.
Use with caution in severe respiratory disease and monitor sedation.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4
Phenobarbital crosses the placenta and is associated with malformations and neonatal haemorrhage due to vitamin K deficiency.
Avoid in the first trimester; give vitamin K to the newborn.
Present in breast milk; can cause sedation in the infant — monitor.
Use effective contraception; phenobarbital reduces the efficacy of hormonal contraceptives.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Long-acting barbiturate with anticonvulsant, sedative and hypnotic properties. As an anticonvulsant, it raises the seizure threshold and limits the spread of seizure activity; as a sedative, it produces sedation at doses below the hypnotic ones. Oral onset of action is ≥1 hour and the duration of action is 10–12 hours.
Barbiturates potentiate GABAergic inhibition: they bind to the GABA-A receptor complex, prolonging the duration of chloride channel opening and hyperpolarising the neurone. At higher doses they also depress excitatory (glutamatergic) neurotransmission.
Approximately 25–50% of a dose of phenobarbital is eliminated unchanged in the urine — excretion of unmetabolised barbiturate distinguishes the long-acting category from others, which are almost entirely metabolised. Weak acids such as barbiturates are absorbed to varying degrees; the salts are absorbed more rapidly and absorption is increased on an empty stomach.
Barbiturates are metabolised primarily by the hepatic microsomal enzyme system; the metabolic products are excreted in the urine and, less commonly, in the faeces. Phenobarbital is a potent hepatic enzyme inducer — it accelerates its own metabolism and that of many other drugs.
The plasma half-life of phenobarbital in adults ranges between 53 and 118 hours, with a mean of 79 hours; in children and newborns (<48 hours) it ranges between 60 and 180 hours (mean 110 hours). It is the barbiturate with the lowest lipid solubility, lowest protein binding and longest duration of action.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
