Antiepileptics. Barbiturates
ATC code: N03AA02 (Phenobarbital)
Brand names
Luminal, Solfoton, Phenobarbital sodium
Allosterically enhances GABA-A signaling, prolongs chloride channel opening. Essential Medicines List for epilepsy, especially in resource-limited settings. Replaced by newer antiepileptics in developed countries due to sedation and CYP induction. In Russia, present in combination OTC sedatives (Corvalol, Valocordin) – chronic use causes dependence and cognitive impairment.
First line
Phenobarbital remains the first-line drug for neonatal seizures per international and Russian guidelines. Loading dose 20 mg/kg IV; if seizures persist, additional 10 mg/kg. Maintenance dose 3–5 mg/kg/day. Seizure control 40–60%; if ineffective, add phenytoin or levetiracetam. includes phenobarbital in the Essential Medicines List for neonatal seizure treatment.
After seizure control, gradually transition to long-term antiepileptics with better neurodevelopmental profile (levetiracetam, lamotrigine).
Sources
Second line
Phenobarbital is used in status epilepticus in resource-limited settings when modern second-line drugs (fosphenytoin, valproate, levetiracetam) are unavailable. 2016 and Essential Medicines List support this. Dose 15–20 mg/kg IV slowly. For refractory status, high-dose phenobarbital (barbiturate coma) is a third-line option in critical care.
Third line
Phenobarbital retains efficacy in focal and generalized epilepsy in adults. NG217 and ILAE do not list phenobarbital as first-line due to pronounced sedative and cognitive effects, plus dependence risk. Used as reserve in cases refractory to first- and second-line agents. In resource-limited countries and the Essential Medicines List, it retains a role as a basic antiepileptic.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Use of phenobarbital and combination products containing it (Corvalol, Valocordin, Barboval) for anxiety, insomnia, or cardiovascular symptoms is not supported by international guidelines. Barbiturates were displaced by benzodiazepines in the 1970s due to a narrower therapeutic index and high dependence risk. Long-term regular use of Corvalol and similar products leads to physical dependence, withdrawal with seizures and psychosis, and bromide accumulation (bromism). In the EU these combinations are banned or regulated as prescription psychoactive substances.
Corvalol and Valocordin are sold over-the-counter in Russia, and their regular use remains a common cause of dependence and toxicity.
Long-term phenobarbital use is associated with decreased vitamin B12 level in some patients. When symptoms appear (megaloblastic anemia, neuropathy) or serum level drops, give oral replacement 1000 µg/day.
Source: FDA: Phenobarbital sodium injection prescribing information (2019)
Phenobarbital reduces folate level with long-term therapy through impaired absorption and accelerated metabolism. In women of reproductive age, folic acid 4–5 mg/day is recommended 1–3 months preconception to reduce neural tube defect risk. In adults on long-term therapy, 1–5 mg folic acid/day is given.
Source: FDA: Phenobarbital sodium injection prescribing information (2019)
Phenobarbital induces CYP24A1 and accelerates 25(OH) vitamin D catabolism. Long-term therapy (over 2 years) reduces vitamin D level and causes osteopenia and osteomalacia. Check 25(OH) vitamin D annually and supplement cholecalciferol 800–2000 IU/day when level falls to 30 ng/mL or below.
Source: FDA: Phenobarbital sodium injection prescribing information (2019)
Phenobarbital induces vitamin K catabolism. In pregnant women in the third trimester and in newborns of mothers on phenobarbital, the risk of hemorrhagic disease of the newborn is increased. Prophylaxis: mother – vitamin K1 10 mg/day orally in the last month of pregnancy; newborn – vitamin K1 1 mg IM immediately after delivery.
Source: FDA: Phenobarbital sodium injection prescribing information (2019)
1 pair found. Sorted from critical to minor.
Mechanism
Phenobarbital is a strong CYP3A4 inducer; it lowers oestradiol levels by 40–60%. On menopausal hormone therapy, menopausal symptoms may return. On combined oral contraceptives, unplanned pregnancy risk arises.
Symptoms
Return of vasomotor symptoms: hot flushes, night sweats, sleep disturbance. On oral contraceptives: breakthrough bleeding, conception risk.
Management
On menopausal hormone therapy, raise the oestradiol dose or switch to transdermal forms. For contraception on phenobarbital, combined oral contraceptives are unsuitable — choose a levonorgestrel IUS, copper IUD, or depot medroxyprogesterone acetate. In young women with epilepsy, consider switching phenobarbital to levetiracetam or lamotrigine (no CYP3A4 induction).
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FDA category D. First-trimester use carries risks of cleft palate, cardiac defects, and digital hypoplasia; third-trimester use of hemorrhagic disease of the newborn and neonatal withdrawal. Women of reproductive age are switched to safer antiepileptics (levetiracetam, lamotrigine). If therapy continues, give folic acid 4–5 mg/day and vitamin K1 (phytomenadione) to the mother in the last month and to the newborn after birth.
Passes into breast milk at 36–100% of maternal plasma level. LactMed advises caution and infant monitoring (sedation, poor feeding). Breastfeeding may need to be limited if infant develops significant symptoms.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Phenobarbital is evaluated for the following indications with varying evidence strength: Neonatal seizures (evidence tier A), Status epilepticus (evidence tier A), Focal epilepsy (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Phenobarbital (≥ 1 in 100): Sedation, drowsiness, fatigue, Incoordination, dizziness, Cognitive impairment, especially in children and elderly, Paradoxical excitement in children, Depressed mood. See the Safety section for uncommon and serious reactions.
FDA category D. FDA category D. First-trimester use carries risks of cleft palate, cardiac defects, and digital hypoplasia; third-trimester use of hemorrhagic disease of the newborn and neonatal withdrawal. Women of reproductive age are switched to safer antiepileptics (levetiracetam, lamotrigine). If therapy continues, give folic acid 4–5 mg/day and vitamin K1 (phytomenadione) to the mother in the last month and to the newborn after birth.
Passes into breast milk at 36–100% of maternal plasma level. LactMed advises caution and infant monitoring (sedation, poor feeding). Breastfeeding may need to be limited if infant develops significant symptoms.
Phenobarbital is contraindicated in: Hypersensitivity to barbiturates; Severe respiratory insufficiency; Severe hepatic impairment; Acute intermittent porphyria; History of substance use disorder. Full list in the Safety section.
regular Corvalol, Valocordin, and similar products cause physical phenobarbital dependence. Withdrawal causes anxiety, insomnia, seizures. Additionally, bromide accumulates with bromism (mental disturbances, dermatitis, tremor). For cardiac symptoms, see a cardiologist, not Corvalol.
remains first-line for neonatal seizures. Included in WHO Essential Medicines List.
phenobarbital and bromide impair concentration and reaction time for 24–48 hours; with regular use this effect is constant.