Version July 2025
Concomitant use of phenobarbital products and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. If a decision is made for concomitant use of these drugs, limit dosages and durations to the minimum required, and follow patients for signs and symptoms of respiratory depression and sedation.
The continued use of phenobarbital may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although indicated only for short-term use, if used for a longer duration than recommended, abrupt discontinuation or rapid dosage reduction may precipitate acute withdrawal reactions, which can be life-threatening. For patients receiving for longer duration than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue use.
Not approved for use in adolescents or adults. The unapproved use, in adolescents and adults exposes them to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of phenobarbital commonly involve concomitant use of other drugs, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes.
Alcohol withdrawal syndrome , severe or refractory withdrawal (off-label use) (adjunctive agent):
Note: For use in severe or refractory withdrawal (eg, delirium tremens) despite benzodiazepine therapy. Safety: Use only by clinicians experienced with phenobarbital therapy in settings (eg, critical care or emergency department) with monitoring for adverse effects (eg, oversedation, respiratory compromise) (Ref). Consider dose reduction in patients at risk for oversedation or respiratory compromise (Ref). Optimal dosing and regimens have not been identified; refer to institutional protocols.
Example regimens are presented below:
IV: Initial: 130 mg or 260 mg once, followed by 130 mg every 15 to 30 minutes as needed until resolution of symptoms. Once symptoms are controlled, use maintenance dose of 130 to 260 mg/day in 2 to 3 divided doses for 3 to 5 days (Ref). Maximum dose has not been established; some experts do not exceed cumulative doses of 15 mg/kg within the first 24 hours (Ref).
IM (use only if IV access is not available): 60 to 260 mg as a single dose (Ref).
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 (Ref).
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 (Ref).
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: Usual dosage range (limited data available): 2 mg/kg/day in divided doses (Ref). 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 (Ref).
Manufacturer's labeling: Oral: Dosing in the prescribing information may not reflect current clinical practice. 60 to 200 mg/day or 50 to 100 mg 2 to 3 times daily.
Sedative/hypnotic withdrawal (off-label use): Several regimens have been evaluated:
Taper following dosage conversion: Oral: 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 (Ref).
Fixed dose taper: Oral: 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 (Ref).
Discontinuation of therapy: When discontinuing chronic therapy, gradually taper dose over ≥6 months (eg, may reduce dose in decrements of 10% to 25% of original dose on a monthly basis) to minimize risk of withdrawal syndrome, including increased seizure frequency (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: When 1 or 2 doses are administered in urgent settings (eg, status epilepticus), no dosage adjustment is necessary for any degree of kidney dysfunction or in patients receiving kidney replacement therapies (Ref).
Altered kidney function:
eGFR ≥10 mL/minute/1.73 m2: Oral, IV, IM: No dosage adjustment necessary; individualize dosage regimen based upon clinical response and serum concentrations (Ref).
eGFR <10 mL/minute/1.73 m2: Oral, IV, IM: Administer 50% to 66% of the usual indication-specific dose; individualize dosage regimen based upon clinical response and serum concentrations (Ref).
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal SCr concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).
Oral, IV, IM: No data available; no dosage adjustment necessary; individualize dosage regimen based upon clinical response and serum concentrations (Ref).
Hemodialysis, intermittent (thrice weekly): Dialyzable (~40% removal reported in overdose situations) (Ref):
Oral, IV, IM: Administer 50% to 66% of the usual indication-specific dose; individualize dosage regimen based upon clinical response and serum concentrations (Ref).
Supplemental dose: Patients at moderate to high risk of seizures may require a supplemental dose of ~50% of the usual dose given after the hemodialysis session; patients suffering intradialytic seizures may need the supplemental dose to be administered prior to hemodialysis (Ref). Consider obtaining pre- and post-hemodialysis phenobarbital serum concentrations to further individualize the necessary supplemental dose (Ref).
Peritoneal dialysis: Dialyzable (35% in one case report) (Ref):
Oral, IV, IM: Administer 50% to 66% of the usual indication-specific dose; individualize dosage regimen based upon clinical response and serum concentrations (Ref).
CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, for seizure control, sedation) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, respiratory depression) due to drug accumulation is important.
Oral, IV, IM: Significant removal by CRRT may occur. No dosage adjustment necessary; individualize dosage regimen based upon clinical response and serum concentrations (Ref).
PIRRT ( eg , sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, for seizure control, sedation) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, respiratory depression) due to drug accumulation is important.
Oral, IV, IM: Administer 50% to 66% of the usual indication specific dose; individualize dosage regimen based upon clinical response and serum concentrations (Ref).
Supplemental dose: Patients at moderate to high risk of seizures may require a supplemental dose of ~50% of the usual dose given after the PIRRT session; patients suffering intradialytic seizures may need the supplemental dose to be administered prior to PIRRT. Removal by PIRRT will be variable based on effluent flow rates and treatment duration, so it will be necessary to utilize pre- and post-PIRRT phenobarbital serum concentrations to further individualize the necessary supplemental dose (Ref).
The liver dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FCCP, FAST; Jeong Park, PharmD, MS, BCTXP, FCCP, FAST; Arun Jesudian, MD; Sasan Sakiani, MD.
Note: In a small pharmacokinetic study, the elimination half-life of phenobarbital is significantly prolonged in patients with cirrhosis (~130 hours), especially in the setting of hypoalbuminemia, as compared to healthy controls (~86 hours); moreover, accumulation of phenobarbital occurs with repeat dosing in healthy individuals, which is expected to be more pronounced in the setting of cirrhosis (Ref).
Liver impairment prior to treatment initiation:
Initial or dose adjustment in patients with preexisting liver cirrhosis:
Note: Although the manufacturer’s labeling states use of phenobarbital in patients with marked liver impairment is contraindicated, initiation in patients with preexisting liver cirrhosis may be considered if the benefits outweigh the risks but should only occur in a monitored setting where an advanced airway is available (eg, a hospital); an alternative agent should be considered based on indication (Ref). Monitor for oversedation and/or worsening encephalopathy during use and following dose titration (Ref).
Child-Turcotte-Pugh class A: Oral, IV, IM: Initial: No dosage adjustment necessary (Ref); use with caution. Individualize dosage regimen based upon clinical response and serum concentrations (Ref).
Child-Turcotte-Pugh class B and C:
Loading dose: Avoid unless required to rapidly achieve steady-state concentration (Ref).
Maintenance dose: Oral, IV, IM: Administer 50% of the usual indication-specific dose (Ref); use with caution. Individualize dosage regimen based upon clinical response and serum concentrations (Ref).
Avoid use (Ref).
(For additional information see "Phenobarbital: Pediatric drug information")
Seizures, maintenance therapy:
Note: Phenobarbital as monotherapy is effective for the management of focal-onset or generalized tonic-clonic seizures (Ref). Maintenance dose usually starts 12 hours after loading dose. Dosage should be individualized based upon clinical response and serum concentration; once-daily doses usually administered at bedtime in children and adolescents.
Infants and Children ≤5 years: Oral: 3 to 5 mg/kg/day in 1 to 2 divided doses (Ref).
Children >5 years and Adolescents: Oral: 2 to 3 mg/kg/day in 1 to 2 divided doses (Ref).
Status epilepticus (alternate agent): Infants, Children, and Adolescents: IV: Initial: 15 to 20 mg/kg; maximum dose: 1,000 mg/dose; may repeat with an additional 5 to 10 mg/kg 10 minutes after loading dose (Ref). 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.
Hyperbilirubinemia: Limited data available; efficacy results variable (Ref): Infants and Children: Oral: Usual range: 3 to 8 mg/kg/day in 2 to 3 divided doses; doses up to 10 mg/kg/day in divided doses have been used in case reports (Ref); for the treatment of hyperbilirubinemia in Crigler-Najjar Syndrome, a dose of 5 mg/kg/day has been used to reduce serum bilirubin concentrations (Ref); not recommended for management of biliary cirrhosis due to sedation and other adverse effects (Ref).
Conversion of PENTobarbital to PHENobarbital (withdrawal prevention) (Ref): Note: For use when total cumulative PENTobarbital dose is ≥25 mg/kg or duration ≥5 to 7 days; this conversion method is based on preliminary data in mechanically-ventilated patients. Closely monitor respiratory status and evaluate patient for withdrawal symptoms.
Infants, Children, and Adolescents: Limited data available: Note: Dosing is based on last PENTobarbital dose.
Discontinue PENTobarbital infusion; administer half of the PHENobarbital IV loading dose 6 hours after discontinuation of PENTobarbital infusion; 6 hours later, administer the second half of the PHENobarbital IV loading dose; administer each loading dose over 1 hour.
Loading dose: Based on last pentobarbital dose as follows: IV:
|
PENTobarbital Infusion Rate (mg/kg/hour) |
PHENobarbital IV Total Loading Dose (mg/kg) |
|---|---|
|
1 to 2 |
8 |
|
2 to 3 |
15 |
|
3 to 4 |
20 |
Maintenance dose: IV: Begin 6 hours after total loading dose completed: Maintenance dose is 1/3 of initial loading dose every 12 hours. Once patient is stabilized, may switch to oral therapy and begin tapering 10% to 20% weekly (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No specific dosage adjustment provided in manufacturer's labeling; reduced doses are recommended. The following guidelines have been used by some clinicians (Ref):
Infants, Children, and Adolescents: Note: Renally adjusted dose recommendations are based on doses of 3-7 mg/kg/day every 12-24 hours
GFR ≥10 mL/minute/1.73 m2: No adjustment necessary
GFR <10 mL/minute/1.73 m2: Decrease normal dose by 50% and administer every 24 hours
Intermittent hemodialysis [moderately dialyzable (20% to 50%)]: Supplemental dose may be needed during and after dialysis depending on individual seizure threshold
Peritoneal dialysis (PD): 40% to 50% removed; amount varies depending on number of cycles
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 (Ref).
There are no specific dosage adjustments provided in manufacturer's labeling. Phenobarbital exposure is increased with hepatic impairment; reduced doses are recommended; use with caution.
Barbiturates, including phenobarbital, may cause cardiovascular (CV) adverse reactions such as hypotension and bradycardia (Ref) in all ages. Evidence is limited to rare studies that suggest a negative effect of IV barbiturates on cardiac function (Ref). Hypotension requiring fluid resuscitation and vasopressor use was reported in 32% of adult patients receiving continuous IV pentobarbital (Ref). Another study in adults receiving IV thiopental reported a 30% to 40% decrease in cardiac index (Ref). A direct depressant effect on contractility of the left ventricle with a transient decrease in systolic blood pressure was reported in up to 30% of children receiving IV phenobarbital; a return to baseline was observed within 12 to 24 hours of the loading dose and prior to initiation of the maintenance dose (Ref).
Mechanism: Not clearly established; left ventricular dysfunction with decreased ejection fraction due to direct depression of myocardial function (Ref).
Onset: Rapid; occurred 30 minutes after an IV loading dose in one study (Ref).
Risk factors:
• IV formulation (Ref)
• Rapid IV administration
• Preexisting left ventricular dysfunction (Ref)
• Coronary artery disease (Ref)
• Concurrent benzodiazepines (Ref)
Phenobarbital may cause CNS adverse reactions, including drowsiness, ataxia, vertigo, cognitive dysfunction, changes in thinking, and memory impairment, in all ages (Ref). Phenobarbital, like other antiseizure medications, may lead to a cerebellar syndrome (Ref). Patients with dementia may experience cognitive adverse reactions on relatively low doses more frequently than patients without dementia (Ref). Incidence of CNS adverse reactions is unclear; one study described subjective cognitive impairment as “common” in patients with epilepsy on antiseizure medications that may lead to dosage change or discontinuation in >10% of patients (Ref). Some data suggest more cognitive adverse reactions with phenobarbital compared to other antiseizure medications (eg, phenytoin, carbamazepine, levetiracetam, valproate) (Ref). In pediatric patients, phenobarbital has been shown to decrease cognitive performance, increase behavioral changes (including ADHD), and has long-term negative effects on learning ability (Ref); adverse neurodevelopmental outcomes have also been reported in neonates (Ref). Drowsiness is mostly transient, persisting for days to weeks (Ref). Patients may also experience paradoxical central nervous system stimulation (Ref).
Mechanism: Dose-related; related to the pharmacologic action (Ref); depresses the sensory cortex, motor activity, and cerebellar function.
Onset: Drowsiness often occurs with phenobarbital initiation (Ref).
Risk factors:
• Higher doses/higher serum concentrations (Ref)
• Comorbid dementia (Ref)
Phenobarbital is associated with a variety of delayed hypersensitivity reactions, ranging from mild with maculopapular rash to severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) (often referred to as a hypersensitivity syndrome) in all ages (Ref). In cases of DRESS, long-term complications may arise after drug discontinuation including type 1 diabetes mellitus and alopecia areata universalis (Ref).
Mechanism: Non–dose-related; immunologic. Delayed hypersensitivity reactions, including maculopapular eruptions and SCARs, are T-cell-mediated (Ref). Accumulation of toxic arene oxide metabolite due to a defect in epoxide hydrolase-mediated detoxification may lead to cell necrosis or apoptosis or may initiate secondary immunological responses (Ref).
Onset: Delayed hypersensitivity reactions: Varied; maculopapular rash usually occurs 3 to 20 days following initiation of therapy (Ref). SCARs usually occur 1 to 8 weeks after initiation (Ref); re-exposure may lead to more rapid onset (usually with 1 to 4 days) (Ref).
Risk factors:
• Genetic factors: HLA-B*13:01 may increase risk of SCARs in Thai children (Ref); HLA-B*1502 may increase risk of SJS in Han Chinese (Ref).
• Family history of DRESS to an aromatic anticonvulsant (eg, phenytoin, carbamazepine, phenobarbital): An increased risk has been suggested, although one study showed that phenobarbital may be tolerated in some family members who develop reactions to phenytoin (Ref)
• Reactivation of viruses: Viral reactivation, in particular human herpesvirus 6 (HHV-6) reactivation may be associated with a prolonged and more severe course of DRESS (Ref).
• Cross-reactivity: High degree of cross-reactivity exists between aromatic antiseizure medications, including phenytoin, carbamazepine, phenobarbital, primidone, and oxcarbazepine (Ref).
• Age: Pediatric patients <12 years and older adult patients may be at risk for severe SCARs associated with aromatic antiseizure medications, including phenobarbital (Ref)
• Radiation therapy (especially cranial irradiation): May increase the risk of cutaneous reactions, including erythema multiforme and SJS/TEN (Ref)
Phenobarbital may cause respiratory depression, a known adverse reaction of phenobarbital in all ages (Ref). Incidence is unclear; one study in pediatric patients with status epilepticus found 1 out of 30 patients developed respiratory depression that required bag and mask ventilation (Ref). In another retrospective review of eight adult patients who received phenobarbital for status epilepticus (5 to 19.8 mg/kg), none required intubation but one needed supplemental oxygen (Ref).
Mechanism: Dose-related; at high concentrations, phenobarbital has been found to directly activate GABA-A receptors even in the absence of GABA (Ref).
Onset: Rapid; immediately after administration of high dose IV formulation (Ref).
Risk factors:
• Higher doses
• Rapid IV administration
• Preexisting obstructive lung disease
• Concurrent use of benzodiazepines and opioids (Ref)
• Concurrent use of antiseizure medications (Ref)
Antiseizure medications have been associated with suicidal ideation and suicidal tendencies in all ages (Ref). However, the FDA meta-analysis has been criticized due to several important limitations (Ref). The risk of suicide is increased in epilepsy (Ref), but the occurrence of suicidal ideation/tendencies in epilepsy is multi-factorial. While some antiseizure medications (but not all) have been associated with treatment-emergent psychiatric effects such as anxiety and depression, other factors such as post-ictal suicidal behavior and pertinent patient history must also be evaluated to provide an accurate assessment of risk for any individual drug (Ref). A cohort of 28 children with epilepsy showed that treatment with phenobarbital compared with carbamazepine or no antiseizure medication, was associated with higher rates of depression (38% vs 0%) (Ref). Patients with a history of depression treated with phenobarbital whose medication was changed to carbamazepine or no medication showed nonsignificant trends toward declines in both the frequency and severity of depression (Ref).
Onset: Varied; peak incidence of suicidality across antiseizure medications (not specific to individual agents) has been noted to occur between 1 and 12 weeks of therapy (Ref). A review of clinical trials noted that risk extended from 1 week to 24 weeks of therapy, corresponding to the duration of most trials.
Risk factors:
• History of depression (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Hypotension (neonates: 16%) (table 1)
|
Drug (Phenobarbital) |
Comparator (Levetiracetam) |
Population |
Dosage Form |
Indication |
Number of Patients (Phenobarbital) |
Number of Patients (Levetiracetam) |
|---|---|---|---|---|---|---|
|
16% |
0% |
Neonates |
IV |
Seizures |
32 |
19 |
Gastrointestinal: Change in appetite (feeding disorder; neonates: 16%) (table 2)
|
Drug (Phenobarbital) |
Comparator (Levetiracetam) |
Population |
Dosage Form |
Indication |
Number of Patients (Phenobarbital) |
Number of Patients (Levetiracetam) |
Comments |
|---|---|---|---|---|---|---|---|
|
16% |
5% |
Neonates |
IV |
Seizures |
32 |
19 |
Feeding disorder |
Nervous system: Sedated state (neonates: 16%) (table 3)
|
Drug (Phenobarbital) |
Comparator (Levetiracetam) |
Population |
Dosage Form |
Indication |
Number of Patients (Phenobarbital) |
Number of Patients (Levetiracetam) |
|---|---|---|---|---|---|---|
|
16% |
5% |
Neonates |
IV |
Seizures |
32 |
19 |
Respiratory: Changes in respiration (neonates: 25% [including respiratory depression and respiratory insufficiency]) (table 4)
|
Drug (Phenobarbital) |
Comparator (Levetiracetam) |
Population |
Dosage Form |
Indication |
Number of Patients (Phenobarbital) |
Number of Patients (Levetiracetam) |
Comments |
|---|---|---|---|---|---|---|---|
|
25% |
5% |
Neonates |
IV |
Seizures |
32 |
19 |
Including respiratory depression and respiratory insufficiency |
1% to 10%:
Cardiovascular: Bradycardia (neonates: 3%) (table 5)
|
Drug (Phenobarbital) |
Comparator (Levetiracetam) |
Population |
Dosage Form |
Indication |
Number of Patients (Phenobarbital) |
Number of Patients (Levetiracetam) |
|---|---|---|---|---|---|---|
|
3% |
0% |
Neonates |
IV |
Seizures |
32 |
19 |
Endocrine & metabolic: Hyponatremia (neonates: 3%) (table 6)
|
Drug (Phenobarbital) |
Comparator (Levetiracetam) |
Population |
Dosage Form |
Indication |
Number of Patients (Phenobarbital) |
Number of Patients (Levetiracetam) |
|---|---|---|---|---|---|---|
|
3% |
0% |
Neonates |
IV |
Seizures |
32 |
19 |
Frequency not defined:
Cardiovascular: Circulatory shock, syncope
Dermatologic: Alopecia (areata universalis; associated with hypersensitivity syndrome) (Huang 2009), eczema, exfoliative dermatitis, fixed drug eruption (Chadly 2014), maculopapular rash (Nafei 2019), Stevens-Johnson syndrome (Mockenhaupt 2005), toxic epidermal necrolysis (Mockenhaupt 2005)
Endocrine & metabolic: Type 1 diabetes mellitus (associated with hypersensitivity syndrome) (Zou 2008), vitamin D deficiency (Hahn 1972)
Gastrointestinal: Constipation, nausea, vomiting
Hematologic & oncologic: Leukemoid reaction (associated with hypersensitivity syndrome) (Zeng 2013), megaloblastic anemia, thrombocytopenia (associated with hypersensitivity syndrome) (Nafei 2019)
Hepatic: Hepatotoxicity
Hypersensitivity: Angioedema, drug reaction with eosinophilia and systemic symptoms (Baruzzi 2003)
Local: Injection-site reaction
Nervous system: Agitation, anxiety, ataxia (Iivanainen 1983), behavioral changes (Gaitatzis 2003, Wolf 1978), central nervous system depression (Iivanainen 1983), changes in thinking (Iivanainen 1983), cognitive dysfunction (Calendre 1990, Farwell 1990, Gaitatzis 2003), confusion, decreased deep tendon reflex (absent), depression (Brent 1990), dizziness, drowsiness (Iivanainen 1983), hallucination, hangover effect, headache, hypotonia, impaired consciousness, insomnia, lethargy, memory impairment (Iivanainen 1983), nervousness, neurological abnormality, nightmares, paradoxical central nervous system stimulation (Verrotti 2018), psychiatric disturbance, vertigo, withdrawal syndrome (with longer duration of use than recommended)
Neuromuscular & skeletal: Hyperkinetic muscle activity, laryngospasm, osteomalacia, rheumatism (Jha 2020)
Renal: Renal insufficiency
Respiratory: Apnea, hypoventilation
Miscellaneous: Fever
Hypersensitivity to phenobarbital, barbiturates, or any component of the formulation; marked hepatic impairment; dyspnea or airway obstruction; porphyria (manifest and latent).
Additional contraindications: Solution for injection: Intra-arterial or SUBQ administration; use in patients with a history of sedative/hypnotic substance use disorder; nephritic patients (large doses).
Disease-related concerns:
• Anemia: Use with caution in patients with severe anemia.
• Diabetes: Use with caution in patients with diabetes.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Hyperthyroidism: Use with caution in patients with hyperthyroidism.
• Hypoadrenalism: Use with caution in patients with hypoadrenalism.
• Porphyria: Sezaby: May precipitate life-threatening, acute attacks of porphyria in patients with acute porphyria; symptoms may include abdominal pain, anxiety, confusion, hyponatremia, limb pain, muscle weakness, and seizures.
• Renal impairment: Use with caution in patients with renal impairment.
• Substance use disorder: Use with caution in patients with a history of substance use disorder; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.
Special populations:
• Bariatric surgery: Presurgical assessment of the indication for use, symptoms, and goals of therapy should be documented to enable postsurgical assessment. A single case report discusses breakthrough seizures post–Roux-en-Y gastric bypass in a patient maintained on the same dose of phenobarbital as before surgery (Pournaras 2011). Consider therapeutic drug monitoring before and after bariatric surgery. Monitor for continued efficacy after bariatric surgery and consider switching to an alternate medication if symptoms worsen.
• Debilitated patients: Use with caution in patients who are debilitated.
• Fever: Use with caution in patients with a fever.
• Pediatric: May cause paradoxical responses, including agitation and hyperactivity. 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: Avoid perivascular extravasation or intra-arterial injection due to highly alkaline nature. Discontinue use with signs of discoloration, pain, swelling, or temperature change in the limb. 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.
• 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: Antiseizure medications 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.
Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Phenobarbital elixir and oral solutions contain 15% alcohol.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Elixir, Oral:
Generic: 20 mg/5 mL (5 mL, 473 mL); 30 mg/7.5 mL (7.5 mL); 60 mg/15 mL (15 mL)
Solution, Injection, as sodium:
Generic: 65 mg/mL (1 mL); 130 mg/mL (1 mL)
Solution Reconstituted, Intravenous, as sodium [preservative free]:
Sezaby: 100 mg (1 ea)
Tablet, Oral:
Generic: 15 mg, 16.2 mg, 30 mg, 32.4 mg, 60 mg, 64.8 mg, 97.2 mg, 100 mg
May be product dependent
Elixir (PHENobarbital Oral)
20 mg/5 mL (per mL): $0.19 - $1.14
Solution (PHENobarbital Sodium Injection)
65 mg/mL (per mL): $21.00 - $31.62
130 mg/mL (per mL): $43.20 - $82.08
Solution (reconstituted) (Sezaby Intravenous)
100 mg (per each): $160.06
Tablets (PHENobarbital Oral)
15 mg (per each): $0.10 - $0.34
16.2 mg (per each): $0.12 - $0.53
30 mg (per each): $0.11 - $0.42
32.4 mg (per each): $0.17 - $0.68
60 mg (per each): $0.20 - $0.53
64.8 mg (per each): $0.19 - $0.84
97.2 mg (per each): $0.25 - $1.19
100 mg (per each): $0.26 - $0.74
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Elixir, Oral:
Generic: 25 mg/5 mL (100 mL)
Solution, Injection:
Generic: 30 mg/mL (1 mL); 120 mg/mL (1 mL)
Tablet, Oral:
Generic: 15 mg, 30 mg, 60 mg, 100 mg
C-IV
May be administered IV, IM, or orally.
According to the manufacturer, rapid IV administration >60 mg/minute should be avoided. In the setting of status epilepticus, the Neurocritical Care Society recommends administration at a rate of 50 to 100 mg/minute (Ref). May be an irritant; avoid extravasation. Intra-arterial injection is contraindicated. Discontinue administration of injection if patient complains of limb pain. Avoid subcutaneous administration.
For IM administration, inject deep into muscle. Do not exceed 5 mL per injection site due to potential for tissue irritation.
Bariatric surgery: Phenobarbital is available as an oral solution and elixir. These formulations may contain nonabsorbable sugars (eg, mannitol, sorbitol, xylitol) that can cause dumping syndrome after bariatric surgery (Ref). Refer to product labeling and monitor for tolerability with use.
Oral: Once-daily doses may be administered at bedtime due to sedation. Administer liquid formulations with an accurate measuring device; do not use a household teaspoon.
Parenteral: IV: Do not administer intra-arterially. SUBQ administration is not recommended. Avoid extravasation. Avoid small veins, such as those on the dorsum of the hand or wrist, and avoid varicose veins. Preference is given to larger veins. Discontinue administration of injection if there is any evidence of pain, swelling, discoloration, or temperature change in the limb.
Inject slow IV; the maximum rate recommended by the manufacturer for adults is 60 mg/minute. In the setting of status epilepticus, the Neurocritical Care Society recommends administration at a rate of 50 to 100 mg/minute (Ref). Administration over 15 to 30 minutes has been recommended in neonates (Ref); large loading doses (eg, 40 mg/kg) in neonates have been infused over 60 minutes (Ref). Too rapid administration may result in severe respiratory depression, apnea, laryngospasm, hypertension, or vasodilation with fall in blood pressure.
Sedation: Use as a sedative
Seizures: Management of generalized tonic-clonic, status epilepticus, and partial seizures; management of neonatal seizures in term and preterm infants (Sezaby only).
Alcohol withdrawal syndrome, severe or refractory withdrawal; Sedative/hypnotic withdrawal
PHENobarbital may be confused with PENTobarbital, Phenergan, phenytoin
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (pediatric liquid medications requiring measurement) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
Beers Criteria: Phenobarbital is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its high rate of physical dependence, tolerance to sleep benefits, and increased risk of overdose at low dosages (Beers Criteria [AGS 2023]).
Substrate of CYP2C19 (Major with inhibitors), CYP2C19 (Minor with inducers), CYP2C9 (Minor), CYP2E1 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP1A2 (Weak), CYP2A6 (Weak), CYP2B6 (Weak), CYP3A4 (Moderate), UGT1A1;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abemaciclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Abemaciclib. Risk X: Avoid
Abiraterone Acetate: CYP3A4 Inducers (Moderate) may decrease serum concentration of Abiraterone Acetate. Risk C: Monitor
Acalabrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Acalabrutinib. Risk C: Monitor
Acetaminophen: PHENobarbital may increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Acoramidis: UGT1A1 Inducers may decrease serum concentration of Acoramidis. Risk X: Avoid
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Afatinib: PHENobarbital may decrease serum concentration of Afatinib. Management: Consider increasing the afatinib dose by 10 mg as tolerated in patients requiring chronic coadministration of phenobarbital with afatinib. Reduce afatinib dose back to the original afatinib dose 2 to 3 days after discontinuation of phenobarbital. Risk D: Consider Therapy Modification
Ajmaline: Phenobarbital-Primidone may decrease serum concentration of Ajmaline. Risk C: Monitor
Albendazole: PHENobarbital may decrease active metabolite exposure of Albendazole. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alfacalcidol: Phenobarbital-Primidone may decrease serum concentration of Alfacalcidol. Risk C: Monitor
ALfentanil: CYP3A4 Inducers (Moderate) may decrease serum concentration of ALfentanil. Management: If concomitant use of alfentanil and moderate CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Risk D: Consider Therapy Modification
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alpelisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Alpelisib. Risk C: Monitor
ALPRAZolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of ALPRAZolam. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
AmLODIPine: CYP3A4 Inducers (Moderate) may decrease serum concentration of AmLODIPine. Risk C: Monitor
Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease serum concentration of Antihepaciviral Combination Products. Risk X: Avoid
Apixaban: Phenobarbital-Primidone may decrease serum concentration of Apixaban. Risk C: Monitor
Apremilast: CYP3A4 Inducers (Moderate) may decrease serum concentration of Apremilast. Risk C: Monitor
Aprepitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Aprepitant. Risk C: Monitor
ARIPiprazole Lauroxil: CYP3A4 Inducers (Moderate) may decrease serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor
ARIPiprazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of ARIPiprazole. Risk C: Monitor
Artemether and Lumefantrine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Artemether and Lumefantrine. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Atazanavir: May decrease serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of Atazanavir. Risk X: Avoid
Atogepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider Therapy Modification
Atorvastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atorvastatin. Risk C: Monitor
Atrasentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atrasentan. Risk X: Avoid
Avacopan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avacopan. Risk X: Avoid
Avanafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avanafil. Risk X: Avoid
Avapritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avapritinib. Risk X: Avoid
Axitinib: Phenobarbital-Primidone may decrease serum concentration of Axitinib. Management: Concurrent use of axitinib with phenobarbital or primidone, which is metabolized to phenobarbital, should be avoided when possible. If any such combination is necessary, monitor for reduced axitinib efficacy. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Bazedoxifene: PHENobarbital may decrease serum concentration of Bazedoxifene. This may lead to loss of efficacy or, if bazedoxifene is combined with estrogen therapy, an increased risk of endometrial hyperplasia. Risk C: Monitor
Bedaquiline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bedaquiline. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Bedaquiline. Risk X: Avoid
Belumosudil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Belumosudil. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benzhydrocodone: PHENobarbital may increase CNS depressant effects of Benzhydrocodone. PHENobarbital may decrease active metabolite exposure of Benzhydrocodone. Specifically, phenobarbital may decrease serum concentrations of hydrocodone. Management: Avoid use of benzhydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased benzhydrocodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Bictegravir: PHENobarbital may decrease serum concentration of Bictegravir. Management: When possible consider using an alternative antiseizure drug with concurrent bictegravir, emtricitabine, and tenofovir alafenamide. If the combination must be used, monitor closely for evidence of reduced antiviral effectiveness. Risk D: Consider Therapy Modification
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Blood Pressure Lowering Agents: Barbiturates may increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Bortezomib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bortezomib. Risk C: Monitor
Bosutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bosutinib. Risk C: Monitor
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Brexpiprazole. Risk C: Monitor
Brigatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Risk D: Consider Therapy Modification
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Brivaracetam: PHENobarbital may decrease serum concentration of Brivaracetam. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: PHENobarbital may increase CNS depressant effects of Buprenorphine. PHENobarbital may decrease serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
BuPROPion: CYP2B6 Inducers (Weak) may decrease serum concentration of BuPROPion. Risk C: Monitor
BusPIRone: CYP3A4 Inducers (Moderate) may decrease serum concentration of BusPIRone. Risk C: Monitor
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cabotegravir: UGT1A1 Inducers may decrease serum concentration of Cabotegravir. Risk X: Avoid
Cabozantinib: Phenobarbital-Primidone may decrease serum concentration of Cabozantinib. Management: For cabozantinib tablets (Cabometyx), avoid combined use if possible. If combined, increase cabozantinib by 20 mg from previous dose, max 80 mg daily. For cabozantinib capsules (Cometriq), monitor for reduced cabozantinib efficacy if combined. Risk D: Consider Therapy Modification
Calcifediol: Phenobarbital-Primidone may decrease serum concentration of Calcifediol. Risk X: Avoid
Calcitriol (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Calcitriol (Systemic). Risk C: Monitor
Canagliflozin: PHENobarbital may decrease serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider Therapy Modification
Cannabidiol: Phenobarbital-Primidone may decrease serum concentration of Cannabidiol. Cannabidiol may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor
Cannabis: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor
Capivasertib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Capivasertib. Risk X: Avoid
Capmatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Capmatinib. Risk X: Avoid
CarBAMazepine: CYP3A4 Inducers (Moderate) may decrease serum concentration of CarBAMazepine. Risk C: Monitor
Cariprazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cariprazine. Risk X: Avoid
Carmustine: PHENobarbital may decrease serum concentration of Carmustine. Management: Consider alternatives to phenobarbital when using carmustine. If combined, monitor for reduced carmustine efficacy. Risk D: Consider Therapy Modification
Cenobamate: May increase CNS depressant effects of Phenobarbital-Primidone. Cenobamate may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor
Ceritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ceritinib. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Charcoal, Activated: May decrease serum concentration of PHENobarbital. Risk C: Monitor
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chloramphenicol (Systemic): PHENobarbital may decrease serum concentration of Chloramphenicol (Systemic). Chloramphenicol (Systemic) may increase serum concentration of PHENobarbital. Risk C: Monitor
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cholestyramine Resin: May decrease serum concentration of PHENobarbital. Management: Administer phenobarbital at least 1 hour before or 4 to 6 hours after administration of cholestyramine in order to minimize the risk for any significant interaction. Risk D: Consider Therapy Modification
Clarithromycin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Clarithromycin. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A4 inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Risk D: Consider Therapy Modification
Clindamycin (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Clindamycin (Systemic). Risk C: Monitor
CloBAZam: Phenobarbital-Primidone may increase CNS depressant effects of CloBAZam. Phenobarbital-Primidone may decrease serum concentration of CloBAZam. Risk C: Monitor
CloZAPine: CYP1A2 Inducers (Weak) may decrease serum concentration of CloZAPine. Risk C: Monitor
CloZAPine: CYP3A4 Inducers (Moderate) may decrease serum concentration of CloZAPine. Risk C: Monitor
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cobicistat: PHENobarbital may decrease serum concentration of Cobicistat. Risk X: Avoid
Cobimetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cobimetinib. Risk X: Avoid
Codeine: PHENobarbital may increase CNS depressant effects of Codeine. PHENobarbital may decrease serum concentration of Codeine. Management: Avoid use of codeine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Copanlisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Copanlisib. Risk C: Monitor
Crinecerfont: CYP3A4 Inducers (Moderate) may decrease serum concentration of Crinecerfont. Management: Double the evening dose of crinecerfont and continue the morning dose unchanged during coadministration with moderate CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider Therapy Modification
Crizotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Crizotinib. Risk C: Monitor
CycloPHOSphamide: PHENobarbital may increase active metabolite exposure of CycloPHOSphamide. More specifically, phenobarbital may increase the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. PHENobarbital may decrease serum concentration of CycloPHOSphamide. Risk C: Monitor
CycloSPORINE (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of CycloSPORINE (Systemic). Risk C: Monitor
CYP2C19 Inducers (Moderate): May decrease serum concentration of PHENobarbital. Risk C: Monitor
CYP2C19 Inducers (Strong): May decrease serum concentration of PHENobarbital. Risk C: Monitor
CYP2C19 Inhibitors (Moderate): May increase serum concentration of PHENobarbital. Risk C: Monitor
CYP2C19 Inhibitors (Strong): May increase serum concentration of PHENobarbital. Risk C: Monitor
CYP2C9 Inhibitors (Moderate): May increase serum concentration of PHENobarbital. Risk C: Monitor
CYP2E1 Inhibitors (Moderate): May increase serum concentration of PHENobarbital. Risk C: Monitor
Dabigatran Etexilate: PHENobarbital may decrease serum concentration of Dabigatran Etexilate. Risk C: Monitor
Daclatasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Risk D: Consider Therapy Modification
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dapsone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Dapsone (Systemic). Risk C: Monitor
Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor
Daridorexant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Daridorexant. Risk X: Avoid
Darunavir: May decrease serum concentration of PHENobarbital. Risk C: Monitor
Dasabuvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dasabuvir. Risk X: Avoid
Dasatinib: CYP3A4 Inducers (Moderate) may increase serum concentration of Dasatinib. Risk C: Monitor
Deferasirox: UGT1A1 Inducers may decrease serum concentration of Deferasirox. Management: Avoid concomitant use of deferasirox and UGT1A1 inducers when possible. If combined, consider a 50% increase in the initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical response to guide further dosing. Risk D: Consider Therapy Modification
Deflazacort: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Deflazacort. Risk X: Avoid
Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor
DexAMETHasone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of DexAMETHasone (Systemic). Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Dexmethylphenidate: May increase serum concentration of PHENobarbital. Risk C: Monitor
DiazePAM: CYP3A4 Inducers (Moderate) may decrease serum concentration of DiazePAM. Risk C: Monitor
Dienogest: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dienogest. Risk C: Monitor
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
DilTIAZem: CYP3A4 Inducers (Moderate) may decrease serum concentration of DilTIAZem. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Disopyramide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Disopyramide. Risk C: Monitor
Disulfiram: May increase adverse/toxic effects of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid
Dolutegravir: PHENobarbital may decrease serum concentration of Dolutegravir. Risk X: Avoid
Doravirine: Phenobarbital-Primidone may decrease serum concentration of Doravirine. Risk X: Avoid
Doxercalciferol: Phenobarbital-Primidone may increase active metabolite exposure of Doxercalciferol. Risk C: Monitor
DOXOrubicin (Conventional): CYP3A4 Inducers (Moderate) may decrease serum concentration of DOXOrubicin (Conventional). Risk X: Avoid
Doxycycline: Barbiturates may decrease serum concentration of Doxycycline. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroNABinol: CYP3A4 Inducers (Moderate) may decrease serum concentration of DroNABinol. Risk C: Monitor
Dronedarone: Phenobarbital-Primidone may decrease serum concentration of Dronedarone. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Duvelisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Duvelisib. Management: Avoid if possible. If used, on day 12 of combination increase duvelisib from 25 mg twice daily to 40 mg twice daily or from 15 mg twice daily to 25 mg twice daily. Resume prior duvelisib dose 14 days after stopping moderate CYP3A4 inducer. Risk D: Consider Therapy Modification
Dydrogesterone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dydrogesterone. Risk C: Monitor
Efavirenz: CYP3A4 Inducers (Moderate) may decrease serum concentration of Efavirenz. Risk C: Monitor
Elacestrant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elacestrant. Risk X: Avoid
Elbasvir and Grazoprevir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid
Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk C: Monitor
Elexacaftor, Tezacaftor, and Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk C: Monitor
Eliglustat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Eliglustat. Risk C: Monitor
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Encorafenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Encorafenib. Risk C: Monitor
Ensartinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ensartinib. Risk X: Avoid
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Entrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Entrectinib. Risk X: Avoid
Enzalutamide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Enzalutamide. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Enzalutamide. Risk C: Monitor
Erdafitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Erdafitinib. Management: If a moderate CYP3A4 inducer must be used at the start of erdafitinib, administer erdafitinib at a dose of 9 mg daily. If a moderate CYP3A4 inducer is discontinued, continue erdafitinib at the same dose unless there is evidence of drug toxicity. Risk D: Consider Therapy Modification
Erlotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Erlotinib. Management: Avoid the combination of erlotinib and strong CYP3A4 inducers whenever possible. If this combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Risk D: Consider Therapy Modification
Esketamine (Injection): Phenobarbital-Primidone may decrease serum concentration of Esketamine (Injection). Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Eslicarbazepine: PHENobarbital may decrease serum concentration of Eslicarbazepine. Risk C: Monitor
Estrogen Derivatives: CYP3A4 Inducers (Moderate) may decrease serum concentration of Estrogen Derivatives. Risk C: Monitor
Ethosuximide: Phenobarbital-Primidone may decrease serum concentration of Ethosuximide. Risk C: Monitor
Etoposide Phosphate: CYP3A4 Inducers (Moderate) may decrease serum concentration of Etoposide Phosphate. Risk C: Monitor
Etoposide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Etoposide. Risk C: Monitor
Etravirine: Phenobarbital-Primidone may decrease serum concentration of Etravirine. Risk X: Avoid
Everolimus: CYP3A4 Inducers (Moderate) may decrease serum concentration of Everolimus. Risk C: Monitor
Exemestane: CYP3A4 Inducers (Moderate) may decrease serum concentration of Exemestane. Risk C: Monitor
Fedratinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fedratinib. Risk X: Avoid
Felbamate: PHENobarbital may decrease serum concentration of Felbamate. Felbamate may increase serum concentration of PHENobarbital. Management: Initiate felbamate at typical doses (1,200 mg/day in 3 or 4 divided doses for adults and children 14 years of age or older; 15 mg/kg/day in 3 or 4 divided doses in children 2 to 14 years of age) while reducing the phenobarbital dose by 20%. Risk D: Consider Therapy Modification
Felodipine: Phenobarbital-Primidone may decrease serum concentration of Felodipine. Risk C: Monitor
Fenoprofen: PHENobarbital may decrease serum concentration of Fenoprofen. Risk C: Monitor
FentaNYL: PHENobarbital may increase CNS depressant effects of FentaNYL. PHENobarbital may decrease serum concentration of FentaNYL. Management: Avoid use of fentanyl and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Fexinidazole: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Fexinidazole. Risk X: Avoid
Finerenone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Finerenone. Risk X: Avoid
Flibanserin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Flibanserin. Risk X: Avoid
Fludrocortisone: Phenobarbital-Primidone may decrease serum concentration of Fludrocortisone. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Folic Acid: May decrease serum concentration of PHENobarbital. Risk C: Monitor
Fosamprenavir: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fosamprenavir. Risk C: Monitor
Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Risk C: Monitor
Fosnetupitant: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fosnetupitant. Risk C: Monitor
Fosphenytoin-Phenytoin: May increase CNS depressant effects of Phenobarbital-Primidone. Phenobarbital-Primidone may decrease serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor
Fostamatinib: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fostamatinib. Risk C: Monitor
Fruquintinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fruquintinib. Management: Avoid this combination when possible. If combined, continue the same fruquintinib dose, but monitor for reduced fruquintinib efficacy. Risk D: Consider Therapy Modification
Ganaxolone: May increase CNS depressant effects of Phenobarbital-Primidone. Phenobarbital-Primidone may decrease serum concentration of Ganaxolone. Management: Avoid this combination if possible. In patients stabilized on ganaxolone who initiate or dose escalate phenobarbital or primidone the ganaxolone dose may need to be increased, but should not exceed the maximum recommended daily dose. Risk D: Consider Therapy Modification
Gefitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gefitinib. Risk C: Monitor
Gemigliptin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gemigliptin. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Gemigliptin. Risk C: Monitor
Gepirone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gepirone. Risk C: Monitor
Gepotidacin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gepotidacin. Risk C: Monitor
Gestrinone: PHENobarbital may decrease serum concentration of Gestrinone. Risk C: Monitor
Glasdegib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Risk D: Consider Therapy Modification
Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor
Griseofulvin: Barbiturates may decrease serum concentration of Griseofulvin. Risk C: Monitor
GuanFACINE: CYP3A4 Inducers (Moderate) may decrease serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Risk D: Consider Therapy Modification
Haloperidol: Phenobarbital-Primidone may decrease serum concentration of Haloperidol. Risk C: Monitor
Hemin: Barbiturates may decrease therapeutic effects of Hemin. Risk X: Avoid
Hormonal Contraceptives: CYP3A4 Inducers (Moderate) may decrease serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider Therapy Modification
HYDROcodone: PHENobarbital may increase CNS depressant effects of HYDROcodone. PHENobarbital may decrease serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Hydrocortisone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Hydrocortisone (Systemic). Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Ibrexafungerp: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ibrexafungerp. Risk X: Avoid
Ibrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ibrutinib. Risk C: Monitor
Idelalisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Idelalisib. Risk C: Monitor
Ifosfamide: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Ifosfamide. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Ifosfamide. Risk C: Monitor
Imatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Imatinib. Risk C: Monitor
Indinavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and moderate CYP3A4 inducers whenever possible due to the risk for decreased indinavir concentrations, reduced efficacy, and development of resistance. If combined, monitor for indinavir treatment failure. Risk D: Consider Therapy Modification
Irinotecan Products: Phenobarbital-Primidone may decrease serum concentration of Irinotecan Products. Management: Avoid administration of phenobarbital or primidone during irinotecan treatment, and substitute non-CYP3A4 inducing agents at least 2 weeks prior to irinotecan initiation, whenever possible. If combined, monitor closely for reduced irinotecan efficacy. Risk D: Consider Therapy Modification
Isavuconazonium Sulfate: Phenobarbital-Primidone may decrease active metabolite exposure of Isavuconazonium Sulfate. Specifically, isavuconazole serum concentrations may be reduced. Risk X: Avoid
Isradipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Isradipine. Risk C: Monitor
Istradefylline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Istradefylline. Risk C: Monitor
Itraconazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Itraconazole. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Itraconazole. Risk C: Monitor
Ivabradine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ivabradine. Risk X: Avoid
Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Ivacaftor. Risk C: Monitor
Ixabepilone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ixabepilone. Risk C: Monitor
Ixazomib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ixazomib. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketamine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ketamine. Risk C: Monitor
Ketoconazole (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Ketoconazole (Systemic). Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lacosamide: May increase CNS depressant effects of PHENobarbital. PHENobarbital may decrease serum concentration of Lacosamide. Risk C: Monitor
LamoTRIgine: May increase adverse/toxic effects of Phenobarbital-Primidone. Specifically, the risk for hematologic toxicities may be increased. Phenobarbital-Primidone may decrease serum concentration of LamoTRIgine. Management: For patients taking primidone or phenobarbital without valproate, lamotrigine dose adjustments are recommended for lamotrigine initiation. Recommendations vary based on lamotrigine indication and age. See full interact monograph for details. Risk D: Consider Therapy Modification
Lapatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lapatinib. Risk C: Monitor
Larotrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Larotrectinib. Management: Double the larotrectinib dose if used together with a moderate CYP3A4 inducer. Following discontinuation of the moderate CYP3A4 inducer, resume the previous dose of larotrectinib after a period of 3 to 5 times the inducer's half-life. Risk D: Consider Therapy Modification
Lazertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lazertinib. Risk X: Avoid
Ledipasvir: PHENobarbital may decrease serum concentration of Ledipasvir. Risk X: Avoid
Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Lefamulin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Lemborexant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lemborexant. Risk X: Avoid
Lenacapavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lenacapavir. Risk X: Avoid
Leniolisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Leniolisib. Risk X: Avoid
Lercanidipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lercanidipine. Risk C: Monitor
Letermovir: UGT1A1 Inducers may decrease serum concentration of Letermovir. Risk X: Avoid
Leucovorin Calcium-Levoleucovorin: May decrease serum concentration of PHENobarbital. Risk C: Monitor
Levamlodipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Levamlodipine. Risk C: Monitor
LevETIRAcetam: May increase CNS depressant effects of PHENobarbital. PHENobarbital may decrease serum concentration of LevETIRAcetam. Risk C: Monitor
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Levoketoconazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Levoketoconazole. Risk C: Monitor
Levomethadone: PHENobarbital may increase CNS depressant effects of Levomethadone. PHENobarbital may decrease serum concentration of Levomethadone. Management: Avoid concomitant use of levomethadone and phenobarbital when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Levonorgestrel (IUD): Phenobarbital-Primidone may decrease therapeutic effects of Levonorgestrel (IUD). Phenobarbital-Primidone may decrease serum concentration of Levonorgestrel (IUD). Risk C: Monitor
Lidocaine (Systemic): Phenobarbital-Primidone may decrease serum concentration of Lidocaine (Systemic). Risk C: Monitor
LinaGLIPtin: CYP3A4 Inducers (Moderate) may decrease serum concentration of LinaGLIPtin. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lonafarnib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lonafarnib. Risk X: Avoid
Lopinavir: PHENobarbital may decrease serum concentration of Lopinavir. Management: Increased doses of lopinavir may be necessary when using these agents in combination. Do not use a once daily lopinavir/ritonavir regimen together with phenobarbital. Increase monitoring of therapeutic response in all patients using this combination. Risk D: Consider Therapy Modification
Lorlatinib: CYP3A4 Inducers (Moderate) may increase hepatotoxic effects of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, increase lorlatinib to 125 mg daily. Monitor for reduced lorlatinib efficacy and consider closer monitoring of AST, ALT, and bilirubin. Risk D: Consider Therapy Modification
Lovastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lovastatin. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Lumacaftor and Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Lumacaftor and Ivacaftor. Risk C: Monitor
Lumateperone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lumateperone. Risk X: Avoid
Lurasidone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lurasidone. Management: After chronic treatment (7 days or more) with a moderate CYP3A4 inducer, lurasidone dose increases may be needed. Monitor closely for decreased lurasidone effects and increase the lurasidone dose as needed. Risk D: Consider Therapy Modification
Macitentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Macitentan. Risk C: Monitor
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Maraviroc: CYP3A4 Inducers (Moderate) may decrease serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider Therapy Modification
Maribavir: PHENobarbital may decrease serum concentration of Maribavir. Management: Increase the dose of maribavir to 1,200 mg twice daily with concomitant use of phenobarbital. Risk D: Consider Therapy Modification
Mavacamten: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mavacamten. Risk X: Avoid
Mavorixafor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mavorixafor. Risk C: Monitor
Mefloquine: May decrease therapeutic effects of PHENobarbital. PHENobarbital may decrease serum concentration of Mefloquine. Mefloquine may decrease serum concentration of PHENobarbital. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If phenobarbital is being used for another indication, monitor for decreased concentrations and efficacy of both phenobarbital and mefloquine. Risk D: Consider Therapy Modification
Meperidine: PHENobarbital may increase CNS depressant effects of Meperidine. PHENobarbital may increase active metabolite exposure of Meperidine. Management: Avoid concomitant use of meperidine and phenobarbital when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methadone: PHENobarbital may increase CNS depressant effects of Methadone. PHENobarbital may decrease serum concentration of Methadone. Management: Avoid concomitant use of methadone and phenobarbital when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Methotrimeprazine: May increase CNS depressant effects of Products Containing Ethanol. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid
Methoxyflurane: Barbiturates may increase nephrotoxic effects of Methoxyflurane. Barbiturates may increase metabolism of Methoxyflurane. Risk X: Avoid
Methylphenidate: May increase serum concentration of PHENobarbital. Risk C: Monitor
MethylPREDNISolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of MethylPREDNISolone. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetroNIDAZOLE (Systemic): May increase adverse/toxic effects of PHENobarbital. A disulfiram-like reaction may occur if combined with phenobarbital dosage forms that contain propylene glycol or alcohol. PHENobarbital may decrease serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor
MetroNIDAZOLE (Topical): May increase adverse/toxic effects of Products Containing Ethanol. A disulfiram-like reaction may occur. Risk C: Monitor
MetyraPONE: Coadministration of Antiseizure Agents and MetyraPONE may alter diagnostic results. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider Therapy Modification
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Mianserin: May increase CNS depressant effects of Barbiturates. Mianserin may decrease therapeutic effects of Barbiturates. Barbiturates may decrease serum concentration of Mianserin. Risk X: Avoid
Midazolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of Midazolam. Risk C: Monitor
Midostaurin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Midostaurin. Risk C: Monitor
MiFEPRIStone: CYP3A4 Inducers (Moderate) may decrease serum concentration of MiFEPRIStone. Management: Avoid combined use in patients treated for Cushing's disease. When used for pregnancy termination, mifepristone efficacy may be reduced and an alternative pregnancy termination procedure may be warranted. Ensure a follow-up assessment after combined use. Risk D: Consider Therapy Modification
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mirodenafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mirodenafil. Risk C: Monitor
Mitapivat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mitapivat. Management: Consider alternatives to this combination when possible. If combined, monitor hemoglobin and titrate mitapivat beyond 50 mg twice daily, if needed, but do not exceed doses of 100 mg twice daily. Risk D: Consider Therapy Modification
Mobocertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mobocertinib. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Mobocertinib. Risk X: Avoid
Montelukast: Phenobarbital-Primidone may decrease serum concentration of Montelukast. Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease serum concentration of Barbiturates. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Naldemedine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Naldemedine. Risk C: Monitor
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Naloxegol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Naloxegol. Risk C: Monitor
Nelfinavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nelfinavir. Risk C: Monitor
Neratinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Neratinib. Risk X: Avoid
Netupitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Netupitant. Risk C: Monitor
Nevirapine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nevirapine. Risk C: Monitor
NIFEdipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of NIFEdipine. Risk C: Monitor
Nilotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nilotinib. Risk C: Monitor
Nilvadipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nilvadipine. Risk C: Monitor
NiMODipine: Phenobarbital-Primidone may decrease serum concentration of NiMODipine. Risk X: Avoid
Nirmatrelvir and Ritonavir: May decrease serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of Nirmatrelvir and Ritonavir. Risk X: Avoid
Nirogacestat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nirogacestat. Risk X: Avoid
Nisoldipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nisoldipine. Risk X: Avoid
Nitric Oxide: May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: CYP1A2 Inducers (Weak) may decrease serum concentration of OLANZapine. Risk C: Monitor
Olaparib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olaparib. Risk X: Avoid
Olmutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olmutinib. Risk C: Monitor
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Olutasidenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olutasidenib. Risk X: Avoid
Omaveloxolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Omaveloxolone. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: Antiseizure Agents may decrease serum concentration of Opipramol. Risk C: Monitor
Orlistat: May decrease serum concentration of Antiseizure Agents. Risk C: Monitor
Ornidazole: PHENobarbital may decrease serum concentration of Ornidazole. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Osimertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Osimertinib. Risk C: Monitor
OXcarbazepine: Phenobarbital-Primidone may decrease serum concentration of OXcarbazepine. Risk C: Monitor
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: Barbiturates may increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
OxyCODONE: PHENobarbital may increase CNS depressant effects of OxyCODONE. PHENobarbital may decrease serum concentration of OxyCODONE. Management: Avoid use of oxycodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
PACLitaxel (Conventional): CYP3A4 Inducers (Moderate) may decrease serum concentration of PACLitaxel (Conventional). Risk C: Monitor
PACLitaxel (Protein Bound): CYP3A4 Inducers (Moderate) may decrease serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor
Pacritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pacritinib. Risk C: Monitor
Palbociclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Palbociclib. Risk C: Monitor
Paliperidone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Paliperidone. Risk C: Monitor
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Palovarotene: CYP3A4 Inducers (Moderate) may decrease serum concentration of Palovarotene. Risk X: Avoid
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
PAZOPanib: CYP3A4 Inducers (Moderate) may decrease serum concentration of PAZOPanib. Risk C: Monitor
Pemigatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pemigatinib. Risk X: Avoid
Perampanel: CYP3A4 Inducers (Moderate) may decrease serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with moderate CYP3A4 inducers. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if the inducer is discontinued. Risk D: Consider Therapy Modification
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pimavanserin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pimavanserin. Risk X: Avoid
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piperaquine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Piperaquine. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pirtobrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pirtobrutinib. Management: Avoid concomitant use if possible. If combined, if the current pirtobrutinib dose is 200 mg once daily, increase to 300 mg once daily. If current pirtobrutinib dose is 50 mg or 100 mg once daily, increase the dose by 50 mg. Risk D: Consider Therapy Modification
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
PONATinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of PONATinib. Risk C: Monitor
Pralsetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pralsetinib. Management: If this combo cannot be avoided, increase pralsetinib dose from 400 mg daily to 600 mg daily; from 300 mg daily to 500 mg daily; and from 200 mg daily to 300 mg daily. Risk D: Consider Therapy Modification
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Praziquantel: CYP3A4 Inducers (Moderate) may decrease serum concentration of Praziquantel. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for reduced praziquantel efficacy. If possible, stop the moderate CYP3A4 inducer 2 to 4 weeks before praziquantel initiation. Risk D: Consider Therapy Modification
PrednisoLONE (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of PrednisoLONE (Systemic). Risk C: Monitor
PredniSONE: CYP3A4 Inducers (Moderate) may decrease serum concentration of PredniSONE. Risk C: Monitor
Pretomanid: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pretomanid. Risk X: Avoid
Prilocaine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor
Primaquine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Primaquine. Specifically, the risk for methemoglobinemia may be increased. Management: Avoid concomitant use of primaquine and other drugs that are associated with methemoglobinemia when possible. If combined, monitor methemoglobin levels closely. Risk D: Consider Therapy Modification
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Propacetamol: PHENobarbital may increase metabolism of Propacetamol. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Pyridoxine: May decrease serum concentration of PHENobarbital. Risk C: Monitor
Pyrimethamine: Phenobarbital-Primidone may decrease serum concentration of Pyrimethamine. Risk C: Monitor
QUEtiapine: CYP3A4 Inducers (Moderate) may decrease serum concentration of QUEtiapine. Risk C: Monitor
QuiNIDine: CYP3A4 Inducers (Moderate) may decrease serum concentration of QuiNIDine. Risk C: Monitor
QuiNINE: May increase serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of QuiNINE. Management: Consider alternatives to this combination when possible. If coadministration of phenobarbital and quinine cannot be avoided, monitor for reduced quinine efficacy and for increased phenobarbital serum concentrations and toxicities. Risk D: Consider Therapy Modification
Quizartinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Quizartinib. Risk X: Avoid
Ranolazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ranolazine. Risk X: Avoid
Reboxetine: Phenobarbital-Primidone may decrease serum concentration of Reboxetine. Risk C: Monitor
Regorafenib: Phenobarbital-Primidone may decrease serum concentration of Regorafenib. Phenobarbital-Primidone may increase active metabolite exposure of Regorafenib. Risk C: Monitor
Repaglinide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Repaglinide. Risk C: Monitor
Repotrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Repotrectinib. Risk X: Avoid
Revumenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Revumenib. Risk X: Avoid
Ribociclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ribociclib. Risk C: Monitor
Rifapentine: May decrease serum concentration of PHENobarbital. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rilpivirine: PHENobarbital may decrease serum concentration of Rilpivirine. Risk X: Avoid
Rimegepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Rimegepant. Risk X: Avoid
Ripretinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ripretinib. Management: Avoid this combination if possible. If concomitant use is required, increase ripretinib to 150 mg twice daily. Decrease ripretinib to 150 mg once daily 14 days after stopping a moderate CYP3A4 inducer. Monitor patients for ripretinib response and toxicity Risk D: Consider Therapy Modification
RisperiDONE: CYP3A4 Inducers (Moderate) may decrease serum concentration of RisperiDONE. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of RisperiDONE. Risk C: Monitor
Ritlecitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ritlecitinib. Risk C: Monitor
Ritonavir: May decrease serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of Ritonavir. Management: Consider avoiding this combination due to the potential for decreased ritonavir concentrations and the possible development of resistance. If combined, monitor for decreased phenobarbital and ritonavir concentrations and effects during coadministration. Risk D: Consider Therapy Modification
Rivaroxaban: Phenobarbital-Primidone may decrease serum concentration of Rivaroxaban. Risk C: Monitor
Roflumilast (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Roflumilast (Systemic). CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Roflumilast (Systemic). Risk C: Monitor
Roflumilast (Systemic): Phenobarbital-Primidone may decrease serum concentration of Roflumilast (Systemic). Risk C: Monitor
Rolapitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Rolapitant. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Rufinamide: May increase serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of Rufinamide. Risk C: Monitor
Sacituzumab Govitecan: UGT1A1 Inducers may decrease active metabolite exposure of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be decreased. Risk X: Avoid
Samidorphan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Samidorphan. Risk C: Monitor
Sapropterin: PHENobarbital may decrease serum concentration of Sapropterin. Specifically, phenobarbital may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor
Saquinavir: PHENobarbital may decrease serum concentration of Saquinavir. Risk X: Avoid
Secnidazole: Products Containing Ethanol may increase adverse/toxic effects of Secnidazole. Risk X: Avoid
Selpercatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Selpercatinib. Risk X: Avoid
Selumetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Selumetinib. Risk X: Avoid
Sertraline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sertraline. Risk C: Monitor
Sildenafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sildenafil. Risk C: Monitor
Simeprevir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Simeprevir. Risk X: Avoid
Simvastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Simvastatin. Risk C: Monitor
Sirolimus (Conventional): CYP3A4 Inducers (Moderate) may decrease serum concentration of Sirolimus (Conventional). Risk C: Monitor
Sirolimus (Protein Bound): CYP3A4 Inducers (Moderate) may decrease serum concentration of Sirolimus (Protein Bound). Risk C: Monitor
Sodium Nitrite: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Sofosbuvir: PHENobarbital may decrease serum concentration of Sofosbuvir. Risk X: Avoid
Sonidegib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sonidegib. Risk X: Avoid
SORAfenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of SORAfenib. Risk C: Monitor
Sotorasib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sotorasib. Risk C: Monitor
Sparsentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sparsentan. Risk C: Monitor
Stiripentol: Phenobarbital-Primidone may decrease serum concentration of Stiripentol. Stiripentol may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor
SUFentanil: PHENobarbital may increase CNS depressant effects of SUFentanil. PHENobarbital may decrease serum concentration of SUFentanil. Management: Avoid use of sufentanil and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased sufentanil efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Sulthiame: May increase adverse/toxic effects of PHENobarbital. Risk C: Monitor
SUNItinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of SUNItinib. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Suzetrigine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Suzetrigine. Risk X: Avoid
Tacrolimus (Systemic): Phenobarbital-Primidone may decrease serum concentration of Tacrolimus (Systemic). Risk C: Monitor
Tadalafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tadalafil. Risk C: Monitor
Tamoxifen: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tamoxifen. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Tamoxifen. Risk C: Monitor
Tasimelteon: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tasimelteon. Risk C: Monitor
Tazemetostat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tazemetostat. Risk X: Avoid
Temsirolimus: CYP3A4 Inducers (Moderate) may decrease serum concentration of Temsirolimus. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Temsirolimus. Specifically, sirolimus concentrations may be decreased. Risk C: Monitor
Teniposide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Teniposide. Risk C: Monitor
Tenofovir Alafenamide: PHENobarbital may decrease serum concentration of Tenofovir Alafenamide. Risk X: Avoid
Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor
Tetrahydrocannabinol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tetrahydrocannabinol. Risk C: Monitor
Tezacaftor and Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Tezacaftor and Ivacaftor. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Theophylline Derivatives: Barbiturates may decrease serum concentration of Theophylline Derivatives. Risk C: Monitor
Thiotepa: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Thiotepa. CYP3A4 Inducers (Moderate) may decrease serum concentration of Thiotepa. Risk C: Monitor
Thiothixene: PHENobarbital may decrease serum concentration of Thiothixene. Risk C: Monitor
Thyroid Products: PHENobarbital may decrease serum concentration of Thyroid Products. Risk C: Monitor
TiaGABine: Phenobarbital-Primidone may decrease serum concentration of TiaGABine. Risk C: Monitor
Ticagrelor: Phenobarbital-Primidone may decrease serum concentration of Ticagrelor. Risk C: Monitor
Timolol (Systemic): PHENobarbital may increase hypotensive effects of Timolol (Systemic). PHENobarbital may decrease serum concentration of Timolol (Systemic). Risk C: Monitor
Tipranavir: PHENobarbital may decrease serum concentration of Tipranavir. Tipranavir may decrease serum concentration of PHENobarbital. Risk C: Monitor
Tivozanib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tivozanib. Risk C: Monitor
Tofacitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tofacitinib. Risk C: Monitor
Tolvaptan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tolvaptan. Risk C: Monitor
Toremifene: Phenobarbital-Primidone may decrease serum concentration of Toremifene. Risk C: Monitor
Trabectedin: Phenobarbital-Primidone may decrease serum concentration of Trabectedin. Risk C: Monitor
TraMADol: PHENobarbital may increase CNS depressant effects of TraMADol. PHENobarbital may decrease serum concentration of TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
TraZODone: CYP3A4 Inducers (Moderate) may decrease serum concentration of TraZODone. Risk C: Monitor
Tretinoin (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Tretinoin (Systemic). Risk C: Monitor
Triazolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of Triazolam. Risk C: Monitor
Tricyclic Antidepressants: Barbiturates may increase metabolism of Tricyclic Antidepressants. Management: Monitor for decreased efficacy of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. Tricyclic antidepressant dose adjustments are likely required. Risk D: Consider Therapy Modification
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Tropisetron: Phenobarbital-Primidone may decrease serum concentration of Tropisetron. Risk C: Monitor
Tucatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tucatinib. Risk C: Monitor
Ubrogepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Risk D: Consider Therapy Modification
Ulipristal: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ulipristal. Risk X: Avoid
Upadacitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Upadacitinib. Risk C: Monitor
Valbenazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Valbenazine. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Valbenazine. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valproic Acid and Derivatives: May increase CNS depressant effects of Barbiturates. Valproic Acid and Derivatives may increase serum concentration of Barbiturates. Barbiturates may decrease serum concentration of Valproic Acid and Derivatives. Risk C: Monitor
Vandetanib: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Vandetanib. CYP3A4 Inducers (Moderate) may decrease serum concentration of Vandetanib. Risk C: Monitor
Vanzacaftor, Tezacaftor, and Deutivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Risk X: Avoid
Velpatasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Velpatasvir. Risk X: Avoid
Vemurafenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vemurafenib. Risk C: Monitor
Venetoclax: CYP3A4 Inducers (Moderate) may decrease serum concentration of Venetoclax. Risk X: Avoid
Verapamil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Verapamil. Risk C: Monitor
Vilazodone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vilazodone. Risk C: Monitor
VinCRIStine: CYP3A4 Inducers (Moderate) may decrease serum concentration of VinCRIStine. Risk C: Monitor
Vitamin K Antagonists: Barbiturates may increase metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. Anticoagulant dose increases of 30% to 60% may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction. Risk D: Consider Therapy Modification
Voclosporin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voclosporin. Risk X: Avoid
Vonoprazan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vonoprazan. Risk X: Avoid
Vorapaxar: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vorapaxar. Risk X: Avoid
Voriconazole: PHENobarbital may decrease serum concentration of Voriconazole. Risk X: Avoid
Vortioxetine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vortioxetine. Risk C: Monitor
Voxelotor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,000 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider Therapy Modification
Voxilaprevir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voxilaprevir. Risk X: Avoid
Zaleplon: Phenobarbital-Primidone may decrease serum concentration of Zaleplon. Risk C: Monitor
Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zanubrutinib. Management: Avoid this combination if possible. If coadministration of zanubrutinib and a moderate CYP3A4 inducer is required, increase the zanubrutinib dose to 320 mg twice daily. Risk D: Consider Therapy Modification
Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification
Zonisamide: May increase CNS depressant effects of PHENobarbital. PHENobarbital may decrease serum concentration of Zonisamide. Risk C: Monitor
Zopiclone: PHENobarbital may increase CNS depressant effects of Zopiclone. PHENobarbital may decrease serum concentration of Zopiclone. Risk C: Monitor
Zuranolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zuranolone. Risk X: Avoid
Phenobarbital increases the hepatic metabolism of vitamin D to inactive compounds and reduces calcium absorption (Gough 1986). Management: Increase intake of foods rich in vitamin D. Supplementation of vitamin D and/or calcium may be necessary.
Phenobarbital crosses the placenta (Harden 2009b). Barbiturates can be detected in the placenta, fetal liver, and fetal brain. Fetal and maternal blood concentrations may be similar following parenteral administration. An increased incidence of fetal abnormalities may occur following maternal use. When used during the third trimester of pregnancy, withdrawal symptoms may occur in the neonate, including seizures and hyperirritability; symptoms of withdrawal may be delayed in the neonate up to 14 days after birth. Use during labor does not impair uterine activity; however, respiratory depression may occur in the newborn; resuscitation equipment should be available, especially for premature infants. Use for the treatment of epilepsy should be avoided during pregnancy (Harden 2009a).
A registry is available for women exposed to phenobarbital during pregnancy: Pregnant women may enroll themselves into the North American Antiepileptic Drug (AED) Pregnancy Registry (888-233-2334 or http://www.aedpregnancyregistry.org).
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.
Folate and vitamin B: Phenobarbital use has been associated with low serum concentrations of folate, vitamin B2 (riboflavin), B6 (pyridoxine) and B12 (cyanocobalamin), which may contribute to hyperhomocysteinemia. Hyperhomocysteinemia may contribute to cardiovascular disease, venous thromboembolic disease, dementia, neuropsychiatric symptoms and poor seizure control. Some clinicians recommend administering folic acid, riboflavin, pyridoxine and cyanocobalamin supplements in patients taking phenobarbital (Apeland 2003; Apeland 2008; Belcastro 2012; Bochyńska 2012).
Vitamin D and calcium: Phenobarbital increases the hepatic metabolism of vitamin D to inactive compounds and reduces calcium absorption (Gough 1986); increase intake of foods rich in vitamin D. Supplementation of vitamin D and/or calcium may be necessary.
Injection may contain sodium.
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); dermatological reactions.
IV use: Respiratory rate, heart rate, blood pressure; monitor infusion site.
Seizures:
Timing of serum samples: Draw trough just before next dose (Hiemke 2018).
Therapeutic reference range: A clear correlation between serum phenobarbital concentrations and therapeutic response has not been demonstrated; however, a range of 10 to 40 mcg/mL (SI: 43.1 to 172.4 micromole/L) has been reported (Patsalos 2018). In select clinical circumstances (eg, refractory status epilepticus, weaning pentobarbital), higher serum phenobarbital concentrations have been targeted in adults (Byun 2015; NCS [Brophy 2012]).
Laboratory alert level: 50 mcg/mL (SI: 215.5 micromole/L) (Hiemke 2018).
Long-acting barbiturate with sedative, hypnotic, and antiseizure properties. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, barbiturates exhibit antiseizure activity; barbiturates produce dose-dependent respiratory depression.
Onset of action: Oral: ≥60 minutes; IV: 5 minutes.
Peak effect: IV: CNS depression: ≥15 minutes.
Duration: Oral: 10 to 12 hours; IV: >6 hours.
Absorption: Oral: Adults: Rapid and complete; Newborns: Delayed and incomplete (Patsalos 2008).
Distribution: Vd:
Neonates: 0.85 ± 0.059 L/kg (Heimann 1977).
2 to 3 months: 0.857 ± 0.089 L/kg (Heimann 1977).
4 to 12 months: 0.57 ± 0.046 L/kg (Heimann 1977).
1 to 5 years: 0.666 ± 0.073 L/kg (Heimann 1977).
Adults: 0.61 L/kg (Patsalos 2018).
Protein binding:
Neonates and young infants: 36% to 43% (Patsalos 2008).
Adults: 48% (Patsalos 2018).
Metabolism: Hepatic by oxidation via CYP2C9 and to a lesser extent via CYP2C19 and CYP2E1, and by N-glucosidation (Patsalos 2018).
Bioavailability: Oral:
Neonates and young infants: ~48.9 (Marsot 2014).
Adults: 90% (Patsalos 2018).
Half-life elimination:
≤10 days of life: 114.2 ± 43 hours (Alonso Gonzalez 1993; Patsalos 2008).
11 to 30 days of life: 73.19 ± 24.17 hours (Alonso Gonzalez 1993; Patsalos 2008).
2 to 3 months: 62.9 ± 5.2 hours (Heimann 1977).
4 to 12 months: 63.2 ± 4.2 hours (Heimann 1977).
1 to 5 years: 68.5 ± 3.2 hours (Heimann 1977).
Adults: ~79 hours (range: 53 to 118 hours).
Time to peak, serum: Oral:
Newborns: 1.5 to 6 hours (Patsalos 2008).
Adults: 2 to 4 hours (Patsalos 2018).
Excretion: Urine (25% to 50% as unchanged drug); feces (minimal).
