IDEXX Catalyst Dx® Chemistry Analyzer
Phenobarbital Toxicity and Testing
by William D. Saxon, DVM, DACVIM, DACVECC and
Michelle Frye, DVM, SM
Introduction
Phenobarbital is the most commonly used first-line antiepileptic drug (AED) in dogs and
cats. It is used to treat idiopathic epilepsy (seizures for which no cause can be identified)
and is effective in patients with symptomatic epilepsy (e.g., brain tumor, inflammatory CNS
disease, post-trauma) or presumed symptomatic epilepsy (organic cause suspected but
not proven). As a single agent, it controls seizures in 60%–80% of epileptic dogs and in
most cats.1, 2
Risks
Though generally well-tolerated, side effects may include transient mild sedation during
the first 1–2 weeks of therapy, polyuria/polydipsia and polyphagia with weight gain. Bone
marrow suppression resulting in pancytopenia is a rare idiosyncratic reaction that resolves
with discontinuation of the drug. In cats, facial pruritus, limb edema and blood dyscrasias
rarely may occur and resolve with discontinuation of phenobarbital. Superficial necrolytic
dermatitis is a rare, serious side effect with a poor prognosis.
Hepatotoxicity is the most serious potential side effect of phenobarbital in dogs (not cats)
and may result in significant elevation in liver enzymes and lead to chronic inflammation,
cirrhosis, or hepatocutaneous syndrome. The incidence of hepatotoxicity has decreased
due to heightened awareness and increased therapeutic drug monitoring. The risk of
hepatotoxicity can be further minimized with appropriate pretreatment evaluation followed
by regular monitoring of liver enzymes and phenobarbital serum concentration during
therapy. Phenobarbital can also increase liver enzymes by induction. In order to determine
if liver function is compromised, a bile acids test is recommended.
Protocol and Dosage
Prior to starting administration of phenobarbital, every attempt should be made to
identify and treat any primary intracranial disease, such as neoplasia or granulomatous
meningoencephalitis. A baseline CBC, biochemical profile and urinalysis are performed
to rule out extracranial causes of seizures (e.g., hypoglycemia and hypocalcemia), and
to determine if there are contraindications to phenobarbital use, such as preexisting
liver disease.
The starting oral dose of phenobarbital in dogs and cats is 2.5–3.0 mg/kg, twice a day.
Steady state serum levels are achieved 2–4 weeks after beginning oral therapy. When
rapid control of seizures is necessary, phenobarbital is given intravenously at 2–6 mg/kg,
up to the maximum loading dose of 16 mg/kg in 24 hours. Phenobarbital is not an
effective treatment for status epilepticus because it takes 15–20 minutes after intravenous
administration to reach effect.
References:
1. Farnbach GC. Serum concentrations and efficacy of phenytoin, phenobarbital and primidone in canine epilepsy. JAAHA. 1988;184(9):1117–1120.
2. Schwartze-Porsche D, Loscher W, Frey HH. Therapeutic efficacy of phenobarbital and primidone in canine epilepsy. JAVMA. 1985;8(2):113–119.
Treatment and
Monitoring
Monitoring patients on phenobarbital is important to optimize dose, minimize side effects
and avoid hepatotoxicity. A serum phenobarbital level is obtained 2–4 weeks after beginning
therapy and every 6–12 months thereafter. In well-controlled patients, once steady state
is achieved, the timing of blood draw relative to dosing is not important. In patients with
breakthrough seizures, peak (4–8 hour after dose) and especially trough (right before dose)
levels may help determine if a change in dosage or frequency of administration is indicated.
Serum separator tubes should not be used, as drug binding to the gel may falsely lower
phenobarbital concentration. Additional monitoring includes a CBC and biochemical profile
when the first phenobarbital level is drawn and then every 6–12 months.
The desired therapeutic range is 15–45 µg/mL in dogs and 23–30 µg/mL in cats. In dogs,
maintaining phenobarbital levels between 20–35 µg/mL will lead to optimal seizure control
while minimizing the risk of hepatotoxicity.
Adjusting phenobarbital levels
To adjust the dose of phenobarbital, increase or decrease in 5 µg/mL increments to
30–35 µg/mL (dog) and in 3 µg/mL increments to a maximum of 25 µg/mL (cat)
according to the following formula:*
New dose = desired new concentration/current concentration x total current mg phenobarbital
Example
A
30-kg German shepherd currently receives 60 mg of phenobarbital
twice a day. Seizures are increasing in frequency and severity.
Current phenobarbital level is 20 µg/mL.
New dose = 25 µg/mL/20 µg/mL x 60 = 75 mg twice a day
*If there is no phenobarbital level available, increase or decrease the dose by 25%.
If seizures continue and trough phenobarbital level is low, increasing to three times daily
administration of the current dose may be effective.
A phenobarbital level should be taken 2–4 weeks after any dosage adjustment.
If severe hepatotoxicity or bone marrow suppression develop, immediate withdrawal or
rapid taper (over a few days) is necessary. To prevent breakthrough seizures, this must be
accompanied by the institution of another AED, such as potassium bromide (KBr), using a
loading dose of 400–600 mg/kg divided over 4 doses, zonisamide at 10 mg/kg twice a day,
or levetiracetam at 20 mg/kg three times a day.
If seizures are not adequately controlled when the target phenobarbital level is obtained,
adding a second AED is indicated. Options include KBr, zonisamide, levetiracetam
(Keppra®) and pregabalin/gabapentin.
Phenobarbital therapy usually is lifelong. In patients that remain seizure-free for
6–12 months, a gradual taper—25% dose reduction every 1–2 months—can be
attempted. Careful monitoring of phenobarbital levels and liver status will ensure safe
and effective treatment.
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