Phenobarbital

N03A - Antiepileptics ATC N03AA02 Small molecule approved 2022 Parenteral Natural product Narrow therapeutic index Withdrawn Black-box warning

🧬 Cross-allergy: Aromatic anticonvulsants

JFDA label: Phenotal Tablet

⚠ Black-Box Warning

Mechanism of Action

Long-acting barbiturate with sedative, hypnotic, and anticonvulsant properties. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, barbiturates exhibit anticonvulsant activity; barbiturates produce dose-dependent respiratory depression.

Indications

Approved

Sedation
Seizures

Off-label

Alcohol withdrawal
Sedative/hypnotic withdrawal

Contraindications

Source: Lexicomp

Hypersensitivity to phenobarbital, barbiturates or any component of the formulation Absolute
dyspnea or airway obstruction Absolute
intra-arterial administration, subcutaneous administration (not recommended) Absolute
marked hepatic impairment Absolute
nephritic patients (large doses) Absolute
nephritic patients (large doses) Additional contraindications: IV only: Intra-arterial or subcutaneous administration Absolute
porphyria (manifest and latent) Absolute
use in patients with a history of sedative/hypnotic addiction Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Not Known Bradycardia · hypotension · syncope · thrombophlebitis (IV)

Nervous system disorders (16)

Not Known Agitation · anxiety · ataxia · central nervous system depression · central nervous system stimulation · confusion · dizziness · drowsiness · hallucination · hangover effect · headache · impaired judgement · insomnia · lethargy · nervousness · nightmares

Renal and urinary disorders (1)

Not Known Oliguria

Blood and lymphatic system disorders (3)

Not Known Agranulocytosis · megaloblastic anemia · thrombocytopenia

Gastrointestinal disorders (3)

Not Known Constipation · nausea · vomiting

Skin and subcutaneous tissue disorders (3)

Not Known Exfoliative dermatitis · skin rash · Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders (2)

Not Known Hyperkinesia · laryngospasm

General disorders and administration site conditions (1)

Not Known Pain at injection site

Respiratory, thoracic and mediastinal disorders (3)

Not Known Apnea (especially with rapid IV use) · hypoventilation · respiratory depression

Dosing

Source: Lexicomp

Sedation: Oral, IV, IM: 30 to 120 mg/day in 2 to 3 divided doses; maximum: 400 mg/day Preoperative sedation: IM: 100 to 200 mg 60 to 90 minutes before surgery Status epilepticus: IV: American Epilepsy Society recommendations: 15 mg/kg as a single dose. Note: AES recommends phenobarbital as a second line option only if first line options (lorazepam, diazepam, or midazolam) or other second line options (eg, fosphenytoin, valproic acid, levetiracetam) are unavailable (AES [Glauser 2016]). Neurocritical Care Society recommendation: 20 mg/kg (infused at 50 to 100 mg/minute); if necessary, may repeat once after 10 minutes with an additional 5 to 10 mg/kg (NCS [Brophy 2012]) Note: Additional respiratory support may be required particularly when maximizing loading dose or if concurrent sedative therapy. Repeat doses administered sooner than 10 to 15 minutes may not allow adequate time for peak CNS concentrations to be achieved and may lead to CNS depression. Seizures: Maintenance dose: Note: Maintenance dose usually starts 12 hours after loading dose Manufacturer’s labeling: Oral: 60 to 200 mg/day or 50 to 100 mg 2 to 3 times daily Alternative dosing (limited data available) Usual dosing range: Oral, IV: 2 mg/kg/day in divided doses (Murphy 2010; Winter 2010). Note: Dosage should be individualized based upon clinical response and serum concentration; 2 mg/kg/day typically produces a steady-state level of 20 mg/L (Winter 2010). Alcohol withdrawal (off-label use): IV: Initial dose of 260 mg, followed by subsequent doses of 130 mg as needed. Note: Clinical Institute Withdrawal Assessment (CIWA) scores were evaluated at 30 minute intervals in the clinical trial (Hendey 2011). Oral: Fixed dose regimen of 60 mg 4 times daily on day 1, followed by 60 mg 3 times daily on day 2, 60 mg twice daily on day 3, and 30 mg twice daily on day 4. In addition, provide 60 mg as needed for breakthrough withdrawal symptoms (Mariani 2006; Rosenthal 1998). May also administer 130 mg IM as needed for more substantial withdrawal symptoms (eg, heart rate >120 bpm, SBP >150 mm Hg, marked agitation) (Rosenthal 1998). Sedative/hypnotic withdrawal (off-label use): Several regimens have been evaluated: Taper following dosage conversion: Initial daily requirement is determined by substituting phenobarbital in an equivalent dose to the baseline medication (clonazepam 1 mg = phenobarbital 60 mg was used in the study). Divided the calculated baseline total dose into 4 doses and administer every 6 hours for 2 days; then decrease the daily requirement by 10% per day over the next 10 days (Sullivan 1993). Fixed dose taper: Initial 200 mg, followed by 100 mg every 4 hours for 5 doses, 60 mg every 4 hours for 4 doses, and then 60 mg every 8 hours for 3 doses (Kawasaki 2012).

(For additional information see "Phenobarbital: Pediatric drug information") Sedation: Note: Newer, shorter-acting agents may be preferable Manufacturer's labeling: IM, IV: Infants, Children, and Adolescents: Preoperative sedation: 1 to 3 mg/kg Oral: Children: 2 mg/kg/dose 3 times daily Alternative dosing (limited data available): Infants and Children: IM, Oral: 2 to 3 mg/kg/day in divided doses every 8 to 12 hours (Nelson 1996) Status epilepticus: Infants, Children, and Adolescents: IV: Initial: American Academy of Pediatrics recommendation: 20 mg/kg (maximum dose: 1000 mg) over 10 minutes; if necessary, may repeat dose after 15 minutes (maximum total dose: 40 mg/kg) (AAP [Hegenbarth 2008]). American Epilepsy Society recommendations: 15 mg/kg as a single dose. Note: AES recommends phenobarbital as a second line option only if first line options (lorazepam, diazepam, or midazolam) or other second line options (eg, fosphenytoin, valproic acid, levetiracetam) are unavailable (AES [Glauser 2016]). Neurocritical Care Society recommendation: 20 mg/kg (infused at 50 to 100 mg/minute); if necessary, may repeat once after 10 minutes with an additional 5 to 10 mg/kg (NCS [Brophy 2012]). Manufacturer’s labeling: 15 to 20 mg/kg over 10 to 15 minutes. Note: Additional respiratory support may be required particularly when maximizing loading dose or if concurrent sedative therapy. Repeat doses administered sooner than 10 to 15 minutes may not allow adequate time for peak CNS concentrations to be achieved and may lead to CNS depression. Seizures: Maintenance dose: Oral, IV: Note: Maintenance dose usually starts 12 hours after loading dose Manufacturer’s labeling: Infants, Children, and Adolescents: Oral: 3 to 6 mg/kg/day Alternative dosing (limited data available) (Geurinni 2006; Kliegman 2011): Initial: Oral, IV: Infants and Children ≤5 years: 3 to 5 mg/kg/day in 1 to 2 divided doses Children >5 years: 2 to 3 mg/kg/day in 1 to 2 divided doses Adolescents: 1 to 3 mg/kg/day in 1 to 2 divided doses (Nelson 1996) Usual dosing range: Oral, IV: Note: Dosage should be individualized based upon clinical response and serum concentration; once daily doses usually administered at bedtime in children and adolescents. Some centers have used: Infants: 5 to 6 mg/kg/day in 1 to 2 divided doses Children: 1 to 5 years: 6 to 8 mg/kg/day in 1 to 2 divided doses 5 to 12 years: 4 to 6 mg/kg/day in 1 to 2 divided doses Adolescents: 1 to 3 mg/kg/day in 1 to 2 divided doses (Nelson 1996)

Avoid use (Beers Criteria [AGS 2015]). If used, initiate at the lowest recommended dose. Refer to adult dosing.

There are no specific dosage adjustments provided in the manufacturer's labeling; reduced doses are recommended. The following guidelines have been recommended by some clinicians: Adults: CrCl ≥10 mL/minute: No dosage adjustment necessary (Aronoff 2007). CrCl Hemodialysis (moderately dialyzable [20% to 50%]): Administer dose before dialysis and 50% of dose after dialysis (Aronoff 2007). Peritoneal dialysis: 35% to 40% removed; administer 50% of normal dose (Aronoff 2007; Asconape 2014; Israni 2006). Continuous renal replacement therapy (CRRT): Administer normal dose and monitor levels (Aronoff 2007). Infants, Children, and Adolescents: Note: Renally adjusted dose recommendations are based on doses of 3 to 7 mg/kg/day every 12 to 24 hours GFR ≥10 mL/minute/1.73 m2: No dosage adjustment necessary (Aronoff 2007). GFR 2: Decrease normal dose by 50% and administer every 24 hours (Aronoff 2007). Intermittent hemodialysis: Moderately dialyzable (20% to 50%): Supplemental dose may be needed during and after dialysis depending on individual seizure threshold (Aronoff 2007). Peritoneal dialysis (PD): 40% to 50% removed; amount varies depending on number of cycles (Aronoff 2007). Continuous renal replacement therapy (CRRT): Monitor serum concentrations; a case report suggests that clearance and volume of distribution increased with CVVH; more frequent and higher dosing may be necessary in some cases (Pasko 2004).

There are no specific dosage adjustments provided in the manufacturer’s labeling; reduced doses are recommended. Phenobarbital exposure is increased with hepatic impairment; use with caution

Warnings & Precautions

Source: Lexicomp

CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Hypersensitivity

Exfoliative dermatitis and Stevens-Johnson syndrome, possibly fatal, may occur; discontinue if dermatological reactions occur.

Paradoxical stimulatory response

May cause paradoxical responses, including agitation and hyperactivity, particularly in patients with acute or chronic pain and pediatric patients.

Respiratory depression

May cause respiratory depression particularly when administered intravenously; use with caution patients with respiratory disease, including status asthmaticus. Disease-related concerns:

Anemia

Use with caution in patients with severe anemia.

Cardiac disease

Use with caution in patients with cardiac disease and in hemodynamically unstable patients (hypotension or shock).

Depression

Use with caution in patients with depression or suicidal tendencies.

Diabetes

Use with caution in patients with diabetes.

Drug abuse

Use with caution in patients with a history of drug abuse; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

Hepatic impairment

Use with caution in patients with hepatic impairment. Avoid use in patients showing the premonitory signs of hepatic coma.

Hyperthyroidism

Use with caution in patients with hyperthyroidism.

Hypoadrenalism

Use with caution in patients with hypoadrenalism.

Renal impairment

Use with caution in patients with renal impairment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Debilitated patients

Use with caution in patients who are debilitated.

Fever

Use with caution in patients with a fever.

Pediatric

Phenobarbital has been associated with cognitive deficits in children receiving therapy for complicated febrile seizures. Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates See manufacturer’s labeling.

Injection

Do not administer intra-arterially or subcutaneously. Avoid perivascular extravasation. Too rapid administration may cause severe respiratory depression, apnea, laryngospasm, hypertension or vasodilation with fall in blood pressure. Phenobarbital IV may require ≥15 minutes before reaching peak concentrations in the brain; injecting phenobarbital until the convulsions stop may lead to severe barbiturate induced depression. Intramuscular (IM) injection should be confined to a total volume of 5 mL and made in a large muscle in order to avoid possible tissue irritation. Discontinue injection in any patient who complains of limb pain.

Propylene glycol

Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007). Other warnings/precautions:

Acute pain

Use with caution in patients with acute or chronic pain; paradoxical excitement could be induced or important symptoms could be masked.

Withdrawal

Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Pregnancy & Lactation

Pregnancy

FDA category D Teratogenic

Caution

Use lowest effective dose. Folic acid 5 mg/day. Neonatal vitamin K. Gradual dose reduction should not be attempted during pregnancy if well-controlled

Lactation

Phenobarbital is excreted in breast milk. A delayed interest in breast-feeding may occur in infants exposed in utero. Infantile spasms and other withdrawal symptoms have been reported following the abrupt discontinuation of breast-feeding (Knott 1987). The manufacturer recommends that caution be exercised when administering phenobarbital to nursing women.

LactMed: monitor the infant.

Monitoring

Clinical pearl	Phenobarbital serum concentrations (as clinically indicated); CNS status; liver enzymes (periodic); CBC with differential (periodic); renal function (periodic); seizure activity; signs and symptoms of suicidality (eg, anxiety, depression, behavior changes) IV use: Respiratory rate, heart rate, blood pressure, IV site (stop injection if patient complains of pain in the limb)

Chemistry & Properties

Formula	C12H12N2O3
Molecular weight	232.24 g/mol
IUPAC name	5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione
CAS	50-06-6
PubChem CID	4763
InChIKey	`DDBREPKUVSBGFI-UHFFFAOYSA-N`
logP	0.7 (XLogP 1.5)
Polar surface area	75.27 Å²
H-bond acceptors / donors	3 / 2
Drug-likeness (QED)	0.74
Lipinski violations	0

SMILES

CCC1(c2ccccc2)C(=O)NC(=O)NC1=O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.12)

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Substrate	—
CYP2C19	Substrate	—
CYP2C9	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCT3 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)MRP2 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abemaciclib	major
Abiraterone	major
Acalabrutinib	major
Alpelisib	major
Apixaban	major
Apremilast	major
Artemether	major
Axitinib	major
Bortezomib	major
Bosutinib	major
Brigatinib	major
Cabozantinib	major
Ceritinib	major
Cobicistat	major
Cobimetinib	major
Codeine	major
Copanlisib	major
Crizotinib	major
Darolutamide	major
Dasatinib	major
Deflazacort	major
Dicoumarol	major
Eliglustat	major
Encorafenib	major
Entrectinib	major
Ethanol	major
Ethinylestradiol	major
Everolimus	major
Fedratinib	major
Fostamatinib	major
Glasdegib	major
Hemin	major
Hydrocodone	major
Ibrutinib	major
Idelalisib	major
Imatinib	major
Irinotecan	major
Irinotecan (liposomal)	major
Ivacaftor	major
Ivosidenib	major

Showing 40 of 100+.

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Phenotal Tablet	Tablet 60 mg	100 tab	Al Saleem Drug Store	2.910
Phenobarbitone B.P Tab.	Tablet 15 mg	1000 tab	The Arab Pharmaceutical Manufacturing PSC/Salt	20.400
Phenobarbitone B.P Tab.	Tablet 30 mg	1000 tab	The Arab Pharmaceutical Manufacturing PSC/Salt	25.200
Phenobarbitone	Tablet 60 mg	1000 tab	The Arab Pharmaceutical Manufacturing PSC/Salt	27.600
Neobital	Ampoule 200 mg/ml	10 ampoule	AL Rahma Drug Store	—