Phenobarbital

Emergency & Prehospital

• Convulsive status epilepticus, benzodiazepine-refractory: phenobarbital is the alternative second therapy when fosphenytoin, valproate and levetiracetam are all unavailable (AES 2016, Level B). It is also used as a later agent after they fail, per local protocol
• Status epilepticus when no first-line benzodiazepine is available: IV phenobarbital works as initial therapy (AES 2016, Level A). It is slower to give than lorazepam, midazolam or diazepam

ED / ICU / Transport

• Neonatal seizures: the first-line antiseizure drug regardless of cause, per the ILAE 2023 neonatal guideline. If a channelopathy is likely, phenytoin or carbamazepine goes first. Sezaby is FDA-approved for term and preterm infants
• Status epilepticus in infants 1–6 months: second-line when they are still seizing 5 min after an adequate benzodiazepine dose (TREKK/EIIC algorithm). Neonates follow the neonatal regimen
• Moderate to severe alcohol withdrawal in patients being admitted: add it to benzodiazepines. SAEM GRACE-4 2024 makes that a conditional recommendation (off-label)
• Benzodiazepine-resistant alcohol withdrawal or delirium tremens: an adjunct in closely monitored settings (off-label). ASAM sees barbiturates as an alternative to benzodiazepines for delirium tremens, not the preferred choice
• Refractory and super-refractory status epilepticus: high-dose phenobarbital in intubated patients on continuous EEG (specialist use)

Other Uses

• Generalized tonic-clonic and focal epilepsy: long-term oral maintenance (labeled; now rarely a first choice in adults)
• Sedative, hypnotic and preanesthetic uses: still on the injection label but largely obsolete

Use these E3 house doses. Where the FDA label parts ways with them, the row tells you.

Available Forms

• Phenobarbital sodium injection: 65 mg/mL and 130 mg/mL in 1 mL vials, in alcohol, propylene glycol and (some products) benzyl alcohol; pH 9.2–10.2. The ED, ICU and transport form. Most US products are marketed without FDA approval.
• Sezaby (phenobarbital sodium powder for injection): 100 mg single-dose vial; reconstitute with 10 mL 0.9% sodium chloride to 10 mg/mL. FDA-approved for neonatal seizures; free of benzyl alcohol and propylene glycol.
• Oral: tablets 15, 16.2, 30, 32.4, 60, 64.8, 97.2 and 100 mg (strengths vary by manufacturer); oral elixir and solution. The grain-based strengths (16.2, 32.4, 64.8, 97.2 mg) sit next to the round numbers. Check the label.

Adult Dosing

Dosing weight: The label names none. ASAM names none for its alcohol-withdrawal regimens either. Status epilepticus loads run on actual body weight.

Pediatric Dosing

Weight-based dose checks: pediatric weight-based dosing.

Preparation & Administration

• Push rate: slow IV only; adults ≤60 mg/min per label. Children: infants 1–6 months 20 mg/kg over 20 min; older children 15 mg/kg over 10–15 min. Never exceed 60 mg/min. Push it fast and it can cause apnea, laryngospasm and hypotension.
• Infusion: loads may run as a short infusion per institutional protocol (e.g. 10 mg/kg in 100 mL 0.9% sodium chloride for alcohol withdrawal). Use a pump. Keep adult rates at or below 60 mg/min.
• Line: use a large vein and skip small or varicose ones. The solution is highly alkaline. Extravasation can cause necrosis, and intra-arterial injection can cause gangrene. Pain along the limb, or a pale, mottled hand, means stop at once.
• IM: deep into a large muscle, no more than 5 mL per site. Subcutaneous injection is not recommended (irritation to necrosis).
• Sezaby: reconstitute each 100 mg vial with 10 mL 0.9% sodium chloride (10 mg/mL); use within 8 hr at room temperature or 24 hr refrigerated.
• Inspect: do not use a discolored solution or one with a precipitate.

Contraindications

• Acute porphyria: manifest or latent, or a personal or family history of acute intermittent porphyria
• Hypersensitivity: to phenobarbital or other barbiturates
• Marked hepatic impairment or signs of impending hepatic coma
• Severe respiratory distress with dyspnea or obstruction when the airway cannot be supported (relative in status epilepticus with airway control)
• Large doses in nephritis (renal inflammation)
• Intra-arterial injection (gangrene); subcutaneous injection is not recommended (tissue necrosis)
• Prior sedative-hypnotic addiction: labeled contraindication for routine use

Precautions

• After benzodiazepines, opioids or alcohol: respiratory depression and hypotension stack on each other. Airway equipment goes to the bedside.
• Neonates: benzyl alcohol in an injection can cause fatal gasping syndrome. Use Sezaby.
• Older, debilitated, renal or hepatic patients: they react more strongly. Use lower doses. Paradoxical excitement or confusion can occur.
• Acute or chronic pain: may bring on paradoxical excitement or mask symptoms.
• Large cumulative IV doses: propylene glycol can open an osmolar gap and drive metabolic acidosis.
• Long-term use: physical dependence builds. Stop abruptly and it can cause seizures and delirium. Taper.
• Depression or suicidal thoughts: antiseizure drugs raise the risk of suicidal thoughts and behavior. Use caution and watch mood on long-term therapy.

Hold / Reassess If

• Alcohol-withdrawal dosing: falling RR or SpO₂, or rising EtCO₂, without airway support: hold and ventilate (thresholds per local protocol)
• Status epilepticus: hypoventilation and hypoxia are common during and after the seizure. Support ventilation (bag-mask, prepare RSI) and complete the load rather than stopping it
• Hypotension (SBP <90 mmHg in adults, or a falling BP): slow the rate; give fluids, vasopressors if needed. In alcohol withdrawal, hold further doses
• Sedated beyond the target (not rousable to voice) during alcohol-withdrawal dosing: hold further doses
• Any rash: stop unless clearly not drug-related

Common

• Somnolence and CNS depression
• Ataxia, dizziness, confusion; paradoxical agitation in children and older adults
• Hypotension and bradycardia during IV loading
• Nausea, vomiting, constipation
• Neonates (Sezaby trial): abnormal respiration 25%, sedation 16%, feeding problems 16%, hypotension 16%
• Long-term use: cognitive slowing, megaloblastic anemia, liver injury, osteomalacia (bone loss)

Serious / Life-Threatening

Overdose & Toxicity Management

• Signs: slurred speech, nystagmus and ataxia come first, then coma, hypoventilation and shock. The pupils are slightly constricted, or in severe poisoning dilated and fixed. Hypothermia, oliguria and Cheyne-Stokes breathing can also appear. Check core temperature and rewarm. Severe poisoning can kill.
• Immediate care: airway, ventilation, IV fluids and vasopressors for shock; check glucose and look for co-ingestants and trauma.
• Antidote: none. flumazenil does not reverse barbiturates.
• Enhanced elimination: multiple-dose activated charcoal is recommended for phenobarbital poisoning (2026 Clinical Toxicology Recommendations Collaborative), in a patient with a protected airway. Hemodialysis removes phenobarbital. Use it for severe poisoning, or for a patient in shock or anuric. Urinary alkalinization increases renal excretion, but it works less well and it is no substitute for either. Use it only on toxicology advice. Discuss with a poison center (1-800-222-1222).

Clinically Significant Interactions

IV Compatibility

• Diluent: 0.9% sodium chloride is the documented diluent, used for Sezaby reconstitution and ED alcohol-withdrawal infusions.
• Alkaline solution (pH 9.2–10.2): do not mix with other drugs in the syringe or bag; flush the line before and after.
• Verify with an institutional compatibility resource.

• Pediatrics: children need higher per-kg doses to reach therapeutic levels. Paradoxical excitement can occur. Long-term use has been linked to cognitive effects. The doses sit in the Pediatric Dosing table.
• Neonates: first-line for neonatal seizures, per the ILAE 2023 neonatal guideline. The half-life is about 1 week, and CYP2C9 activity is negligible at birth. Avoid benzyl alcohol-containing injections, and use Sezaby. Second-line per ILAE 2023: phenytoin, levetiracetam, midazolam or lidocaine. Levetiracetam is preferred with cardiac disease. With a suspected channelopathy, phenytoin or carbamazepine comes first.
• Pregnancy: phenobarbital can cause fetal harm, including major malformations. Fetal levels approach maternal levels. Third-trimester use can cause neonatal withdrawal (seizures, irritability) and neonatal sedation. In status epilepticus, stopping the seizure comes first. For eclampsia, use magnesium sulfate. Enroll patients in the North American Antiepileptic Drug Pregnancy Registry.
• Lactation: it passes into breast milk. Sedation and respiratory depression have been reported in breastfed infants. Watch the infant for drowsiness and poor feeding.
• Older Adults: older adults feel the sedation more and may react with excitement or confusion. Reduce doses. The AGS Beers Criteria 2023 lists barbiturates, phenobarbital included, as drugs to avoid in older adults.
• Renal Impairment: 25–50% of a dose leaves in urine unchanged, so reduce doses. Uremia makes the CNS more sensitive. Hemodialysis removes phenobarbital.
• Hepatic Impairment: contraindicated in marked impairment or impending hepatic coma. Otherwise, start with reduced doses.
• Obesity / Dosing Weight: there is no labeled dosing weight. ASAM gives none for alcohol withdrawal. Status epilepticus loads use actual body weight, and a level guides further dosing.

• Scope: ED, ICU and critical-care or flight transport (RN, paramedic and CCT under protocol). Ground EMS rarely carries it. It varies by state and agency protocol.
• Storage & Stability: vials at 20–25°C (68–77°F), excursions 15–30°C (59–86°F); protect Sezaby from light. Schedule IV: secure storage, counts and witnessed waste.
• Carried Concentration: confirm 65 mg/mL vs 130 mg/mL before drawing up; state the dose in mg and mL at handoff.
• Infusions in Transport: run loads on a pump with continuous SpO₂, EtCO₂, BP and ECG. A patient loaded with phenobarbital after benzodiazepines may lose the airway in transit. Have bag-mask ventilation and intubation equipment ready.
• Handoff Essentials: seizure or withdrawal onset time; benzodiazepine doses and times; phenobarbital start and stop times, total mg and mg/kg, rate; vital-sign changes; current mental status; any serum level.

Mechanism of Action

• It binds the barbiturate site on the GABA-A receptor. That prolongs chloride-channel opening, so neurons hyperpolarize and seizures spread less.
• At high concentrations it opens the channel directly and cuts glutamate (AMPA) excitation. The result is deep CNS depression, which is why it still works when benzodiazepines fail.
• It is a strong inducer of hepatic enzymes, so expect many drug interactions.

Pharmacokinetics

• Half-life: adults 53–118 hr (mean 79 hr); children and newborns 60–180 hr (mean 110 hr); about 1 week in neonates in the first days of life.
• Metabolism: hepatic, mainly CYP2C9, with CYP2C19, CYP2E1 and UGT; no active metabolites.
• Elimination: 25–50% excreted unchanged in urine, more in alkaline urine and at high urine flow.
• Protein binding: 20–45%. It has the lowest lipid solubility of the barbiturates, so onset is slowest and action longest. It crosses the placenta.

Generic Name

Phenobarbital sodium (injection); phenobarbital (tablets, elixir, oral solution). International name: phenobarbitone

Brand Names

Sezaby (phenobarbital sodium powder for injection, neonatal seizures); other US products are generic

Pharmacologic Class

Barbiturate (long-acting); GABA-A receptor modulator

Therapeutic Class

Antiseizure medication; sedative-hypnotic

Controlled Substance

C-IV

ISMP High-Alert

No (not named on the 2024 acute-care list; many institutions apply high-alert checks to IV loads)

Look-Alike / Sound-Alike

PHENobarbital / PENTobarbital; 65 mg/mL / 130 mg/mL vials