Phenobarbital Pharmacokinetic Information and Dosing Calculator

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Phenobarbital Dosing Tool
Phenobarbital Dosing Calculator Using Population Dosing or Levels Under Steady State and Non-Steady State Conditions, Download
The Solver Add-in must be available for the file to run. In Excel do the following: Click File, Click Options, Click Add-ins, Manage Excel Add-in Click Go, Check Solver Add-in, and select OK

Phenobarbital Pharmacokinetic Dosing Information
Usage: FDA-approved for febrile seizures and all types of epilepsy except absence seizures. Non-FDA approved: preterm neonatal seizures due to intracranial hemorrhage, essential tremors in adults, and traumatic brain injury.  
Bioavailability (F):  IM, IV, Oral =1, Rectal  = 0.9
Salt (S): Injection 0.91; capsules, tablets, tablet, elixir = 1      
Route of Administration: IV, IM. oral, rectal (Injectable usually used)
Absorption: slow but complete absorption unaffected by food.
Distribution: Phenobarbital has low lipid solubility. Maximum brain-to-plasma contraptions occur after 60 minutes when IV loading doses are given. Effective brain concentrations are achieved within minutes.
Peak concentrations: oral ~ 2 hours, IM 3 hours, IV immediate, rectal quicker than oral
Protein binding: Neonates < 2 weeks 37%,  2 infants > = 2 weeks, children and adults 51%. Protein binding may be decreased in renal failure accompanied by acidosis.
Metabolism: Extensively metabolized without first-pass effects to inactive metabolites through N-glucoside and cytochrome P4502C9 and 2C19 metabolism. Low hepatic extraction ratio and changes in liver blood flow should not affect clearance.
Excretion: Unchanged drug renal excretion is urine flow and pH-dependent. Normally 20-40%  is excreted unchanged in the urine and can be increased by combined diuresis and alkalization of urine. Hepatic clearance and renal clearance usually offset each other when there is a decline in one or the other. Breast milk levels are approximately 40% of maternal serum levels which may produce therapeutic levels and toxicity in a nursing infant. Phenobarbital is removed by non high flux hemodialysis dialysis ~ 30%, high flux hemodialysis ~ 50%, and little information is available on peritoneal dialysis possibly 8-15% removal.  Renal replacement therapies remove phenobarbital and requires multiple daily doses to maintain therapeutic levels due to high clearance. 
Vd(L/kg): Neonates less than 2 weeks - 0.96 l/kg, infants & children 2 week - 19 years - 0.63 l/kg, adults greater than 19 years - 0.61 l/kg
Cl (L/hour): Clearance increases rapidly in the first 10 postnatal days. Clearance (L/hr/kg) declines from 1 year to 17 years of age. Increasing urine or plasma pH may increase clearance as phenobarbital is a weak acid. Thiese values do not match those calculated from the dosage guidelines below. Due to scarcity of published pharmacokinetic studies and the prolonged half-life of phenobarbital serial levels at weekly intervals is recommended to guide dosage until steady state is achieved.
    Neonates and infants less than 1 year: 0.0047 L/hr/kg
    Children 1 - 19 years: 0.0082 L/hr/kg
    Adults 19- 65 years: 0.0056 L/hr/kg 
    Geriatrics > 65 Years: 0.0024 L/hr/kg
K (1/hours): volume of distribution and clearance dependent
Half-life (hours): Half-life is dependent of volume of distribution and clearance
Dosage Forms:
  Injection, tablets, capsules, and elixir
Usual Interval:  once-daily usually in the evening, but may be divided. Bedtime dosing may help reduce sedative side effects.
Usual Loading and Maintenance Dose:


Age Loading Dose
Maintenance Dose
Calculated Clearance (L/kg/hour) assuming resulting level from maintenance dose is
20 mg/L
Neonates less than 2 weeks 15-25 2-4 0.00625
Infants 2 weeks - to less than 1 year 15-25 5 0.01042
Children  1 - < 5 years 10-20 4.5 0.009375
Children 5 - < 10 years 10-20 3.6 0.0075
10 - <  15 years 10 -20 2.9 0.006042
15 - < 19 years 10-20 2.5 0.005208
Adults 19-65 years 10-20 2 0.004167
Adults > 65 years 10-20 1.1-2 0.003229


Initiation of therapy:  To minimize side effects the dose in usually started at 25% of the final dose, and increased 25% each week until the goal dose is reached. As phenobarbital's half-life is very long, if a loading dose is not given, it will take 2-3 weeks or longer to achieve steady state levels.
Therapeutic Levels: 10-40 mcg/ml, but side effects, CNS depression and ataxia, may appear at the upper end of range.
Febrile Convulsions: 16-30 mg/L
     Hypoxic Ischemic seizures in neonates: > 30 mg/L then 20-30 mg/L after 24-48 hours
     Generalized tonic-clonic seizure: 10-25 mg/L
     Refractory Status Epileptics: >= 70 mg/L
     Cerebral Salvage from Hypoxic or Traumatic Brain Injury for Barbiturate Coma: > 75 mg/L
Serum Sampling Times and Recommended Monitoring: A peak 2-3 hours post loading dose, to allow distribution to complete, may be used to evaluate the need for further loading. Trough levels are recommended for monitoring so levels can be compared over time. Due to the long half-life samples should be drawn for up to 3-4 weeks to determine the steady state level. Weekly levels on initiation may be helpful to ensure levels do not go above the desired range.
Pharmacokinetic Model:  A linear one-compartment open model is adequate for dosage predictions. When levels are at steady state doses can be adjusted proportional to the desired concentration.
Side effects (concentration-dependent): Sedation, impaired cognition; decreased neonatal feeding, respirations, and muscle tone; sedation, slowness, and ataxia; coma
Side Effects (Non-concentration-dependent): folate deficiency, fetal vitamin K deficit from maternal phenobarbital therapy, gingival hyperplasia, vitamin D deficiency, shoulder-hand syndrome, hepatotoxicity
Common Drug interactions: Phenobarbital is a potent inducer of p-glycoprotein and CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP3A4, CYP2D6 enzymes.
     Decrease clearance (Clearance multiplier): Carbamazepine (0.91 in those > 65 years old) Chloramphenicol (0.6), Phenytoin (0.8 in those > 65 years), Valproic acid (0.5-0.7, 2000 mg daily and 1000 mg daily), 
     Increased clearance (Clearance multiplier): Pyridoxine (1.4), Rifampin (> 1), Thioridazine /mesoridazine/phenothiazines (1.3)
      Alkalinization of urine and forced diuresis (> 1)
Disease state or physiologic condition interactions:
     Decrease clearance: cirrhosis, severe renal failure, hepato-renal syndrome,
     Increase clearance: continuous renal replacement therapy (large increase in clearance), hemodialysis (30% removal), peritoneal dialysis (7.5-15% removal), pregnancy  

Dosage Calculations:

BMI: Actual Body Weight / (Height in meters)^2

Body Weight Calculations:
Ideal Body Weight
IBW(kg)  (Devine Formula) Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches greater than 60 inches)
IBW(kg) (Devine Formula) Adult Female (18 years and older): 45.5 + 2.3*(Height in inches greater than 60 inches)

Fat-Free Mass (Janmahasatian Formula):
FFM(kg) Adult Males    = 9270 * Actual Body Weight(kg) / (668 + (216* BMI))
FFM(kg) Adult Females = 9270 * Actual Body Weight(kg) / (8780 / (244*(BMI))

Body Surface Area in Meters Squared = ((Weight in kg)^0.425)*((Height in centimeters)^0.725)*(71.84/10000)

Dosing Weight(kg) =  Total body weight for Vd and clearance calculation, but little to no data is available for obese patients (one case study report Wilkes, L., Danziger, L.H. & Rodvold, K.A. Phenobarbital Pharmacokinetics in Obesity. Clin. Pharmacokinet. 22, 481–484 (1992). A cautious approach to dosing and monitoring is recommended in obesity.
Clearance(L/hr) = clearance(L/hour/kg) * dosing weight(kg)
Vd(L) = Vd(L/kg)* Dosing weight(kg)
K(1/hours) = Clearance / Vd
Maintenance Dose
(mg) = Cpaverage(mg/L) * Tau(Hours) * Clearance(L/hr) / (Fraction*Salt)
Cpssaverage(mg/L) = Salt * Fraction * Dose(mg) / (Clearance(L/hr) * Tau)
Cpssmaximum(mg/L) = Salt * Fraction * Dose(mg) / (Vd(L) * (1-exp(-K*Tau)))
Cpssminimum(mg/L) = Cpmaximum(mg/L) * exp(-K*Tau)
Time to Level from start of dosing (days) = - Ln(1 - (level / Css average)) / (K(1/hours)*24)
Time to Fraction of Steady State (days) = Ln (1- (Fraction of Steady State to Achieve)) / (K(1/hours) * 24)
Time(days) from Known Level to Fraction of Steady State to Achieve =
     Ln[ (1-(Fraction of Steady State to Achieve)) / ( 1- (Current Level / Steady State Level))] / (K*24)
Cp(mg/L) = (S*F*Dose(mg)* (1-Exp(-KNTau))*Exp(-KT)) / (Vd(L)*(1*Exp(-KTau))), where N equals number of doses given

Phenobarbital Dosing Calculator Using Population Dosing or Levels Under Steady State and Non-Steady State Conditions, Download
The Solver Add-in must be available for the file to run. In Excel do the following: Click File, Click Options, Click Add-ins, Manage Excel Add-in Click Go, Check Solver Add-in, and select OK.


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