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Phenobarbital: Drug information

Phenobarbital: Drug information
(For additional information see "Phenobarbital: Patient drug information" and see "Phenobarbital: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Luminal [DSC]
Pharmacologic Category
  • Antiseizure Agent, Barbiturate;
  • Barbiturate
Dosing: Adult
Alcohol withdrawal syndrome

Alcohol withdrawal syndrome (off-label use):

Severe or refractory withdrawal (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, followed by a taper of 10% dose reduction/day (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

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

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

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

Sedative/hypnotic withdrawal (off-label use): Several regimens have been evaluated:

Taper following dosage conversion: 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: 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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no specific dosage adjustments provided in the manufacturer's labeling; reduced doses are recommended. The following guidelines have been recommended by some clinicians:

CrCl ≥10 mL/minute: No dosage adjustment necessary (Ref).

CrCl <10 mL/minute: Administer dose every 12 to 16 hours (Ref).

Hemodialysis (moderately dialyzable [20% to 50%]): Administer dose before dialysis and 50% of dose after dialysis (Ref).

Peritoneal dialysis: 35% to 40% removed; administer 50% of normal dose (Ref).

Continuous renal replacement therapy (CRRT): Administer normal dose and monitor levels (Ref).

Dosing: Hepatic Impairment: Adult

There are no specific dosage adjustments provided in the manufacturer’s labeling; reduced doses are recommended. Phenobarbital exposure is increased with hepatic impairment; use with caution

Dosing: Pediatric

(For additional information see "Phenobarbital: Pediatric drug information")

Seizures, maintenance therapy

Seizures, maintenance therapy: Note: 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.

Manufacturer's labeling: Infants, Children, and Adolescents: Oral: 3 to 6 mg/kg/day.

Alternate dosing: Limited data available (Ref):

Initial: Oral:

Infants and Children ≤5 years: 3 to 5 mg/kg/day in 1 to 2 divided doses.

Children >5 years and Adolescents: 2 to 3 mg/kg/day in 1 to 2 divided doses.

Status epilepticus

Status epilepticus: 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

Hyperbilirubinemia: Limited data available: 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.

Dosing: Kidney Impairment: Pediatric

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).

Dosing: Hepatic Impairment: Pediatric

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.

Dosing: Older Adult

Avoid use (Ref).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Elixir, Oral:

Generic: 20 mg/5 mL (5 mL, 7.5 mL, 15 mL, 473 mL)

Solution, Injection, as sodium:

Luminal: 130 mg/mL (1 mL [DSC])

Generic: 65 mg/mL (1 mL); 130 mg/mL (1 mL)

Tablet, Oral:

Generic: 15 mg, 16.2 mg, 30 mg, 32.4 mg, 60 mg, 64.8 mg, 97.2 mg, 100 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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

Product Availability

Sezaby: FDA approved November 2022; availability anticipated in the fourth quarter of 2023. Information pertaining to this product within the monograph is pending revision. Sezaby is indicated for the treatment of neonatal seizures in term and preterm infants and is supplied as 100 mg of phenobarbital sodium lyophilized powder in single dose vials for reconstitution. Consult the prescribing information for additional information.

Controlled Substance

C-IV

Administration: Adult

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.

Administration: Pediatric

Oral: 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. 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. Discontinue administration of injection if patient complains of limb pain.

IM: For IM administration, inject deep into muscle; do not exceed 5 mL per injection site (adults) due to potential for tissue irritation.

Use: Labeled Indications

Sedation: Use as a sedative

Seizures: Management of generalized tonic-clonic, status epilepticus, and partial seizures

Use: Off-Label: Adult

Alcohol withdrawal syndrome; Sedative/hypnotic withdrawal

Medication Safety Issues
Sound-alike/look-alike issues:

PHENobarbital may be confused with PENTobarbital, Phenergan, phenytoin

Older Adult: High-Risk Medication:

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 2019]).

Pharmacy Quality Alliance (PQA): Phenobarbital is identified as a high-risk medication in patients 65 years and older on the PQA’s, Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (PQA 2017).

Adverse Reactions (Significant): Considerations
Cardiovascular effects

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)

CNS effects

Phenobarbital may cause CNS adverse reactions, including drowsiness, ataxia, vertigo, abnormality 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). 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)

Hypersensitivity reactions (delayed)

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: Presence of HLA-A*01:01 with phenobarbital hypersensitivity and HLA-B*13:01 with SCARs in Thai children may be potential risk factors (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)

Respiratory depression

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 (Ref)

• Concurrent use of antiseizure medications (Ref)

Suicidal ideation/tendencies

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)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Bradycardia, circulatory shock, hypotension (Doshi 2019), syncope

Dermatologic: Alopecia (areata universalis; associated with hypersensitivity syndrome) (Huang 2009), exfoliative dermatitis, 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)

Gastrointestinal: Constipation, nausea, vomiting

Hematologic & oncologic: 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: Abnormality in thinking (Iivanainen 1983), agitation, anxiety, ataxia (Iivanainen 1983), central nervous system depression (Iivanainen 1983), confusion, depression (Brent 1990), dizziness, drowsiness (Iivanainen 1983), hallucination, hangover effect, headache, insomnia, lethargy, memory impairment (Iivanainen 1983), nervousness, nightmares, paradoxical central nervous system stimulation (Verrotti 2018), psychiatric disturbance, vertigo

Neuromuscular & skeletal: Hyperkinetic muscle activity, laryngospasm, osteomalacia

Respiratory: Apnea, hypoventilation, respiratory depression

Miscellaneous: Fever

Contraindications

Hypersensitivity to phenobarbital, barbiturates, or any component of the formulation; marked hepatic impairment; dyspnea or airway obstruction; porphyria (manifest and latent).

Additional contraindications: IV only: Intra-arterial or SubQ administration; use in patients with a history of sedative/hypnotic substance use disorder; nephritic patients (large doses).

Warnings/Precautions

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. Avoid use in patients showing the premonitory signs of hepatic coma.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism.

• Hypoadrenalism: Use with caution in patients with hypoadrenalism.

• 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:

• 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: 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.

Warnings: Additional Pediatric Considerations

Rapid IV administration may cause respiratory depression, apnea, laryngospasm, or hypotension; use with caution in hemodynamically unstable patients (hypotension or shock). Phenobarbital may cause CNS depression and effects with other sedative drugs may be potentiated; when treating status epilepticus, additional respiratory support may be required particularly when maximizing loading dose or if concurrent sedative therapy (AAP [Shenoi 2020]).

Cognitive deficits observed with phenobarbital were further described in a retrospective chart review of 280 pediatric patients who had received either phenobarbital, levetiracetam, or both for treatment of neonatal seizures. A subset of the study group (n=67) had a Bayley Scales of Infant Development (BSID) completed at 24 months corrected age. Based on the analysis of cumulative exposures, the investigators observed that increased phenobarbital exposure was associated with a significant decrease in BSID cognitive (8 points) and motor (9 points) scores and an increased probability for the development of cerebral palsy (2.3-fold) for every 100 mg/kg of phenobarbital exposure (Maitre 2013).

Pediatric patients may be at increased risk for vitamin D deficiency; with chronic therapy, phenobarbital may cause catabolism of vitamin D; the daily vitamin D requirement may be increased in these patients (≥400 units/day); vitamin D status should be periodically monitored with laboratory data (Misra 2008; Wagner 2008). A retrospective study demonstrated that enzyme-inducing antiepileptic drugs (AEDs) (carbamazepine, phenobarbital, and phenytoin) increased systemic clearance of antileukemic drugs (teniposide and methotrexate) and were associated with a worse event-free survival, CNS relapse, and hematologic relapse (ie, lower efficacy), in B-lineage ALL children receiving chemotherapy; the authors recommend using nonenzyme-inducing AEDs in patients receiving chemotherapy for ALL (Relling 2000).

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.

Metabolism/Transport Effects

Substrate of CYP2C19 (minor), 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), CYP2C9 (weak), CYP3A4 (strong), UGT1A1

Drug Interactions

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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abemaciclib. Risk X: Avoid combination

Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid when possible. If the combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during combined use. Reduce abiraterone dose back to the prior dose and frequency once strong inducer is discontinued. Risk D: Consider therapy modification

Acalabrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Risk D: Consider therapy modification

Acetaminophen: PHENobarbital may increase the metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor therapy

Adagrasib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Adagrasib. Risk X: Avoid combination

Afatinib: PHENobarbital may decrease the 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

Albendazole: PHENobarbital may decrease serum concentrations of the active metabolite(s) of Albendazole. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfacalcidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alfacalcidol. Risk C: Monitor therapy

Alfentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and strong 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alpelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alpelisib. Risk X: Avoid combination

ALPRAZolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of ALPRAZolam. Risk C: Monitor therapy

Amiodarone: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Amiodarone. CYP3A4 Inducers (Strong) may decrease the serum concentration of Amiodarone. Risk C: Monitor therapy

AmLODIPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of AmLODIPine. Risk C: Monitor therapy

Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products. Risk X: Avoid combination

Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Management: Avoid concurrent use of apixaban with strong CYP3A4 inducers whenever possible. Use of a strong CYP3A4 inducer with apixaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Risk D: Consider therapy modification

Apremilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast. Risk X: Avoid combination

Aprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant. Risk X: Avoid combination

ARIPiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of ARIPiprazole. Management: For indications other than major depressive disorder: double the oral aripiprazole dose over 1 to 2 weeks and closely monitor. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Risk D: Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Risk D: Consider therapy modification

Artemether and Lumefantrine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether and Lumefantrine. Risk X: Avoid combination

Asunaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir. Risk X: Avoid combination

Atazanavir: May decrease the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Atazanavir. Management: Coadministration of phenobarbital and atazanavir without ritonavir is not recommended. If atazanavir and ritonavir are coadministered with phenobarbital, phenobarbital dose increases may be required. Risk D: Consider therapy modification

Atogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Atogepant. Management: The recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with strong or moderate CYP3A4 inducers. Risk D: Consider therapy modification

Atorvastatin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Atorvastatin. Risk C: Monitor therapy

Avacopan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avacopan. Risk X: Avoid combination

Avanafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avanafil. Risk X: Avoid combination

Avapritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avapritinib. Risk X: Avoid combination

Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Barnidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Barnidipine. Risk C: Monitor therapy

Bazedoxifene: PHENobarbital may decrease the 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 therapy

Bedaquiline: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Bedaquiline. CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Risk X: Avoid combination

Belumosudil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Belumosudil. Management: Increase the dose of belumosudil to 200 mg twice daily when coadministered with strong CYP3A4 inducers. Risk D: Consider therapy modification

Benidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benidipine. Risk C: Monitor therapy

Benperidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benperidol. Risk C: Monitor therapy

Benzhydrocodone: PHENobarbital may enhance the CNS depressant effect of Benzhydrocodone. PHENobarbital may decrease serum concentrations of the active metabolite(s) 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 strong CYP3A4 inducer, monitor for decreased benzhydrocodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

Betamethasone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Betamethasone (Systemic). Risk C: Monitor therapy

Bictegravir: PHENobarbital may decrease the 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

Bisoprolol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bisoprolol. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect 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 enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Risk X: Avoid combination

Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. Risk X: Avoid combination

Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if the strong CYP3A4 inducer is discontinued. Risk D: Consider therapy modification

Brigatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brigatinib. Risk X: Avoid combination

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Brivaracetam: PHENobarbital may decrease the serum concentration of Brivaracetam. Risk C: Monitor therapy

Bromocriptine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bromocriptine. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Brotizolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brotizolam. Risk C: Monitor therapy

Buprenorphine: PHENobarbital may enhance the CNS depressant effect of Buprenorphine. PHENobarbital may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider therapy modification

BuPROPion: CYP2B6 Inducers (Weak) may decrease the serum concentration of BuPROPion. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inducers (Strong) may decrease the serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed. Risk D: Consider therapy modification

Cabazitaxel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabazitaxel. Risk C: Monitor therapy

Cabotegravir: UGT1A1 Inducers may decrease the serum concentration of Cabotegravir. Risk X: Avoid combination

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, increase cabozantinib capsules (Cometriq) by 40 mg from previous dose, max 180 mg daily. Increase cabozantinib tablets (Cabometyx) by 20 mg from previous dose, max 80 mg daily Risk D: Consider therapy modification

Calcifediol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcifediol. Risk C: Monitor therapy

Calcitriol (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcitriol (Systemic). Risk C: Monitor therapy

Canagliflozin: PHENobarbital may decrease the 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: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Cannabidiol. CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabidiol. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabis: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor therapy

Capmatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Capmatinib. Risk X: Avoid combination

CarBAMazepine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Cariprazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cariprazine. Risk X: Avoid combination

Carmustine: PHENobarbital may decrease the 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 the serum concentration of PHENobarbital. Risk C: Monitor therapy

Ceritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib. Risk X: Avoid combination

Charcoal, Activated: May decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

Chloramphenicol (Systemic): PHENobarbital may decrease the serum concentration of Chloramphenicol (Systemic). Chloramphenicol (Systemic) may increase the serum concentration of PHENobarbital. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

ChlorproPAMIDE: CYP3A4 Inducers (Strong) may decrease the serum concentration of ChlorproPAMIDE. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the 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

Cilnidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cilnidipine. Risk C: Monitor therapy

Citalopram: CYP3A4 Inducers (Strong) may decrease the serum concentration of Citalopram. Risk C: Monitor therapy

Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Strong) may decrease the serum concentration 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 may impair clarithromycin efficacy. Risk D: Consider therapy modification

Clindamycin (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Clindamycin (Systemic). Risk C: Monitor therapy

ClonazePAM: CYP3A4 Inducers (Strong) may decrease the serum concentration of ClonazePAM. Risk C: Monitor therapy

CloZAPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine. Management: Avoid use with strong CYP3A4 inducers when possible. If combined, monitor patients closely and consider clozapine dose increases. Clozapine dose reduction and further monitoring may be required when strong CYP3A4 inducers are discontinued. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Cobicistat: PHENobarbital may decrease the serum concentration of Cobicistat. Risk X: Avoid combination

Cobimetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cobimetinib. Risk X: Avoid combination

Codeine: PHENobarbital may enhance the CNS depressant effect of Codeine. PHENobarbital may decrease the serum concentration of Codeine. Management: Avoid use of codeine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Risk D: Consider therapy modification

Copanlisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Copanlisib. Risk X: Avoid combination

Cosyntropin: May enhance the hepatotoxic effect of PHENobarbital. Risk C: Monitor therapy

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Risk X: Avoid combination

CycloSPORINE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of CycloSPORINE (Systemic). Management: Monitor closely for reduced cyclosporine concentrations when combined with strong CYP3A4 inducers. Cyclosporine dose increases will likely be required to maintain adequate serum concentrations. Risk D: Consider therapy modification

Cyproterone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cyproterone. Risk C: Monitor therapy

Dabigatran Etexilate: PHENobarbital may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy

Daclatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir. Risk X: Avoid combination

Dapsone (Systemic): May enhance the adverse/toxic effect of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Dapsone (Systemic). Risk C: Monitor therapy

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy

Daridorexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daridorexant. Risk X: Avoid combination

Darunavir: May decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

Dasabuvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasabuvir. Risk X: Avoid combination

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid concurrent use of dasatinib with strong CYP3A4 inducers when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification

Deferasirox: PHENobarbital may decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Risk D: Consider therapy modification

Deflazacort: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Risk X: Avoid combination

Delamanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Delamanid. Risk X: Avoid combination

Delavirdine: PHENobarbital may decrease the serum concentration of Delavirdine. Risk X: Avoid combination

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexAMETHasone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of DexAMETHasone (Systemic). Management: Consider dexamethasone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced dexamethasone efficacy. Consider avoiding this combination when treating life threatening conditions (ie, multiple myeloma). Risk D: Consider therapy modification

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect 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 the serum concentration of PHENobarbital. Risk C: Monitor therapy

DiazePAM: CYP3A4 Inducers (Strong) may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

DilTIAZem: CYP3A4 Inducers (Strong) may decrease the serum concentration of DilTIAZem. Management: Consider alternatives to this combination when possible. If combined, monitor for decreased diltiazem efficacy. Risk D: Consider therapy modification

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Disopyramide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Disopyramide. Risk C: Monitor therapy

Disulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid combination

DOCEtaxel: CYP3A4 Inducers (Strong) may decrease the serum concentration of DOCEtaxel. Risk C: Monitor therapy

Dolutegravir: PHENobarbital may decrease the serum concentration of Dolutegravir. Risk X: Avoid combination

Domperidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Domperidone. Risk C: Monitor therapy

Doravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Doravirine. Risk X: Avoid combination

Doxercalciferol: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

Doxycycline: Barbiturates may decrease the serum concentration of Doxycycline. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol. Risk C: Monitor therapy

Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Risk X: Avoid combination

Droperidol: May enhance the CNS depressant effect 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 (Strong) may decrease the serum concentration of Duvelisib. Risk X: Avoid combination

Dydrogesterone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dydrogesterone. Risk C: Monitor therapy

Ebastine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ebastine. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ebastine. Risk C: Monitor therapy

Efavirenz: CYP3A4 Inducers (Strong) may decrease the serum concentration of Efavirenz. Risk C: Monitor therapy

Elagolix: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elagolix. Risk C: Monitor therapy

Elagolix, Estradiol, and Norethindrone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elagolix, Estradiol, and Norethindrone. Risk C: Monitor therapy

Elbasvir and Grazoprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk X: Avoid combination

Eliglustat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat. Risk X: Avoid combination

Elvitegravir: PHENobarbital may decrease the serum concentration of Elvitegravir. Risk X: Avoid combination

Encorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Encorafenib. Risk X: Avoid combination

Enfortumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Entrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Entrectinib. Risk X: Avoid combination

Enzalutamide: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Enzalutamide. CYP3A4 Inducers (Strong) may decrease the serum concentration of Enzalutamide. Management: Consider using an alternative agent that has no or minimal CYP3A4 induction potential when possible. If this combination cannot be avoided, increase the dose of enzalutamide from 160 mg daily to 240 mg daily. Risk D: Consider therapy modification

Eplerenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eplerenone. Risk C: Monitor therapy

Eravacycline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers. Risk D: Consider therapy modification

Erdafitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erdafitinib. Risk X: Avoid combination

Erlotinib: CYP3A4 Inducers (Strong) may decrease the 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

Escitalopram: CYP3A4 Inducers (Strong) may decrease the serum concentration of Escitalopram. Risk C: Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Eslicarbazepine: PHENobarbital may decrease the serum concentration of Eslicarbazepine. Risk C: Monitor therapy

Estazolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Estazolam. Risk C: Monitor therapy

Estrogen Derivatives: CYP3A4 Inducers (Strong) may decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Eszopiclone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eszopiclone. Risk C: Monitor therapy

Ethosuximide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ethosuximide. Risk C: Monitor therapy

Etizolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etizolam. Risk C: Monitor therapy

Etoposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. Risk D: Consider therapy modification

Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response. Risk D: Consider therapy modification

Etoricoxib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoricoxib. Risk C: Monitor therapy

Etravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etravirine. Risk X: Avoid combination

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers if possible. If coadministration cannot be avoided, monitor for decreased everolimus serum concentrations and effects, and adjust everolimus dose as needed. Risk D: Consider therapy modification

Evogliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Evogliptin. Risk C: Monitor therapy

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Increase the exemestane dose to 50 mg once daily in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity or inadequate clinical response. Risk D: Consider therapy modification

Fedratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fedratinib. Risk X: Avoid combination

Felbamate: PHENobarbital may decrease the serum concentration of Felbamate. Felbamate may increase the 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: CYP3A4 Inducers (Strong) may decrease the serum concentration of Felodipine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced felodipine efficacy and the need for felodipine dose increases. Risk D: Consider therapy modification

Fenfluramine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fenfluramine. Management: Avoid concurrent use of strong CYP3A4 inducers with fenfluramine when possible. If combined use cannot be avoided, consider increasing the fenfluramine dose, but do not exceed the fenfluramine maximum daily dose. Risk D: Consider therapy modification

FentaNYL: PHENobarbital may enhance the CNS depressant effect of FentaNYL. PHENobarbital may decrease the serum concentration of FentaNYL. Management: Avoid use of fentanyl and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider therapy modification

Fesoterodine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

Fexinidazole: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Fexinidazole. Risk X: Avoid combination

Finerenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Finerenone. Risk X: Avoid combination

Flibanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Flibanserin. Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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 the serum concentration of PHENobarbital. Risk C: Monitor therapy

Fosamprenavir: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant. Risk X: Avoid combination

Fosnetupitant: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosnetupitant. Risk X: Avoid combination

Fosphenytoin: May enhance the CNS depressant effect of PHENobarbital. Fosphenytoin may increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Fosphenytoin. Risk C: Monitor therapy

Fostamatinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostamatinib. Risk X: Avoid combination

Fostemsavir: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostemsavir. Risk X: Avoid combination

Futibatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Futibatinib. Risk C: Monitor therapy

Ganaxolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and strong CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider therapy modification

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase the gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Risk D: Consider therapy modification

Gemigliptin: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Gemigliptin. CYP3A4 Inducers (Strong) may decrease the serum concentration of Gemigliptin. Risk X: Avoid combination

Gestrinone: PHENobarbital may decrease the serum concentration of Gestrinone. Risk C: Monitor therapy

Gilteritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gilteritinib. Risk C: Monitor therapy

Glasdegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glasdegib. Risk X: Avoid combination

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy

Griseofulvin: Barbiturates may decrease the serum concentration of Griseofulvin. Risk C: Monitor therapy

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the 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: CYP3A4 Inducers (Strong) may decrease the serum concentration of Haloperidol. Risk C: Monitor therapy

Hemin: Barbiturates may diminish the therapeutic effect of Hemin. Risk X: Avoid combination

Hormonal Contraceptives: CYP3A4 Inducers (Strong) may decrease the 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 strong CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

HYDROcodone: PHENobarbital may enhance the CNS depressant effect of HYDROcodone. PHENobarbital may decrease the serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

Hydrocortisone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect 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 (Strong) may decrease the serum concentration of Ibrexafungerp. Risk X: Avoid combination

Ibrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrutinib. Risk X: Avoid combination

Idelalisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib. Risk X: Avoid combination

Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid use of imatinib and strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Doses up to 1200 mg/day (600 mg twice daily) have been used. Risk D: Consider therapy modification

Indinavir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and strong 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

Infigratinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination

Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Management: Avoid administration of strong CYP3A4 inducers during irinotecan treatment, and substitute non-CYP3A4 inducing agents at least 2 weeks prior to irinotecan initiation, whenever possible. If combined, monitor for reduced irinotecan efficacy. Risk D: Consider therapy modification

Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Risk X: Avoid combination

Isradipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Isradipine. Risk C: Monitor therapy

Istradefylline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Istradefylline. Risk X: Avoid combination

Itraconazole: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Itraconazole. CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole. Risk X: Avoid combination

Ivabradine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivabradine. Risk X: Avoid combination

Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor. Risk X: Avoid combination

Ivosidenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivosidenib. Risk X: Avoid combination

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Risk D: Consider therapy modification

Ixazomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixazomib. Risk X: Avoid combination

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ketamine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ketamine. Risk C: Monitor therapy

Ketoconazole (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Ketoconazole (Systemic). Management: The use of ketoconazole concurrently with or within 2 weeks of a strong CYP3A4 inducer is not recommended. If such a combination cannot be avoided, monitor patients closely for evidence of diminished clinical response to ketoconazole. Risk D: Consider therapy modification

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lacidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lacidipine. Risk C: Monitor therapy

LamoTRIgine: PHENobarbital may enhance the adverse/toxic effect of LamoTRIgine. Specifically, the risk for hematologic toxicities may be increased. PHENobarbital may decrease the serum concentration of LamoTRIgine. Management: For patients taking 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 (Strong) may decrease the serum concentration of Lapatinib. Management: If concomitant use cannot be avoided, titrate lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk D: Consider therapy modification

Larotrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer's half-life. Risk D: Consider therapy modification

Ledipasvir: PHENobarbital may decrease the serum concentration of Ledipasvir. Risk X: Avoid combination

Lefamulin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lemborexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lemborexant. Risk X: Avoid combination

Lenacapavir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lenacapavir. Risk X: Avoid combination

Lercanidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lercanidipine. Risk C: Monitor therapy

Letermovir: UGT1A1 Inducers may decrease the serum concentration of Letermovir. Risk X: Avoid combination

Leucovorin Calcium-Levoleucovorin: May decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

Leuprolide and Norethindrone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Leuprolide and Norethindrone. Specifically, norethindrone concentrations may be decreased. Risk C: Monitor therapy

Levamlodipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Levamlodipine. Risk C: Monitor therapy

LevETIRAcetam: May enhance the CNS depressant effect of PHENobarbital. PHENobarbital may decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

Levoketoconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Levoketoconazole. Risk X: Avoid combination

Levomefolate: May decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

Levomethadone: PHENobarbital may enhance the CNS depressant effect of Levomethadone. PHENobarbital may decrease the 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): CYP3A4 Inducers (Strong) may diminish the therapeutic effect of Levonorgestrel (IUD). CYP3A4 Inducers (Strong) may decrease the serum concentration of Levonorgestrel (IUD). Risk C: Monitor therapy

Lidocaine (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

LinaGLIPtin: CYP3A4 Inducers (Strong) may decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lonafarnib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lonafarnib. Risk X: Avoid combination

Lopinavir: PHENobarbital may decrease the 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 (Strong) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib. Risk X: Avoid combination

Lovastatin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lovastatin. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Risk X: Avoid combination

Lumateperone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumateperone. Risk X: Avoid combination

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Risk X: Avoid combination

Lurbinectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurbinectedin. Risk X: Avoid combination

Macimorelin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macimorelin. Risk X: Avoid combination

Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. Risk X: Avoid combination

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Manidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. Risk D: Consider therapy modification

Maraviroc: CYP3A4 Inducers (Strong) may decrease the 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 the 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 (Strong) may decrease the serum concentration of Mavacamten. Risk X: Avoid combination

Mefloquine: May diminish the therapeutic effect of PHENobarbital. PHENobarbital may decrease the serum concentration of Mefloquine. Mefloquine may decrease the 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 enhance the CNS depressant effect of Meperidine. PHENobarbital may increase serum concentrations of the active metabolite(s) 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

Methadone: PHENobarbital may enhance the CNS depressant effect of Methadone. PHENobarbital may decrease the 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: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combination

Methoxyflurane: Barbiturates may enhance the nephrotoxic effect of Methoxyflurane. Barbiturates may increase the metabolism of Methoxyflurane. Risk X: Avoid combination

Methylergonovine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Methylergonovine. Risk C: Monitor therapy

Methylfolate: May decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

Methylphenidate: May increase the serum concentration of PHENobarbital. Risk C: Monitor therapy

MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of PHENobarbital. A disulfiram-like reaction may occur if combined with phenobarbital dosage forms that contain propylene glycol or alcohol. PHENobarbital may decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor therapy

MetyraPONE: Antiseizure Agents may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Mianserin: May enhance the CNS depressant effect of Barbiturates. Mianserin may diminish the therapeutic effect of Barbiturates. Barbiturates may decrease the serum concentration of Mianserin. Risk X: Avoid combination

Midazolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Midazolam. Risk C: Monitor therapy

Midostaurin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Midostaurin. Risk X: Avoid combination

MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Risk X: Avoid combination

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirabegron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirabegron. Risk C: Monitor therapy

Mirodenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Risk D: Consider therapy modification

Mirtazapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirtazapine. Risk C: Monitor therapy

Mitapivat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mitapivat. Risk X: Avoid combination

Mobocertinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Mobocertinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Mobocertinib. Risk X: Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Barbiturates. Risk C: Monitor therapy

Naldemedine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naldemedine. Risk X: Avoid combination

Naloxegol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol. Risk X: Avoid combination

Nateglinide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nateglinide. Risk C: Monitor therapy

Nelfinavir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nelfinavir. Risk C: Monitor therapy

Neratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Neratinib. Risk X: Avoid combination

Netupitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant. Risk X: Avoid combination

Nevirapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nevirapine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced nevirapine efficacy. Risk D: Consider therapy modification

NiCARdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiCARdipine. Risk C: Monitor therapy

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Management: Avoid coadministration of nifedipine with strong CYP3A4 inducers when possible and if combined, monitor patients closely for clinical signs of diminished nifedipine response. Risk D: Consider therapy modification

Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination

Nilvadipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilvadipine. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiMODipine. Risk X: Avoid combination

Nintedanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nintedanib. Risk C: Monitor therapy

Nirmatrelvir and Ritonavir: May decrease the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Nirmatrelvir and Ritonavir. Risk X: Avoid combination

Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination

Nitrazepam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nitrazepam. Risk C: Monitor therapy

Nitrendipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nitrendipine. Risk C: Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

OLANZapine: CYP1A2 Inducers (Weak) may decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Olaparib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib. Risk X: Avoid combination

Olmutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olmutinib. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Olutasidenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olutasidenib. Risk X: Avoid combination

Ondansetron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ondansetron. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect 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

Orelabrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Orelabrutinib. Risk X: Avoid combination

Orlistat: May decrease the serum concentration of Antiseizure Agents. Risk C: Monitor therapy

Ornidazole: PHENobarbital may decrease the serum concentration of Ornidazole. Risk C: Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Osilodrostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osilodrostat. Risk C: Monitor therapy

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Management: Avoid coadministration of osimertinib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase osimertinib to 160 mg daily. Reduce osimertinib to 80 mg daily 3 weeks after discontinuation of the strong CYP3A4 inducer. Risk D: Consider therapy modification

OXcarbazepine: CYP3A4 Inducers (Strong) may decrease the serum concentration of OXcarbazepine. Specifically, the concentrations of the 10-monohydroxy active metabolite of oxcarbazepine may be decreased. Risk C: Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: PHENobarbital may enhance the CNS depressant effect of OxyCODONE. PHENobarbital may decrease the serum concentration of OxyCODONE. Management: Avoid use of oxycodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

PACLitaxel (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inducers (Strong) may decrease the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Pacritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pacritinib. Risk X: Avoid combination

Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. Risk X: Avoid combination

Palovarotene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palovarotene. Risk X: Avoid combination

Panobinostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat. Risk X: Avoid combination

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

PAZOPanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib. Risk X: Avoid combination

Pemigatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pemigatinib. Risk X: Avoid combination

Perampanel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with strong 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

Pexidartinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pexidartinib. Risk X: Avoid combination

Phenytoin: May enhance the CNS depressant effect of PHENobarbital. PHENobarbital may decrease the serum concentration of Phenytoin. Phenytoin may increase the serum concentration of PHENobarbital. Risk C: Monitor therapy

Pimavanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin. Risk X: Avoid combination

Piperaquine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Piperaquine. Risk X: Avoid combination

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pitolisant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: If on a stable pitolisant dose of 8.9 mg or 17.8 mg/day and starting a strong CYP3A4 inducer, double the pitolisant dose over 7 days (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Reduce pitolisant dose by 50% when the inducer is discontinued. Risk D: Consider therapy modification

Polatuzumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Risk C: Monitor therapy

PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. Management: Avoid coadministration of ponatinib with strong CYP3A4 inducers unless the potential benefit of concomitant treatment outweighs the risk of reduced ponatinib exposure. Monitor patients for reduced ponatinib efficacy if combined. Risk D: Consider therapy modification

Ponesimod: UGT1A1 Inducers may decrease the serum concentration of Ponesimod. Risk X: Avoid combination

Pralsetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pralsetinib. Management: Avoid concomitant use of pralsetinib with strong CYP3A4 inducers when possible. If combined, increase the starting dose of pralsetinib to double the current pralsetinib dosage starting on day 7 of coadministration. Risk D: Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Risk X: Avoid combination

PrednisoLONE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy

PredniSONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE. Risk C: Monitor therapy

Pretomanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pretomanid. Risk X: Avoid combination

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Propacetamol: PHENobarbital may increase the metabolism of Propacetamol. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor therapy

Propafenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Propafenone. Risk C: Monitor therapy

Pyridoxine: May decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: An increase in quetiapine dose (as much as 5 times the regular dose) may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7 to 14 days of discontinuing the inducer. Risk D: Consider therapy modification

QuiNIDine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

QuiNINE: May increase the serum concentration of PHENobarbital. PHENobarbital may decrease the 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

Radotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Risk D: Consider therapy modification

Ramelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ramelteon. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination

Reboxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Reboxetine. Risk C: Monitor therapy

Regorafenib: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Risk X: Avoid combination

Repaglinide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

Ribociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ribociclib. Risk X: Avoid combination

Rifabutin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rifabutin. Risk C: Monitor therapy

Rifapentine: May decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

Rilpivirine: PHENobarbital may decrease the serum concentration of Rilpivirine. Risk X: Avoid combination

Rimegepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rimegepant. Risk X: Avoid combination

Riociguat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Riociguat. Risk C: Monitor therapy

Ripretinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ripretinib. Risk X: Avoid combination

RisperiDONE: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of RisperiDONE. CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Careful monitoring for reduced risperidone efficacy and possible dose adjustment are recommended when combined with strong CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider therapy modification

Ritonavir: May decrease the serum concentration of PHENobarbital. PHENobarbital may decrease the 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: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Management: Consider alternatives to use of rivaroxaban with strong CYP3A4 inducers. Use of a strong CYP3A4 inducer with rivaroxaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Risk D: Consider therapy modification

Roflumilast (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Roflumilast (Systemic). CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast (Systemic). Risk X: Avoid combination

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Risk X: Avoid combination

RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Risk X: Avoid combination

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Rufinamide. Risk C: Monitor therapy

Ruxolitinib (Systemic): CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ruxolitinib (Systemic). CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib (Systemic). Risk C: Monitor therapy

Sacituzumab Govitecan: UGT1A1 Inducers may decrease serum concentrations of the active metabolite(s) of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be decreased. Risk X: Avoid combination

Samidorphan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Samidorphan. Risk X: Avoid combination

Sapropterin: PHENobarbital may decrease the serum concentration of Sapropterin. Specifically, phenobarbital may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy

Saquinavir: PHENobarbital may decrease the serum concentration of Saquinavir. Risk X: Avoid combination

SAXagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of SAXagliptin. Risk C: Monitor therapy

Secnidazole: Products Containing Ethanol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination

Secnidazole: Products Containing Propylene Glycol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination

Selpercatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Selpercatinib. Risk X: Avoid combination

Selumetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Selumetinib. Risk X: Avoid combination

Sertindole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sertindole. Risk C: Monitor therapy

Sertraline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sertraline. Risk C: Monitor therapy

Sildenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sildenafil. Risk C: Monitor therapy

Simeprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir. Risk X: Avoid combination

Simvastatin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simvastatin. Risk C: Monitor therapy

Sirolimus (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus (Conventional). Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Risk D: Consider therapy modification

Sirolimus (Protein Bound): CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

Sofosbuvir: PHENobarbital may decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination

Solifenacin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Solifenacin. Risk C: Monitor therapy

Sonidegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sonidegib. Risk X: Avoid combination

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk X: Avoid combination

Sotorasib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sotorasib. Risk X: Avoid combination

Stiripentol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Stiripentol. Management: Avoid concomitant use of stiripentol and strong CYP3A4 inducers when possible. If combined, monitor for reduced stiripentol efficacy and increase the stiripentol dose as needed. Risk D: Consider therapy modification

SUFentanil: PHENobarbital may enhance the CNS depressant effect of SUFentanil. PHENobarbital may decrease the serum concentration of SUFentanil. Management: Avoid use of sufentanil and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased sufentanil efficacy and withdrawal if combined. Risk D: Consider therapy modification

Sulthiame: May enhance the adverse/toxic effect of PHENobarbital. Risk C: Monitor therapy

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If combined, increase sunitinib dose to a max of 87.5 mg daily when treating GIST or RCC. Increase sunitinib dose to a max of 62.5 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect 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

Tacrolimus (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Tacrolimus (Systemic). Management: Monitor for decreased tacrolimus concentrations and effects when combined with strong CYP3A4 inducers. Tacrolimus dose increases will likely be needed during concomitant use. Risk D: Consider therapy modification

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction or benign prostatic hypertrophy: monitor for decreased effectiveness - no standard dose adjustment is recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Risk D: Consider therapy modification

Tamoxifen: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Strong) may decrease the serum concentration of Tamoxifen. Risk X: Avoid combination

Tasimelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon. Risk X: Avoid combination

Taurursodiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Taurursodiol. Specifically, the concentrations of phenylbutyrate may be decreased. Risk C: Monitor therapy

Tazemetostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tazemetostat. Risk X: Avoid combination

Telithromycin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Telithromycin. Risk X: Avoid combination

Temsirolimus: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be decreased. CYP3A4 Inducers (Strong) may decrease the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inducers. If coadministration is unavoidable, increase temsirolimus dose to 50 mg per week. Resume previous temsirolimus dose after discontinuation of the strong CYP3A4 inducer. Risk D: Consider therapy modification

Teniposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Teniposide. Risk C: Monitor therapy

Tenofovir Alafenamide: PHENobarbital may decrease the serum concentration of Tenofovir Alafenamide. Risk X: Avoid combination

Tepotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tepotinib. Risk X: Avoid combination

Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Management: Avoid use of the tetrahydrocannabinol/cannabidiol oromucosal spray and strong CYP3A4 inducers when possible. If combined use is necessary, careful titration is recommended, notably within the two weeks following discontinuation of the inducer. Risk D: Consider therapy modification

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tezacaftor and Ivacaftor. Risk X: Avoid combination

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Theophylline Derivatives: Barbiturates may decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Thiotepa: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Strong) may decrease the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects. Risk D: Consider therapy modification

Thiothixene: PHENobarbital may decrease the serum concentration of Thiothixene. Risk C: Monitor therapy

Thyroid Products: PHENobarbital may decrease the serum concentration of Thyroid Products. Risk C: Monitor therapy

TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Risk X: Avoid combination

Timolol (Systemic): PHENobarbital may enhance the hypotensive effect of Timolol (Systemic). PHENobarbital may decrease the serum concentration of Timolol (Systemic). Risk C: Monitor therapy

Tipranavir: PHENobarbital may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy

Tivozanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tivozanib. Risk X: Avoid combination

Tofacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib. Risk X: Avoid combination

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Risk X: Avoid combination

Toremifene: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Toremifene. CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination

Trabectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin. Risk X: Avoid combination

TraMADol: PHENobarbital may enhance the CNS depressant effect of TraMADol. PHENobarbital may decrease the serum concentration of TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider therapy modification

TraZODone: CYP3A4 Inducers (Strong) may decrease the serum concentration of TraZODone. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers. Risk D: Consider therapy modification

Triamcinolone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Triamcinolone (Systemic). Risk C: Monitor therapy

Triazolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Triazolam. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced triazolam efficacy. Substantial triazolam dose increases will likely be required. Risk D: Consider therapy modification

Tricyclic Antidepressants: Barbiturates may increase the 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tropisetron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tropisetron. Risk C: Monitor therapy

Tucatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tucatinib. Risk X: Avoid combination

Ubrogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ubrogepant. Risk X: Avoid combination

Udenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Udenafil. Risk C: Monitor therapy

Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Risk X: Avoid combination

Upadacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Upadacitinib. Risk X: Avoid combination

Valbenazine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valproate Products: May increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Vandetanib: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Vandetanib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Risk X: Avoid combination

Velpatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Risk X: Avoid combination

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Management: Avoid coadministration of vemurafenib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase the vemurafenib dose by 240 mg as tolerated. Resume prior vemurafenib dose 2 weeks after discontinuation of strong CYP3A4 inducer. Risk D: Consider therapy modification

Venetoclax: CYP3A4 Inducers (Strong) may decrease the serum concentration of Venetoclax. Risk X: Avoid combination

Verapamil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Verapamil. Management: Consider alternatives to this combination. If combined, monitor for reduced verapamil efficacy. Verapamil dose increases may be necessary. Risk D: Consider therapy modification

Vilazodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1 to 2 weeks after inducer discontinuation. Risk D: Consider therapy modification

VinCRIStine: CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine. Risk C: Monitor therapy

VinCRIStine (Liposomal): CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

Vinflunine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinflunine. Risk X: Avoid combination

Vinorelbine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinorelbine. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Barbiturates may increase the 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 (Strong) may decrease the serum concentration of Voclosporin. Risk X: Avoid combination

Vonoprazan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vonoprazan. Risk X: Avoid combination

Vorapaxar: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar. Risk X: Avoid combination

Voriconazole: PHENobarbital may decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Vortioxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Risk D: Consider therapy modification

Voxelotor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,500 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 (Strong) may decrease the serum concentration of Voxilaprevir. Risk X: Avoid combination

Zaleplon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zaleplon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Risk D: Consider therapy modification

Zanubrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zanubrutinib. Risk X: Avoid combination

Ziprasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ziprasidone. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of PHENobarbital. PHENobarbital may decrease the serum concentration of Zonisamide. Risk C: Monitor therapy

Zopiclone: PHENobarbital may enhance the CNS depressant effect of Zopiclone. PHENobarbital may decrease the serum concentration of Zopiclone. Risk C: Monitor therapy

Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy

Food Interactions

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.

Pregnancy Considerations

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).

Breastfeeding Considerations

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.

Dietary Considerations

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.

Monitoring Parameters

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.

Reference Range

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 to 172 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 micromole/L) (Hiemke 2018).

Mechanism of Action

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.

Pharmacokinetics

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).

Pricing: US

Elixir (PHENobarbital Oral)

20 mg/5 mL (per mL): $0.19 - $0.20

Solution (PHENobarbital Sodium Injection)

65 mg/mL (per mL): $25.00 - $31.62

130 mg/mL (per mL): $67.50 - $82.08

Tablets (PHENobarbital Oral)

15 mg (per each): $0.17 - $0.30

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): $0.53

64.8 mg (per each): $0.19 - $0.84

97.2 mg (per each): $0.25 - $1.19

100 mg (per each): $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.

Brand Names: International
  • Alepsal (AR, CR, DO, GT, HN, MX, NI, PA, SV);
  • Aparoxal (FR);
  • Barbee (IN);
  • Barbilettae (FI);
  • Barbiphenyl (FI);
  • Bialminal (PT);
  • Carbital (BR);
  • Comizial (IT);
  • Dormital (PY);
  • Edhanol (BR);
  • Emgard (IN);
  • Farmacoletas (UY);
  • Farmaconal (UY);
  • Fenemal (DK, IS, NO, SE);
  • Fenobarbital (PE, RO);
  • Fenobarbital FNA (NL);
  • Fenobarbitale (IT);
  • Fenobarbitale Sodico (IT);
  • Fenocris (BR);
  • Fenotal (PY);
  • Fenros (AR);
  • Fenton (PK);
  • Garbital (BR);
  • Gardenal (AR, BE, BR, ES, FR, GR, IN, LB, LU, VE, ZA);
  • Gardenal Sodium (GB);
  • Gardenale (IT);
  • Gardenale[inj.] (IT);
  • Kaneuron (FR, GR);
  • Lethyl (ZA);
  • Luminal (AR, CZ, DE, ES, KR, PH, PT, SK, TR);
  • Luminale (IT);
  • Luminaletas (AR, ES, PT);
  • Luminalette (IT);
  • Luminaletten (DE, TR);
  • Luminale[inj.] (IT);
  • Luminalum (PL);
  • Neurobiol (IT);
  • Noberbar (JP);
  • Pevalon (CY);
  • Phenaemal (CZ, EE, SK);
  • Phenaemaletten (CZ);
  • Phenobal (JP);
  • Phenobarbiton (HR);
  • Phenobarbiton-natrium (HR);
  • Phenobarbitone (AU, IL);
  • Phenobarbitone Injection (GB);
  • Phenotal (JO, TH);
  • Phental (ID);
  • Phincotomaline (EG);
  • Rumil (TW);
  • Sedabarb (ZA);
  • Sevenal (HU);
  • Sevenaletta (HU);
  • Sibital (ID);
  • Solminotic (EG);
  • Tridezibarbitur (AT);
  • Uni-Feno (HK)


For country code abbreviations (show table)
  1. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767 [PubMed 30693946]
  2. Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]
  3. Alonso Gonzalez AC, Ortega Valin L, Santos Buelga D, et al. Dosage programming of phenobarbital in neonatal seizures. J Clin Pharm Ther. 1993;18(4):267-270. [PubMed 8227234]
  4. American Society of Addiction Medicine (ASAM). The ASAM clinical practice guideline on alcohol withdrawal management. J Addict Med. 2020:14(3S)(suppl 1):1-72. doi:10.1097/ADM.0000000000000668 [PubMed 32511109]
  5. Apeland T, Frøyland ES, Kristensen O, Strandjord RE, Mansoor MA. Drug-induced pertubation of the aminothiol redox-status in patients with epilepsy: improvement by B-vitamins. Epilepsy Res. 2008;82(1):1-6. doi:10.1016/j.eplepsyres.2008.06.003 [PubMed 18644700]
  6. Apeland T, Mansoor MA, Pentieva K, McNulty H, Strandjord RE. Fasting and post-methionine loading concentrations of homocysteine, vitamin B2, and vitamin B6 in patients on antiepileptic drugs. Clin Chem. 2003;49(6, pt 1):1005-1008. [PubMed 12766014]
  7. Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med. 2010;363(6):542-551. doi:10.1056/NEJMoa0909801 [PubMed 20818889]
  8. Arif H, Buchsbaum R, Weintraub D, Pierro J, Resor SR Jr, Hirsch LJ. Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs. Epilepsy Behav. 2009;14(1):202-209. doi:10.1016/j.yebeh.2008.10.017 [PubMed 19010446]
  9. Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. American College of Physicians; 2007.
  10. Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 2014;119:417-432. [PubMed 24365310]
  11. Audenaert SM, Lock RL, Johnson GL, Pedigo NW Jr. Cardiovascular effects of rectal methohexital in children. J Clin Anesth. 1992;4(2):116-119. doi:10.1016/0952-8180(92)90026-w [PubMed 1562334]
  12. Baruzzi A, Contin M, Barbara G, et al. Drug rash with eosinophilia and systemic symptoms secondary to phenobarbitone. Clin Neuropharmacol. 2003;26(4):177-178. doi:10.1097/00002826-200307000-00004 [PubMed 12897635]
  13. Bavdekar SB, Muranjan MN, Gogtay NJ, Kantharia V, Kshirsagar NA. Anticonvulsant hypersensitivity syndrome: lymphocyte toxicity assay for the confirmation of diagnosis and risk assessment. Ann Pharmacother. 2004;38(10):1648-1650. doi:10.1345/aph.1E042 [PubMed 15304627]
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