Phenobarbiton

Pharmacologic Category

Anticonvulsant, Barbiturate; Barbiturate

Dosing: Adult

Sedation:

Oral, IV, IM: 30 to 120 mg/day in 2 to 3 divided doses; maximum: 400 mg/day

Preoperative sedation: IM: 100 to 200 mg 60 to 90 minutes before surgery

Status epilepticus: IV:

American Epilepsy Society recommendations: 15 mg/kg as a single dose. Note: AES recommends phenobarbital as a second line option only if first line options (lorazepam, diazepam, or midazolam) or other second line options (eg, fosphenytoin, valproic acid, levetiracetam) are unavailable (AES [Glauser 2016]).

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 (NCS [Brophy 2012])

Note: Additional respiratory support may be required particularly when maximizing loading dose or if concurrent sedative therapy. Repeat doses administered sooner than 10 to 15 minutes may not allow adequate time for peak CNS concentrations to be achieved and may lead to CNS depression.

Seizures: Maintenance dose:

Oral, IV: Usual dosage range (limited data available): 2 mg/kg/day in divided doses (Murphy 2010; Winter 2010). 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 (Winter 2010).

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.

Alcohol withdrawal (off-label use):

IV: Initial dose of 260 mg, followed by subsequent doses of 130 mg as needed. Note: Clinical Institute Withdrawal Assessment (CIWA) scores were evaluated at 30 minute intervals in the clinical trial (Hendey 2011).

Oral: Fixed dose regimen of 60 mg 4 times daily on day 1, followed by 60 mg 3 times daily on day 2, 60 mg twice daily on day 3, and 30 mg twice daily on day 4. In addition, provide 60 mg as needed for breakthrough withdrawal symptoms (Mariani 2006; Rosenthal 1998). May also administer 130 mg IM as needed for more substantial withdrawal symptoms (eg, heart rate >120 bpm, SBP >150 mm Hg, marked agitation) (Rosenthal 1998).

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 (Sullivan 1993).

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 (Kawasaki 2012).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Avoid use (Beers Criteria [AGS 2019]).

Dosing: Renal 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 (Aronoff 2007).

CrCl <10 mL/minute: Administer dose every 12 to 16 hours (Aronoff 2007; Israni 2006).

Hemodialysis (moderately dialyzable [20% to 50%]): Administer dose before dialysis and 50% of dose after dialysis (Aronoff 2007).

Peritoneal dialysis: 35% to 40% removed; administer 50% of normal dose (Aronoff 2007; Asconape 2014; Israni 2006).

Continuous renal replacement therapy (CRRT): Administer normal dose and monitor levels (Aronoff 2007).

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

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 (Geurinni 2006; Kliegman 2020):

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: 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 (AES [Glauser 2016]; NCS [Brophy 2012]; Vasquez 2018). 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 (conjugated): 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 (Cies 2007; Nelson 1996); for the treatment of hyperbilirubinemia in Crigler-Najjar Syndrome, a dose of 5 mg/kg/day has been used to reduce serum bilirubin concentrations (Kliegman 2020); not recommended for management of biliary cirrhosis due to sedation and other adverse effects (AASLD [Lindor 2019]).

Conversion of PENTobarbital to PHENobarbital (withdrawal prevention) (Tobias 2000; Tobias 2000a): 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 (Tobias 2000; Tobias 2000a).

Dosing: Renal Impairment: Pediatric

No specific dosage adjustment provided in manufacturer's labeling; reduced doses are recommended. The following guidelines have been used by some clinicians (Aronoff, 2007):

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 (Pasko, 2004)

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.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Creatinine Clearance by Jelliffe
• Creatinine Clearance by Sanaka
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate by Schwartz
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Sedation: Use as a sedative

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

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Alcohol withdrawalLevel of Evidence [C]

Data from a limited number of patients studied in randomized, double-blind and open-label trials suggest that oral and IV phenobarbital may be beneficial for the treatment of alcohol withdrawal Ref. Additional data may be necessary to further define the role of phenobarbital in this condition.

Sedative/hypnotic withdrawalLevel of Evidence [C]

Data from a limited number of patients in a randomized, double-blind controlled trial, a comparative controlled study, and a retrospective review suggest that phenobarbital may be beneficial for sedative/hypnotic withdrawal Ref. Additional data may be necessary to further define the role of phenobarbital in this condition.

Level of Evidence Definitions

Level of Evidence Scale

Use: Unsupported: Adult

Insomnia

Based on American Academy of Sleep Medicine guidelines for the pharmacological treatment of insomnia in adults, barbiturates such as phenobarbital are no longer recommended for the management of insomnia due to the risk of adverse effects and lethal overdose potential (AASM [Sateia 2017]; AASM [Schutte-Rodin 2008]).

Class and Related Monographs

Sedatives and Hypnotics, Barbiturates

Clinical Practice Guidelines

American Epilepsy Society Guidelines, “Treatment of Convulsive Status Epilepticus in Children and Adults,” January 2016

Administration: IM

Inject deep into muscle. Do not exceed 5 mL per injection site due to potential for tissue irritation.

Administration: IV

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 (NCS [Brophy 2012]). Avoid extravasation. Intra-arterial injection is contraindicated. Avoid subcutaneous administration.

Administration: Injectable Detail

Parenteral solutions are highly alkaline.

pH: 9.2 to 10.2

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 (NCS [Brophy 2012]). Administration over 15 to 30 minutes has been recommended in neonates (ISMP 2011); large loading doses (eg, 40 mg/kg) in neonates have been infused over 60 minutes (Hall 1998). Too rapid administration may result in severe respiratory depression, apnea, laryngospasm, hypertension, or vasodilation with fall in blood pressure.

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

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.

Storage/Stability

Oral: Store between 20°C and 25°C (68°F and 77°F). Protect from light.

Injection: Store between 20°C and 25°C (68°F and 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F).

Preparation for Administration: Pediatric

Parenteral: Phenobarbital injection 65 mg/mL diluted in NS to a concentration of 10 mg/mL has been shown to be stable for 4 weeks when stored under refrigeration at 4°C (39.2°F) (Nahata 1986). ISMP and Vermont Oxford Network recommends standard concentrations of 10 mg/mL (diluted) or 65 mg/mL (undiluted) for neonates (ISMP 2011).

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Extemporaneously Prepared

10 mg/mL Oral Suspension

An alcohol-free 10 mg/mL phenobarbital oral suspension may be made from tablets and one of two different vehicles (a 1:1 mixture of Ora-Plus and Ora-Sweet or a 1:1 mixture of Ora-Plus and Ora-Sweet SF). Crush ten phenobarbital 60 mg tablets in a glass mortar and reduce to a fine powder. Mix 30 mL of Ora-Plus and 30 mL of either Ora-Sweet or Ora-Sweet SF; stir vigorously. Add 15 mL of the vehicle to the powder and mix to a uniform paste. Transfer the mixture to a 2 ounce amber plastic prescription bottle. Rinse mortar and pestle with 15 mL of the vehicle; transfer to bottle. Repeat, then add quantity of vehicle sufficient to make 60 mL. Label "shake well." May mix dose with chocolate syrup (1:1 volume) immediately before administration to mask the bitter aftertaste. Stable for 115 days when stored in amber plastic prescription bottles at room temperature.

Cober M and Johnson CE, “Stability of an Extemporaneously Prepared Alcohol-Free Phenobarbital Suspension,” Am J Health Syst Pharm, 2007, 64(6):644-6.[PubMed 17353574]

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to help control certain kinds of seizures.

• It is used to treat anxiety.

• It is used to treat sleep problems.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Fatigue

• Anxiety

• Nausea

• Vomiting

• Constipation

• Trouble sleeping

• Injection site irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice

• Mood changes

• Behavioral changes

• Shortness of breath

• Confusion

• Change in balance

• Muscle spasm

• Nightmares

• Severe loss of strength and energy

• Slow heartbeat

• Restlessness

• Sensing things that seem real but are not

• Trouble breathing

• Severe headache

• Dizziness

• Passing out

• Vision changes

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Geriatric Patients: High-Risk Medication:

Contraindications

Hypersensitivity to phenobarbital, barbiturates or any component of the formulation; marked hepatic impairment; dyspnea or airway obstruction; porphyria (manifest and latent); intra-arterial administration, subcutaneous administration (not recommended); use in patients with a history of sedative/hypnotic addiction; nephritic patients (large doses)

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

Warnings/Precautions

Concern related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypersensitivity: Exfoliative dermatitis and Stevens-Johnson syndrome, possibly fatal, may occur; discontinue if dermatological reactions occur.

• Paradoxical stimulatory response: May cause paradoxical responses, including agitation and hyperactivity, particularly in patients with acute or chronic pain and pediatric patients.

• Respiratory depression: May cause respiratory depression particularly when administered intravenously; use with caution patients with respiratory disease, including status asthmaticus.

Disease-related concerns:

• Anemia: Use with caution in patients with severe anemia.

• Cardiac disease: Use with caution in patients with cardiac disease and in hemodynamically unstable patients (hypotension or shock).

• Depression: Use with caution in patients with depression or suicidal tendencies.

• Diabetes: Use with caution in patients with diabetes.

• Drug abuse: Use with caution in patients with a history of drug abuse; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated patients: Use with caution in patients who are debilitated.

• Fever: Use with caution in patients with a fever.

• Pediatric: 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: Do not administer intra-arterially or subcutaneously. Avoid perivascular extravasation. 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. Intramuscular (IM) injection should be confined to a total volume of 5 mL and made in a large muscle in order to avoid possible tissue irritation. Discontinue injection in any patient who complains of limb pain.

• 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: Anticonvulsants 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.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Using barbiturates in elderly may induce paradoxical stimulation, cause or aggravate depression and confusion. Due to its long half-life and risk of dependence, phenobarbital is not recommended as a sedative or hypnotic in the elderly. Interpretive guidelines from the Centers for Medicare and Medicaid Services (CMS) discourage the use of this agent as a sedative/hypnotic in long-term care residents.

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.

Pregnancy Risk Factor

D

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).

Breast-Feeding 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.

Briggs' Drugs in Pregnancy & Lactation

• Phenobarbital

Adverse Reactions

Frequency not defined.

Cardiovascular: Bradycardia, hypotension, syncope, thrombophlebitis (IV)

Central nervous system: Agitation, anxiety, ataxia, central nervous system stimulation, central nervous system depression, confusion, dizziness, drowsiness, hallucination, hangover effect, headache, impaired judgement, insomnia, lethargy, nervousness, nightmares

Dermatologic: Exfoliative dermatitis, skin rash, Stevens-Johnson syndrome

Gastrointestinal: Constipation, nausea, vomiting

Genitourinary: Oliguria

Hematologic & oncologic: Agranulocytosis, thrombocytopenia, megaloblastic anemia

Local: Pain at injection site

Neuromuscular & skeletal: Hyperkinesia, laryngospasm

Respiratory: Apnea (especially with rapid IV use), hypoventilation, respiratory depression

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Aromatic Anticonvulsant Allergy/Hypersensitivity

Metabolism/Transport Effects

Substrate of CYP2C19 (major), 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 Open Interactions

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 whenever possible. If such a combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during concomitant use. 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: Barbiturates may increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Afatinib: PHENobarbital may decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of phenobarbital, increase afatinib dose by 10 mg as tolerated; reduce to original afatinib dose 2-3 days after stopping phenobarbital. Per Canadian labeling: avoid combination if possible. 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

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

Amphetamines: May decrease the serum concentration of PHENobarbital. 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: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether. Risk X: Avoid combination

Asunaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir. 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): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

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 the serum concentration of Bedaquiline. Risk X: Avoid combination

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

Beta-Blockers: Barbiturates may decrease the serum concentration of Beta-Blockers. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol. Risk C: Monitor therapy

Bictegravir: PHENobarbital may decrease the serum concentration of Bictegravir. Management: When possible consider using an alternative anticonvulsant with concurrent bictegravir, emtricitabine, and tenofovir alafenamide. If the combination must be used, monitor closely for evidence of reduced antiviral effectiveness. Risk D: Consider therapy modification

Blonanserin: CNS Depressants may 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. 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

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

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

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

Calcium Channel Blockers: Barbiturates may increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Exceptions: Clevidipine. 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 the serum concentration of Cannabidiol. Risk C: Monitor therapy

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. 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

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

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

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

Chloramphenicol (Systemic): May decrease the metabolism of Barbiturates. Barbiturates may increase the metabolism of Chloramphenicol (Systemic). 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 4-6 hours after administration of cholestyramine in order to minimize the risk for any significant interaction. Risk D: Consider therapy modification

Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A 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). Refer to the specific clindamycin (systemic) - rifampin drug interaction monograph for information concerning that combination. 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

Corticosteroids (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Corticosteroids (Systemic). Exceptions: Hydrocortisone (Systemic); PrednisoLONE (Systemic); PredniSONE. Risk C: Monitor therapy

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

CYP2C19 Inducers (Moderate): May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination. Some combinations are specifically contraindicated by manufacturers; others may have recommended dose adjustments. If combined, monitor for increased substrate effects. Risk D: Consider therapy modification

CYP3A4 Substrates (High risk with Inducers): CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Exceptions: Benzhydrocodone; Buprenorphine; CarBAMazepine; Etizolam; HYDROcodone; Mirtazapine; TraMADol; Zolpidem; Zonisamide. Risk D: Consider therapy modification

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

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

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

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

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 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

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

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

Dienogest: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dienogest. Management: Avoid use of dienogest for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer. An alternative form of contraception should be used during this time. Risk X: Avoid combination

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

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

Disopyramide: PHENobarbital 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

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

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). Management: Seek alternatives to strong CYP3A4 inducers in patients treated with doxorubicin. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Risk D: Consider therapy modification

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

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

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

Elbasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elbasvir. 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 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

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Risk D: Consider therapy modification

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 combination if possible. If combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Risk D: Consider therapy modification

Esketamine: 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

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

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

Estrogen Derivatives (Contraceptive): Barbiturates may diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a non-hormonal contraceptive is recommended. Risk D: Consider therapy modification

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

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: Exemestane U.S. product labeling recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with concurrent use of strong CYP3A4 inducers. 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: In patients receiving phenobarbital, initiate felbamate at 1200 mg/day in divided doses 3-4 times daily and reduce phenobarbital dose by 20%. Monitor for increased phenobarbital concentrations/effects and decreased felbamate concentrations/effects. 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

Fexinidazole [INT]: May increase the serum concentration of Products Containing Propylene Glycol. Risk X: Avoid combination

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

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Folic Acid: May decrease the serum concentration of PHENobarbital. 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

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase 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

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

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

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 the guanfacine dose by up to double when initiating guanfacine in a patient taking a strong CYP3A4 inducer. Increase guanfacine dose gradually over 1 to 2 weeks if initiating strong CYP3A4 inducer therapy in a patient already taking guanfacine. Risk D: Consider therapy modification

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

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 Barbiturates. Management: Consider a decrease in the barbiturate dose, as appropriate, when used together with hydroxyzine. With concurrent use, monitor patients closely for excessive response to the combination. Risk D: Consider therapy modification

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 concurrent use of imatinib with 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. Risk D: Consider therapy modification

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. Risk X: Avoid combination

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

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

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 adverse/toxic effect of CNS Depressants. 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 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

Letermovir: May increase the serum concentration of UGT1A1 Inducers. Risk X: Avoid combination

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

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

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

Levomethadone: PHENobarbital may decrease the serum concentration of Levomethadone. 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. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

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

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

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

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. 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 daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with CrCl less than 30 mL/min. Risk D: Consider therapy modification

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Orlistat: May decrease the serum concentration of Anticonvulsants. 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

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

Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. 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 the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers. Risk D: Consider therapy modification

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. 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 ona 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. Risk X: Avoid combination

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. Management: Use of praziquantel with strong CYP3A4 inducers is contraindicated. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. 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

Primidone: May enhance the adverse/toxic effect of Barbiturates. Primidone is converted to phenobarbital, and thus becomes additive with existing barbiturate therapy. Risk C: Monitor therapy

Progestins (Contraceptive): Barbiturates may diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Risk D: Consider therapy modification

Propacetamol: Barbiturates may increase the metabolism of Propacetamol. This may 1) diminish the desired effects of propacetamol; and 2) increase the risk of liver damage. Risk C: Monitor therapy

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

Pyridoxine: May increase the metabolism of Barbiturates. Apparent in high pyridoxine doses (eg, 200 mg/day) 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 7-14 days of discontinuing the inducer. Risk D: Consider therapy modification

QuiNIDine: PHENobarbital may enhance the hepatotoxic effect of QuiNIDine. PHENobarbital 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 avoiding this combination. If coadministration cannot be avoided, monitor for reduced quinine efficacy and for signs/symptoms of phenobarbital toxicity. Monitor phenobarbital serum concentrations as appropriate. 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 decrease the serum concentration of Regorafenib. Risk X: Avoid combination

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

Rifamycin Derivatives: May increase the metabolism of Barbiturates. 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

RisperiDONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Consider increasing the dose of oral risperidone (to no more than double the original dose) if a strong CYP3A4 inducer is initiated. For patients on IM risperidone, consider an increased IM dose or supplemental doses of oral risperidone. Risk D: Consider therapy modification

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

Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Risk X: Avoid combination

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Management: Avoid rolapitant use in patients requiring chronic administration of strong CYP3A4 inducers. Monitor for reduced rolapitant response and the need for alternative or additional antiemetic therapy even with shorter-term use of such inducers. Risk D: Consider therapy modification

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

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: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib. 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

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

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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

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

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

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

Sirolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus. 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

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

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

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

Somatostatin Acetate: May enhance the adverse/toxic effect of Barbiturates. Specifically, Somatostatin Acetate may enhance or prolong Barbiturate effects, including sedative effects. Risk X: Avoid combination

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

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

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

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments 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. Management: Consider alternatives to concomitant use of strong CYP3A4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen. Risk D: Consider therapy modification

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

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 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: Barbiturates may decrease the serum concentration of Teniposide. Management: Consider alternatives to combined treatment with barbiturates and teniposide due to the potential for decreased teniposide concentrations. If the combination cannot be avoided, monitor teniposide response closely. Risk D: Consider therapy modification

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

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

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

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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. Exceptions: Dyphylline. 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

TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Management: Approximately 2-fold higher tiagabine doses and a more rapid dose titration will likely be required in patients concomitantly taking a strong CYP3A4 inducer. Risk D: Consider therapy modification

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

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

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. Management: Avoid concurrent use of strong CYP3A4 inducers with the Jynarque brand of tolvaptan. For patients receiving the Samsca brand of tolvaptan, monitor patient response to tolvaptan and adjust tolvaptan dose if required. Risk D: Consider therapy modification

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

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

Ulipristal: Barbiturates 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 the serum concentration of Valbenazine. Risk X: Avoid combination

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 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 coadministartion 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

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 1-2 weeks after inducer discontinuation. Risk D: Consider therapy modification

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

Vitamin K Antagonists (eg, warfarin): Barbiturates may increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. An anticoagulant dose increase 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

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

Voriconazole: Barbiturates 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 concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. 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 zalephon 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

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

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.

Genes of Interest

• Cytochrome P450 2C19
• HLA-B Major Histocompatibility Complex

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)

IV use: Respiratory rate, heart rate, blood pressure, IV site (stop injection if patient complains of pain in the limb)

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).

Laboratory alert level: 50 mcg/mL (SI: 215 micromole/L) (Hiemke 2018).

Advanced Practitioners Physical Assessment/Monitoring

Obtain liver function tests, CBC with differential, and renal function tests periodically. Monitor blood levels; lower dosing indicated for the elderly and those with renal/liver dysfunction. Assess for history of addiction or suicide ideation; long-term use can result in dependence, abuse, or tolerance. Observe for signs of toxicity (slurred speech, unsteady gait, or sustained nystagmus), changes in mood, mental status, depression, or emergence of suicidal thoughts. Evaluate for signs of seizure activity. Do not discontinue abruptly; dose should be tapered gradually. IV Use: Monitor vital signs, respiratory status, and CNS status.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor vital signs. Monitor for signs of toxicity (slurred speech, unsteady gait, or sustained nystagmus) and mental status changes. Educate patient to report signs of seizure activity or signs and symptoms of depression or worsening depression. Discontinue injection if patient complains of limb pain.

Controlled Substance

C-IV

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Elixir, Oral:

Generic: 20 mg/5 mL (473 mL)

Solution, Oral:

Generic: 20 mg/5 mL (473 mL)

Solution, Injection, as sodium:

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

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

Anatomic Therapeutic Chemical (ATC) Classification

• N03AA02

Generic Available (US)

Yes

Pricing: US

Elixir (PHENobarbital Oral)

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

Solution (PHENobarbital Sodium Injection)

65 mg/mL (per mL): $26.18 - $28.78

130 mg/mL (per mL): $67.96 - $74.69

Tablets (PHENobarbital Oral)

15 mg (per each): $0.34

16.2 mg (per each): $0.51 - $0.69

30 mg (per each): $0.42

32.4 mg (per each): $0.64 - $0.85

60 mg (per each): $0.53

64.8 mg (per each): $0.80 - $0.84

97.2 mg (per each): $1.13 - $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.

Mechanism of Action

Long-acting barbiturate with sedative, hypnotic, and anticonvulsant properties. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, barbiturates exhibit anticonvulsant activity; barbiturates produce dose-dependent respiratory depression.

Pharmacodynamics/Kinetics

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).

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Related Information

• Adverse Effects of Anticonvulsants
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Narrow Therapeutic Index Drugs

Pharmacotherapy Pearls

Injectable solutions contain propylene glycol.

Phenobarbital tablets are also available from some generic manufacturers in strengths that are exactly equivalent to fractional grain strengths: 16.2 mg (1/4 grain), 32.4 mg (1/2 grain), 64.8 mg (1 grain). To avoid medication errors, do not prescribe phenobarbital in grains.

Index Terms

Luminal Sodium; Phenobarbital Sodium; Phenobarbitone; Phenylethylmalonylurea

References

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Brand Names: International

Alepsal (AR, CR, DO, GT, HN, MX, NI, PA, SV); Andral (PH); Aparoxal (FR); Aphenylbarbit (CH); 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, CH, 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, NZ); Phenobarbitone Injection (GB); Phenotal (JO, TH); Phental (ID); Phincotomaline (EG); Sedabarb (ZA); Sevenal (HU); Sevenaletta (HU); Sibital (ID); Solminotic (EG); Tridezibarbitur (AT); Uni-Feno (HK)

Last Updated 5/8/20