Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital.
1. Anticoagulants: Gardenal lowers the plasma levels of dicumarol (name previously used: bishydorxycoumarin) and
causes a decrease in anticoagulant activity as measured by the prothrombin time. Gardenal can induce hepatic
microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g.,
warfarin, acenocournarol, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage
adjustments if phenobarbital is added to or withdrawn from their dosage regimen.
2. Corticosteroids: Gardenal appears to enhance the metabolism of exogenous corticosteroids probably through the
induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments
if phenobarbital is added to or withdrawn from their dosage regimen.
3. Griseofulvin: Gardenal appears to interfere with the absorption of orally administered griseofulvin, thus
decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response
has not been established. However, it would be preferable to avoid concomitant administration of these drugs.
4. Doxycycline: Gardenal has been shown to shorten the half- life of doxycycline for as long as 2 weeks after
barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that
metabolize the antibiotic. If phenobarbital and doxycycline are administered concurrently, the clinical response to
doxycycline should be monitored closely.
5. Phenytoin, sodium valproate, valproic acid: The effect of phenobarbital on the metabolism of phenytoin appears to be
variable. Some investigators report an accelerating effect, while others report no effect. Because the effect of
phenobarbital on the metabolism of phenytoin is not predictable, phenytoin and phenobarbital blood levels should be
monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid appear to decrease
phenobarbital metabolism; therefore, phenobarbital blood levels should be monitored and appropriate dosage adjustments
made as indicated.
6. Central nervous system depressants: The concomitant use of other central nervous system depressants including other
sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects.
7. Monoamine oxidase inhibitors (MAOIs): MAOIs prolong the effects of phenobarbital probably because metabolism of the
phenobarbital is inhibited.
8. Estradiol, estrone, progesterone and other steroidal hormones: Pretreatment with or concurrent administration of
phenobarbital may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients
treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. An alternate
contraceptive method might be suggested to women taking phenobarbital.