Additive CNS depression; both are CNS depressants acting on GABA receptors
Management: Expected combination for seizure management. Monitor for excessive sedation. Reduce doses if needed.
Phenobarbital induces hepatic enzymes, reducing ketoconazole levels; ketoconazole may increase phenobarbital levels
Management: Monitor both drug levels. May need dose adjustments.
Phenobarbital increases hepatic metabolism of thyroid hormones, potentially causing falsely low T4 levels
Management: Monitor T4 levels. May need to increase levothyroxine dose. Free T4 by equilibrium dialysis is more reliable.
Chloramphenicol inhibits hepatic enzymes, increasing phenobarbital levels; phenobarbital may reduce chloramphenicol levels
Management: Monitor phenobarbital levels. Dose adjustments may be needed.
Phenobarbital induces hepatic metabolism, potentially decreasing levetiracetam levels; dose adjustment may be needed
Management: Monitor seizure control closely. May need to increase levetiracetam dose by 30-50% when combined with phenobarbital.
Phenobarbital induces CYP3A4, increasing zonisamide clearance and reducing serum levels
Management: Monitor zonisamide levels. May need higher doses when used concurrently with phenobarbital.
Potassium Bromide
moderateAdditive CNS depression; combined use common but requires careful dose titration
Management: Standard combination for refractory epilepsy. Start bromide at lower dose and titrate. Monitor for excessive sedation.
Phenobarbital induces CYP enzymes, increasing methadone metabolism and reducing analgesic efficacy.
Management: May need to increase methadone dose or frequency. Monitor pain scores.
Phenobarbital induces hepatic metabolism of doxycycline, reducing doxycycline half-life and efficacy.
Management: Consider using higher doxycycline dose or alternative antibiotic not affected by enzyme induction (amoxicillin, enrofloxacin).
Phenobarbital induces hepatic metabolism, potentially altering methimazole clearance. Also, phenobarbital lowers total T4 (diagnostic confusion).
Management: Monitor thyroid levels more frequently. Adjust methimazole dose based on T4 response.
Phenobarbital induces hepatic metabolism, reducing digoxin bioavailability and increasing clearance.
Management: Monitor digoxin levels. May need digoxin dose increase.
Phenobarbital induces hepatic CYP enzymes, increasing metronidazole metabolism and reducing its efficacy.
Management: May need to increase metronidazole dose. Monitor clinical response.
Phenobarbital induces hepatic CYP3A4, potentially altering doxorubicin metabolism. Clinical significance in dogs is unclear but theoretical concern for altered drug levels.
Management: Monitor CBC more closely at nadir. Consult veterinary oncologist regarding dose adjustments.
Additive CNS depression when combining anticonvulsants. Phenobarbital enzyme induction does not significantly affect pregabalin (renally eliminated), but sedation is additive.
Management: Expected combination for refractory epilepsy. Start pregabalin at lower dose and titrate. Monitor sedation.
Phenobarbital induces CYP enzymes metabolizing warfarin, reducing anticoagulant effect.
Management: May need warfarin dose increase during phenobarbital therapy. Monitor PT/INR closely when adding or discontinuing phenobarbital.
Mitotane (o,p'-DDD)
moderateBoth are CYP enzyme inducers. Phenobarbital may accelerate mitotane metabolism, reducing its adrenolytic efficacy.
Management: May need higher mitotane dose. Monitor ACTH stimulation test response closely.
Phenobarbital induces CYP1A2, increasing theophylline metabolism and reducing therapeutic levels.
Management: May need to increase aminophylline dose. Monitor theophylline levels and clinical response.
Cannabidiol (CBD)
moderateCBD inhibits CYP2B11 and CYP2C19, reducing phenobarbital metabolism and increasing levels by 10-20%. Also, both cause sedation.
Management: Monitor phenobarbital levels at 2 and 4 weeks after adding CBD. Reduce phenobarbital dose if levels exceed therapeutic range. Monitor for excessive sedation.
Additive CNS depression. Phenobarbital induces CYP enzymes metabolizing clonazepam, potentially reducing clonazepam levels.
Management: Standard adjunct anticonvulsant combination. May need higher clonazepam dose with phenobarbital. Monitor sedation.
Additive CNS depression. Unlike diazepam, lorazepam is conjugated by glucuronidation (not CYP450), so phenobarbital enzyme induction has minimal effect on lorazepam levels.
Management: Standard anticonvulsant combination. Lorazepam preferred over diazepam when adding to phenobarbital (predictable levels). Monitor sedation.
Phenobarbital induces CYP3A4, increasing quinidine metabolism and reducing its antiarrhythmic efficacy.
Management: May need higher quinidine dose. Monitor quinidine levels and ECG response.
Phenobarbital may reduce dopamine's hemodynamic effects through CNS depression and altered autonomic reflexes.
Management: May need higher dopamine infusion rates. Titrate to effect using blood pressure and urine output as endpoints.
Phenobarbital induces hepatic CYP enzymes, increasing griseofulvin metabolism and reducing antifungal efficacy.
Management: May need higher griseofulvin dose. Monitor clinical response. Consider alternative antifungal (itraconazole, terbinafine) not affected by enzyme induction.
Phenobarbital induces CYP enzymes, potentially increasing leflunomide metabolism. Leflunomide is also hepatotoxic — additive liver injury risk with phenobarbital.
Management: Monitor hepatic enzymes closely. May need higher leflunomide dose.
Phenobarbital induces hepatic enzymes, potentially increasing minocycline metabolism (minocycline is more hepatically metabolized than doxycycline).
Management: Monitor clinical response. May need higher minocycline dose.
Phenobarbital induces CYP3A4, increasing topiramate clearance. May need higher topiramate dose for seizure control.
Management: Monitor seizure frequency. Adjust topiramate dose as needed.