Phenobarbital (Luminal) - Uses, Dose, MOA, Brands, Side effects

Phenobarbital is a barbiturate that is available by various brand names including luminal and debritone. It is used in the treatment of patients with seizures (epilepsy), for sedation, and for the treatment of withdrawal symptoms associated with alcohol discontinuation.

Indications of Phenobarbital:

Sedation:
- Used for sedation.
Seizures:
- Used in the management of generalized tonic-clonic, status epilepticus, and partial seizures.
Off Label Use of Phenobarbital in Adults:
- Alcohol withdrawal
- Sedative/hypnotic withdrawal

Phenobarbital dose in adults:

Phenobarbital dose for sedation:

Oral, IV, IM: 30 to 120 mg per 24 hours in 2 to 3 divided doses.
maximum: 400 mg per 24 hours.
Preoperative sedation:
- IM: 100 to 200 mg 60 to 90 minutes prior to surgery.

Phenobarbital Dose in the treatment of Status epilepticus: IV:

American Epilepsy Society recommendations:
- 15 mg/kg as stat dose.
- Note: Used only when the first-line options such as lorazepam, diazepam, or midazolam or other second line options (eg, fosphenytoin, valproic acid, levetiracetam) are not availble as per AES.
Neurocritical Care Society recommendation:
- 20 mg/kg (infused at 50 to 100 mg/minute); the dose may be repeated once after 10 minutes with an additional 5 to 10 mg/kg if required.

Note: May require additional respiratory support in case of concurrent sedation or maximizing the loading dose. Adequate time may not be allowed for achieving peak CNS concentration if repeat doses are administered sooner than 10 to 15 minutes and cause CNS depression.

Phenobarbital (Luminal) Dose in the treatment of Seizures:

Maintenance dose:
- Oral, IV: Usual dosage range (limited data available): 2 mg/kg per 24 hours in divided doses.
- Note: Dosage should according to the individual based upon clinical response and serum concentration; a steady-state level of 20 mg/l is typically achieved by the dose of 2 mg/kg per 24 hours.
Manufacturer's labeling:
- Oral: Current clinical practice may not be reflected by the dosing in the prescribing information. 60 to 200 mg per 24 hours or 50 to 100 mg twice or thrice daily.

Phenobarbital (Luminal) Dose in the treatmend of withdrawal of Alcohol (off-label):

IV: Starting dose of 260 mg, followed by subsequent doses of 130 mg as required.
Note: In clinical trials, Clinical Institute Withdrawal Assessment (CIWA) scores were evaluated at half-hour intervals.
Oral:
- On day 1, a Fixed-dose regimen of 60 mg QID,
- On day 2, 60 mg TDS
- On day 3, 60 mg BD,
- On day 4, 30 mg BD
Additional 60 mg may be given for breakthrough withdrawal symptoms.
In case of substantial withdrawal symptoms including pulse more than 120/min, systolic BP more than 150 mmHg, severe agitation. Given130 mg intramuscular.

Phenobarbital (Luminal) dose in the treatment of Sedative/hypnotic withdrawal (off-label):

Several regimens have been evaluated:

Taper following dosage conversion:
- Initial daily requirement: Phenobarbital was substituted in an equivalent dose to the baseline medication (clonazepam 1 mg = phenobarbital 60 mg was used in the study). The calculated baseline total dose should be divided into 4 doses and administered every 6 hours for 48 hours; then the daily requirement should be decreased by 10% per day over the next 10 days.
Fixed dose taper:
- Start with 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.

Phenobarbital (Luminal) Dose in Childrens

Phenobarbital (Luminal) Dose in the treatment of Status epilepticus:

Infants, Children, and Adolescents:
- IV: Initial: 15-20 mg per kg.
- Max dose: 1000 mg; may be repeated once after 10-15 minutes if required
- Max total dose: 40 mg per kg; adequate time may not be allowed for achieving peak CNS concentration if repeat doses are administered sooner than 10 to 15 minutes and cause CNS depression.

Note: In case of maximizing loading dose or concurrent sedative therapy, additional respiratory support may be required.

Phenobarbital (Luminal) Dose in the maintenance therapy of Seizures:

Note: 12 hours are usually allowed to pass after the loading dose, for the administration of the maintenance dose.

Manufacturer's labeling:
- Infants, Children, and Adolescents: Oral: 3-6 mg/kg/day.
Alternate dosing: Limited data available
- Initial: Oral, IV:
  - Infants and Children ≤5 years: 3-5 mg/kg/day in 1-2 divided doses.
  - Children >5 years: 2-3 mg/kg/day in 1-2 divided doses.
  - Adolescents: 1-3 mg/kg/day in 1-2 divided doses.
- Usual dosing range: Note: Manage dose according to the individual based upon clinical response and serum concentration; OD doses, in children and adolescents, is usually administered at bedtime. Some centers have used:
  - Infants: 5-6 mg/kg/day in 1-2 divided doses.
  - Children:
    - 1-5 years: 6-8 mg/kg/day in 1-2 divided doses.
    - 5-12 years: 4-6 mg/kg/day in 1-2 divided doses.
  - Adolescents: 1-3 mg/kg/day in 1-2 divided doses.

Phenobarbital (Luminal) Dose for Sedation:

Note: Prefer the newer, shorter-acting agents.

Manufacturer's labeling:
- Children and Adolescents: Oral: 2 mg/kg/dose thrice a day.
- maximum dose: 40 mg.
Alternate dosing: Limited data available:
- Infants and Children: IM, Oral: 2-3 mg/kg/day in divided doses (twice or thrice a day).

Phenobarbital (Luminal) dose to treat Insomnia (hypnotic):

Limited data available; shorter-acting agents may be preferable:

Infants and Children:
- IM, Oral: 2-3 mg/kg/dose; dose may be repeated after 12-24 hours as per need
- some centers have used: IM, IV: 3-5 mg/kg at night.

Phenobarbital (Luminal) dose to treat Hyperbilirubinemia: Limited data available:

Infants and Children:
- Oral: Usual range: 3-8 mg/kg/day in 2-3 divided doses; in case reports, doses up to 10 mg/kg/day have been used.
- In Crigler Najjar Syndrome, a dose of 5 mg/kg/day has been used for treating hyperbilirubinemia and for reduction of serum bilirubin concentrations. Not to be used in biliary cirrhosis due to sedation and other adverse effects.

Phenobarbital (Luminal) Dose in the prevention of Sedative/hypnotic withdrawal;

conversion of Pentobarbital to Phenobarbital (Pentobarbital infusion, a total cumulative Pentobarbital dose ≥25 mg/kg or duration ≥5-7 days): Limited data available:

Infants, Children, and Adolescents:
- The following approach transitioning from pentobarbital to phenobarbital has been described: Pentobarbital infusion should be discontinued, half of the phenobarbital IV loading dose (see table) should be given over one hour followed 6 hours later by the remaining half of phenobarbital loading dose IV (over one hour).
- Give intravenous maintenance phenobarbital dose 6 hours after loading dose has been completed; the maintenance phenobarbital dose should be 1/3 of the initial loading dose and given every 12 hours. After the patient stabilizes he should be switched to oral therapy with weekly tapering of 10% to 20%.

Note: This conversion method is based on preliminary data in mechanically ventilated patients. Respiratory status should be monitored closely. Evaluation should be done for withdrawal symptoms.

Pentobarbital Infusion Rate (mg/kg/hour)	Phenobarbital IV Loading Dose (mg/kg)
1 to 2	8
2 to 3	15
3 to 4	20

Pregnancy Risk Factor D

Phenobarbital crosses over the placenta.
You can find barbiturates within the placenta and fetal liver as well as in the fetal brain. Parenteral administration may result in a similar blood concentration for the mother and the fetus.
Increased incidence of fetal abnormalities may be due to maternal use.
The neonate may experience withdrawal symptoms, including seizures and hyperirritability, if used during the third trimester. T
hese withdrawal symptoms can last up to 14 days after the birth.
While uterine activity is not affected if it is used during labor, it can cause respiratory depression in newborns.
Therefore, arrange for resuscitation equipment specifically for premature infants.
Pregnancy is a good time to avoid epilepsy treatment.
For women exposed to phenobarbital during pregnancy, a registry is available:
- During pregnancy, they may enroll themselves into the North American Antiepileptic Drug (AED) Pregnancy Registry (888-2332334 or http://www.aedpregnancyregistry.org).

Use of phenobarbital while breastfeeding

Breast milk contains phenobarbital.
In utero exposure may cause a delayed interest in breastfeeding.
Infantile spasms or other withdrawal symptoms can be caused by abrupt discontinuation of breast-feeding.
The manufacturer suggests that nursing mothers be cautious when administering phenobarbital.

Phenobarbital (Luminal) Dose in Kidney Disease:

No specific dosage adjustments have been provided in the manufacturer's labeling; dosage reduction is recommended. Some clinicians have recommended the following guidelines.
- CrCl ≥10 mL/minute: Dosage adjustment not necessary.
- CrCl <10 mL/minute: Dose should be administered every 12 to 16 hours.
- Hemodialysis (moderately dialyzable [20% to 50%]): 50 % dose should be given dose before dialysis and 50% after dialysis.
- Peritoneal dialysis: 35% to 40% removed; 50% of normal dose should be given.
- Continuous renal replacement therapy (CRRT): A normal dose should be given along with continuous monitoring of drug levels.

Dose in Liver disease:

No specific dosage adjustments have been provided in the manufacturer’s labeling; dosage reduction is recommended.
Hepatic impairment increases the exposure of phenobarbital; use cautiously.

Side effects of Phenobarbital (Luminal):

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

Contraindications to Phenobarbital (Luminal):

Hypersensitivity to phenobarbital, barbiturates, or any other component of the formulation
Hepatic impairment marked
Dyspnea and airway obstruction
Porphyria (manifest, latent)
Intra-arterial administration
Subcutaneous administration
Patients who have a history of sedative/hypnotic dependence;
Nephritic syndrome patients (large doses)

Warnings and Precautions

CNS depression:
- Patients should be aware that CNS depression can occur after using it, impairing mental or physical abilities.
Hypersensitivity
- Exfoliative dermatitis or Stevens-Johnson Syndrome can sometimes lead to death.
- If you experience any allergic reactions, discontinue use.
Paradoxical stimulatory response
- Patients with chronic or acute pain, as well as pediatric patients, can experience paradoxical reactions, such as agitation or hyperactivity.
Respiratory depression
- Intravenous administration can cause respiratory depression. Use caution.
Anemia:
- Be careful when using it in anemic patients.
Cardiac disease
- Avoid use in patients with heart disease or hemodynamically unstable patients (hypotension and shock).
Depression
- Be careful in patients with depression.
Diabetes:
- Be careful in patients with diabetes.
Use of drugs:
- Be cautious as you may become dependent on drugs.
- Tolerance, psychological and/or physical dependence may result from prolonged use.
Hepatic impairment
- Be careful. Patients with premonitory signs or symptoms of hepatic impairment should be avoided.
Hyperthyroidism:
- Be careful in patients with hyperthyroidism.
Hypoadrenalism
- Be careful in patients with adrenal insufficiency.
Renal impairment
- Be careful in patients with kidney impairment.

Phenobarbital: Drug Interaction

Risk Factor C (Monitor therapy)
Acetaminophen	Barbiturates may increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage.
Albendazole	PHENobarbital may decrease serum concentrations of the active metabolite(s) of Albendazole.
Alcohol (Ethyl)	CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).
Alizapride	May enhance the CNS depressant effect of CNS Depressants.
Amphetamines	May decrease the serum concentration of PHENobarbital.
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.
Benperidol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Benperidol.
Beta-Blockers	Barbiturates may decrease the serum concentration of Beta-Blockers. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol.
Blood Pressure Lowering Agents	Barbiturates may enhance the hypotensive effect of Blood Pressure Lowering Agents.
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.
Brexanolone	CNS Depressants may enhance the CNS depressant effect of Brexanolone.
Brimonidine (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Bromopride	May enhance the CNS depressant effect of CNS Depressants.
Calcifediol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcifediol.
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.
Cannabidiol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabidiol.
Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Cannabis	CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased.
Cannabis	May enhance the CNS depressant effect of CNS Depressants.
CarBAMazepine	CYP3A4 Inducers (Strong) may decrease the serum concentration of CarBAMazepine.
Chlorphenesin Carbamate	May enhance the adverse/toxic effect of CNS Depressants.
ChlorproPAMIDE	CYP3A4 Inducers (Strong) may decrease the serum concentration of ChlorproPAMIDE.
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.
CNS Depressants	May enhance the adverse/toxic effect of other CNS Depressants.
Corticosteroids (Systemic)	CYP3A4 Inducers (Strong) may decrease the serum concentration of Corticosteroids (Systemic). Exceptions: Hydrocortisone (Systemic); PrednisoLONE (Systemic); PredniSONE.
Cosyntropin	May enhance the hepatotoxic effect of PHENobarbital.
CYP2C19 Inducers (Moderate)	May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers).
CYP2C19 Inhibitors (Moderate)	May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors).
Dabigatran Etexilate	PHENobarbital may decrease the serum concentration of Dabigatran Etexilate.
Dapsone (Topical)	May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents.
Darunavir	May decrease the serum concentration of PHENobarbital.
Dexmethylphenidate	May increase the serum concentration of PHENobarbital.
Diethylstilbestrol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Diethylstilbestrol.
Dimethindene (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Disopyramide	PHENobarbital may decrease the serum concentration of Disopyramide.
Doxercalciferol	CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol.
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.
Dronabinol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol.
Dronabinol	May enhance the CNS depressant effect of CNS Depressants.
Elagolix	CYP3A4 Inducers (Strong) may decrease the serum concentration of Elagolix.
Esketamine	May enhance the CNS depressant effect of CNS Depressants.
Eslicarbazepine	PHENobarbital may decrease the serum concentration of Eslicarbazepine.
Estriol (Systemic)	CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Systemic).
Estriol (Topical)	CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Topical).
Etizolam	CYP3A4 Inducers (Strong) may decrease the serum concentration of Etizolam.
Evogliptin	CYP3A4 Inducers (Strong) may decrease the serum concentration of Evogliptin.
Folic Acid	May decrease the serum concentration of PHENobarbital.
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.
Gestrinone	PHENobarbital may decrease the serum concentration of Gestrinone.
Glecaprevir and Pibrentasvir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Glecaprevir and Pibrentasvir.
Griseofulvin	Barbiturates may decrease the serum concentration of Griseofulvin.
Hydrocortisone (Systemic)	CYP3A4 Inducers (Strong) may decrease the serum concentration of Hydrocortisone (Systemic).
Ifosfamide	CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide.
Kava Kava	May enhance the adverse/toxic effect of CNS Depressants.
Leucovorin Calcium-Levoleucovorin	May decrease the serum concentration of PHENobarbital.
LevETIRAcetam	PHENobarbital may decrease the serum concentration of LevETIRAcetam.
Levomefolate	May decrease the serum concentration of PHENobarbital.
Levomethadone	PHENobarbital may decrease the serum concentration of Levomethadone.
Local Anesthetics	Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased.
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.
Lumacaftor	May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers).
Magnesium Sulfate	May enhance the CNS depressant effect of CNS Depressants.
Methadone	PHENobarbital may decrease the serum concentration of Methadone.
Methylfolate	May decrease the serum concentration of PHENobarbital.
Methylphenidate	May increase the serum concentration of PHENobarbital.
MetroNIDAZOLE (Systemic)	PHENobarbital may decrease the serum concentration of MetroNIDAZOLE (Systemic).
MetyroSINE	CNS Depressants may enhance the sedative effect of MetyroSINE.
Minocycline	May enhance the CNS depressant effect of CNS Depressants.
Multivitamins/Minerals (with ADEK, Folate, Iron)	May decrease the serum concentration of Barbiturates.
Nabilone	May enhance the CNS depressant effect of CNS Depressants.
Nalmefene	PHENobarbital may decrease the serum concentration of Nalmefene.
Nitric Oxide	May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine.
Orlistat	May decrease the serum concentration of Anticonvulsants.
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.
Piribedil	CNS Depressants may enhance the CNS depressant effect of Piribedil.
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.
Pramipexole	CNS Depressants may enhance the sedative effect of Pramipexole.
PrednisoLONE (Systemic)	CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic).
PredniSONE	CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE.
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.
Primidone	May enhance the adverse/toxic effect of Barbiturates. Primidone is converted to phenobarbital, and thus becomes additive with existing barbiturate therapy.
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.
Propafenone	CYP3A4 Inducers (Strong) may decrease the serum concentration of Propafenone.
Pyridoxine	May increase the metabolism of Barbiturates. Apparent in high pyridoxine doses (eg, 200 mg/day)
QuiNIDine	PHENobarbital may enhance the hepatotoxic effect of QuiNIDine. PHENobarbital may decrease the serum concentration of QuiNIDine.
Ramelteon	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ramelteon.
Reboxetine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Reboxetine.
Rifamycin Derivatives	May increase the metabolism of Barbiturates.
ROPINIRole	CNS Depressants may enhance the sedative effect of ROPINIRole.
Rotigotine	CNS Depressants may enhance the sedative effect of Rotigotine.
Rufinamide	May increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Rufinamide.
Ruxolitinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib.
SAXagliptin	CYP3A4 Inducers (Strong) may decrease the serum concentration of SAXagliptin.
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.
Sertraline	CYP3A4 Inducers (Strong) may decrease the serum concentration of Sertraline.
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.
Sulthiame	May enhance the adverse/toxic effect of PHENobarbital.
Tetrahydrocannabinol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol.
Tetrahydrocannabinol	May enhance the CNS depressant effect of CNS Depressants.
Tetrahydrocannabinol and Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Tetrahydrocannabinol and Cannabidiol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol.
Theophylline Derivatives	Barbiturates may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline.
Thiazide and Thiazide-Like Diuretics	Barbiturates may enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics.
Thiothixene	PHENobarbital may decrease the serum concentration of Thiothixene.
Trimeprazine	May enhance the CNS depressant effect of CNS Depressants.
Tropisetron	CYP3A4 Inducers (Strong) may decrease the serum concentration of Tropisetron.
Udenafil	CYP3A4 Inducers (Strong) may decrease the serum concentration of Udenafil.
Valproate Products	May increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products.
Zonisamide	PHENobarbital may decrease the serum concentration of Zonisamide.
Zuclopenthixol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol.
Risk Factor D (Consider therapy modification)
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.
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.
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.
ARIPiprazole	CYP3A4 Inducers (Strong) may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole.
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.
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.
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.
Blonanserin	CNS Depressants may enhance the CNS depressant effect of Blonanserin.
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.
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.
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.
Cabozantinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details.
Canagliflozin	PHENobarbital may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2.
Chloramphenicol (Systemic)	May decrease the metabolism of Barbiturates. Barbiturates may increase the metabolism of Chloramphenicol (Systemic).
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.
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.
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 14hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy.
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.
CycloSPORINE (Systemic)	Barbiturates may increase the metabolism of CycloSPORINE (Systemic).
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.
CYP2C19 Inhibitors (Strong)	May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors).
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; TraMADol; Zolpidem.
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).
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.
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.
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 steroid efficacy.
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.
Doxycycline	Barbiturates may decrease the serum concentration of Doxycycline.
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.
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.
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.
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.
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.
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.
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.
Etoposide Phosphate	CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response.
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, double the daily dose of everolimus using increments of 5 mg or less. Monitor everolimus serum concentrations closely when indicated.
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.
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.
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.
Flunitrazepam	CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.
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.
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.
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.
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.
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.
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/m to 60 mg/m (given as a 4-hour infusion), as tolerated, should be considered.
LamoTRIgine	Barbiturates may decrease the serum concentration of LamoTRIgine. Management: See lamotrigine prescribing information for specific age-dependent dosing guidelines regarding concurrent use with a barbiturate, as well as for adjusting lamotrigine dosing if concurrent barbiturate therapy is discontinued.
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.
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.
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.
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.
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.
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.
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.
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.
Meperidine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Meperidine. Management: Consider increasing meperidine dose if concomitant use with strong CYP3A4 inducers is required. Monitor for signs and symptoms of opioid withdrawal.
Methotrimeprazine	CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established.
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.
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.
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.
Osimertinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib.
OXcarbazepine	PHENobarbital may decrease serum concentrations of the active metabolite(s) of OXcarbazepine. Specifically, concentrations of the major active 10-monohydroxy metabolite may be reduced. OXcarbazepine may increase the serum concentration of PHENobarbital. Management: Consider increasing the initial adult oxcarbazepine extended release tablet (Oxtellar XR) dose to 900 mg/day. No specific recommendations are available for other oxcarbazepine formulations.
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.
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.
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.
Pitolisant	CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: For patients who are stable on pitolisant doses of 8.9 mg or 17.8 mg/day and who are also taking a strong CYP3A4 inducer, increase the pitolisant dose over 7 days to double the original dose (ie, to either 17.8 mg/day or 35.6 mg/day, respectively).
Progestins (Contraceptive)	Barbiturates may diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended.
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.
QuiNINE	May increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of QuiNINE.
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.
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.
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.
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.
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.
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.
SUNItinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose increases are recommended, and vary by indication. See full monograph for details.
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.
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.
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.
Tapentadol	May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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.
Temsirolimus	CYP3A4 Inducers (Strong) may decrease the serum concentration of Temsirolimus. Management: Consider increasing the dose of temsirolimus to 50 mg IV/week (from 25 mg IV/week) if a concomitant CYP3A4 strong inducer is necessary.
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.
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.
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.
Tipranavir	PHENobarbital may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of PHENobarbital.
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.
Tricyclic Antidepressants	Barbiturates may increase the metabolism of Tricyclic Antidepressants.
Vemurafenib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with a strong CYP3A4 inducer and replace with another agent when possible. If a strong CYP3A4 inducer is indicated and unavoidable, the dose of vemurafenib may be increased by 240 mg (1 tablet) as tolerated.
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.
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.
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.
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.
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 Factor X (Avoid combination)
Abemaciclib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Abemaciclib.
Alpelisib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Alpelisib.
Antihepaciviral Combination Products	CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products.
Apixaban	CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban.
Apremilast	CYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast.
Aprepitant	CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant.
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.
Asunaprevir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir.
Axitinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib.
Azelastine (Nasal)	CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).
Bedaquiline	CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline.
Benznidazole	May enhance the adverse/toxic effect of Products Containing Propylene Glycol.
Bortezomib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib.
Bosutinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib.
Brigatinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Brigatinib.
Bromperidol	May enhance the CNS depressant effect of CNS Depressants.
Cariprazine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Cariprazine.
Ceritinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib.
CloZAPine	CYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine.
Cobicistat	PHENobarbital may decrease the serum concentration of Cobicistat.
Cobimetinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Cobimetinib.
Copanlisib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Copanlisib.
Crizotinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib.
Daclatasvir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir.
Dasabuvir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasabuvir.
Deflazacort	CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Deflazacort.
Delamanid	CYP3A4 Inducers (Strong) may decrease the serum concentration of Delamanid.
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.
Dolutegravir	PHENobarbital may decrease the serum concentration of Dolutegravir.
Doravirine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Doravirine.
Dronedarone	CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone.
Duvelisib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Duvelisib.
Elbasvir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Elbasvir.
Eliglustat	CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat.
Elvitegravir	PHENobarbital may decrease the serum concentration of Elvitegravir.
Encorafenib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Encorafenib.
Entrectinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Entrectinib.
Erdafitinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Erdafitinib.
Etravirine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Etravirine.
Fedratinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Fedratinib.
Flibanserin	CYP3A4 Inducers (Strong) may decrease the serum concentration of Flibanserin.
Fosaprepitant	CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant.
Fosnetupitant	CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosnetupitant.
Fostamatinib	CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostamatinib.
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.
Glasdegib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Glasdegib.
Grazoprevir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Grazoprevir.
Hemin	Barbiturates may diminish the therapeutic effect of Hemin.
Ibrutinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrutinib.
Idelalisib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib.
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.
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.
Itraconazole	CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole.
Ivabradine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivabradine.
Ivacaftor	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor.
Ivosidenib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivosidenib.
Ixazomib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixazomib.
Lapatinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating 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.
Ledipasvir	PHENobarbital may decrease the serum concentration of Ledipasvir.
Lorlatinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib.
Lumefantrine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
Lurasidone	CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone.
Macimorelin	CYP3A4 Inducers (Strong) may decrease the serum concentration of Macimorelin.
Macitentan	CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan.
Methoxyflurane	Barbiturates may enhance the nephrotoxic effect of Methoxyflurane. Barbiturates may increase the metabolism of Methoxyflurane.
Methoxyflurane	CYP2A6 Inducers may enhance the nephrotoxic effect of Methoxyflurane. CYP2A6 Inducers may increase the metabolism of Methoxyflurane.
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.
Midostaurin	CYP3A4 Inducers (Strong) may decrease the serum concentration of Midostaurin.
MiFEPRIStone	CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone.
Naldemedine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Naldemedine.
Naloxegol	CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol.
Neratinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Neratinib.
Netupitant	CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant.
NIFEdipine	CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine.
Nilotinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib.
NiMODipine	CYP3A4 Inducers (Strong) may decrease the serum concentration of NiMODipine.
Nisoldipine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine.
Olaparib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib.
Orphenadrine	CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
Oxomemazine	May enhance the CNS depressant effect of CNS Depressants.
Palbociclib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib.
Panobinostat	CYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat.
Paraldehyde	CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
PAZOPanib	CYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib.
Pexidartinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Pexidartinib.
Pimavanserin	CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin.
Piperaquine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Piperaquine.
PONATinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib.
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.
Pretomanid	CYP3A4 Inducers (Strong) may decrease the serum concentration of Pretomanid.
Ranolazine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine.
Regorafenib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib.
Ribociclib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ribociclib.
Rilpivirine	PHENobarbital may decrease the serum concentration of Rilpivirine.
Rivaroxaban	CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban.
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.
RomiDEPsin	CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin.
Simeprevir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir.
Sofosbuvir	PHENobarbital may decrease the serum concentration of Sofosbuvir.
Somatostatin Acetate	May enhance the adverse/toxic effect of Barbiturates. Specifically, Somatostatin Acetate may enhance or prolong Barbiturate effects, including sedative effects.
Sonidegib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Sonidegib.
SORAfenib	CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib.
Stiripentol	PHENobarbital may decrease the serum concentration of Stiripentol.
Tasimelteon	CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon.
Tenofovir Alafenamide	PHENobarbital may decrease the serum concentration of Tenofovir Alafenamide.
Thalidomide	CNS Depressants may enhance the CNS depressant effect of Thalidomide.
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.
Tofacitinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib.
Tolvaptan	CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed.
Toremifene	CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene.
Trabectedin	CYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin.
Ulipristal	CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal.
Ulipristal	Barbiturates may decrease the serum concentration of Ulipristal.
Upadacitinib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Upadacitinib.
Valbenazine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine.
Vandetanib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib.
Velpatasvir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir.
Venetoclax	CYP3A4 Inducers (Strong) may decrease the serum concentration of Venetoclax.
VinCRIStine (Liposomal)	CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal).
Vinflunine	CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinflunine.
Vorapaxar	CYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar.
Voriconazole	Barbiturates may decrease the serum concentration of Voriconazole.
Voxilaprevir	CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxilaprevir.

Monitoring parameters:

Phenobarbital serum concentrations (as clinically indicated)
CNS status
CBC with differential
Liver function tests
Renal function tests
Seizure activity
Signs and symptoms of suicidality (eg, anxiety, depression, behavior changes)

IV use:

Respiratory rate
Pulse rate
Bp
IV site (stop the injection if patient develops of pain in the limb)

How to administer Phenobarbital (Luminal)?

Administer IV, IM, or orally.
As per the manufacturer the rapid IV administration >60 mg/minute should be avoided.
The Neurocritical Care Society has recommended that in the setting of status epilepticus, it should be administered at a rate of 50 to 100 mg/minute.
Avoid extravasation and SubQ administration.
Contraindicated to be used as an intra-arterial injection.
IM injection should be injected deep into muscle.
Do not exceed dose from 5 ml per injection site as it can cause tissue irritation.

Mechanism of action of Phenobarbital (Luminal):

It is a barbiturate that acts long-lastingly and has sedative, anticonvulsant, and hypnotic properties.
Barbiturates can cause depression in the sensory cortex, lower motor activity, alter cerebellar functions, and induce drowsiness, sleepiness, and hypnosis.
When used in high doses, barbiturates can cause respiratory depression due to their CNS depressant effects.

Start of action:

It takes >=60 minutes for oral administration and 5 minutes for IV administration

Peak effect:

IV: CNS Depression occurs in >=15 Minutes

Duration:

10 to 12 hours with oral administration & >6 hours with IV administration

Absorption:

Rapid absorption when given orally

Distribution:

Neonates and Young Infants: V : 0.71 to 1.17 L/kg
Older Infants and Children: V : 0.57 to 0.7 L/kg
Adults: V : 0.54 to 0.73 L/kg

Protein binding:

Neonates: 36% to 43%
Adults: 50% to 60%

Metabolism:

Metabolised in the liver mainly by oxidation via CYP2C9 and to a lesser extent via CYP2C19 and CYP2E1, and by N-glucosidation

Bioavailability:

Adults: 95% to 100% when given orally

Half-life elimination:

Neonates (<48 hours old)
Infants, and Children: ~110 hours (60 to 180 hours)
Adults: ~79 hours (range: 53 to 118 hours)

Time to peak, serum:

1.4 hours (0.5 to 4 hours) with oral administration

Excretion:

25% to 50% as unchanged drug in urine
minimally excreted in feces

International Brand Names of Phenobarbital:

Alepsal
Andral
Aparoxal
Aphenylbarbit
Barbee
Barbilettae
Barbiphenyl
Bialminal
Carbital
Comizial
Dormital
Edhanol
Emgard
Farmacoletas
Farmaconal
Fenemal
Fenobarbital
Fenobarbital FNA
Fenobarbitale
Fenobarbitale Sodico
Fenocris
Fenotal
Fenros
Fenton
Garbital
Gardenal
Gardenal Sodium
Gardenale
Gardenale[inj.]
Kaneuron
Lethyl
Luminal
Luminale
Luminaletas
Luminalette
Luminaletten
Luminale[inj.]
Luminalum
Neurobiol
Noberbar
Pevalon
Phenaemal
Phenaemaletten
Phenobal
Phenobarbiton
Phenobarbiton-natrium
Phenobarbitone
Phenobarbitone Injection
Phenotal
Phental
Phincotomaline
Sedabarb
Sevenal
Sevenaletta
Sibital
Solminotic
Tridezibarbitur
Uni-Feno

Phenobarbital Brand Names in Pakistan:

Phenobarbitone Injection 200 mg in Pakistan
Phenomed	Medicraft Pharmaceuticals (Pvt) Ltd.

Phenobarbitone Injection 100 mg/ml in Pakistan
Phenobarbitone	Geofman Pharmaceuticals
Phenobarbitone	Lawrence Pharma
Phenobarbitone	Orient Laboratories

Phenobarbitone Injection 200 mg/ml in Pakistan
Phenobarbitone	Amros Pharmaceuticals.

Phenobarbitone Injection 200 mg/ml in Pakistan
Phenobarbitone	Amros Pharmaceuticals.

Phenobarbitone Elixir 20 mg in Pakistan
Phenosun	Hisun Pharmaceuticals

Phenobarbitone Elixir 20 mg/5ml in Pakistan
Butone	Shaheen Agencies
Debritone	Xenon Pharmaceuticals (Pvt) Ltd.
Fenton	Harmann Pharmaceutical Laboratories (Pvt) Ltd.
Phenomed	Medicraft Pharmaceuticals (Pvt) Ltd.

Phenobarbitone Tablets 30 mg in Pakistan
Debritone	Xenon Pharmaceuticals (Pvt) Ltd.
Grayfin	Gray`S Pharmaceuticals
Lenton	Valor Pharmaceuticals
Phenfit	Festel Lab
Phenobar	Pliva Pakistan (Pvt) Limited
Phenobar	Amson Vaccines & Pharma (Pvt) Ltd.
Phenobar	Pliva Pakistan (Pvt) Limited
Phenobarbitone	Lisko Pakistan (Pvt) Ltd
Phenobarbitone	Albro Pharma
Phenobarbitone	Amros Pharmaceuticals.
Phenobarbitone	Albro Pharma
Phenobarbitone	Amros Pharmaceuticals.
Phenobarbitone	Karachi Pharmaceutical Laboratory
Phenobarbitone	Munawar Pharma (Pvt) Ltd.
Phenobarbitone	Ethical Laboratories (Pvt) Ltd.
Phenobarbitone	Unexo Labs (Pvt) Ltd.
Phenobarbitone	Munawar Pharma (Pvt) Ltd.
Phenobarbitone	Euro Pharma International
Phenobarbitone	Irza Pharma (Pvt) Ltd.
Phenobarbitone	Jawa Pharmaceuticals(Pvt) Ltd.
Phenobarbitone	Unison Chemical Works
Phenobarbitone	Irza Pharma (Pvt) Ltd.
Phenobarbitone	Unexo Labs (Pvt) Ltd.
Phenobarbitone	Euro Pharma International
Phenobarbitone	Ferozsons Laboratoies Ltd.
Phenobarbitone	Specific Research Laboratories
Phenobarbitone	Lisko Pakistan (Pvt) Ltd
Phenodan	Danas Pharmaceuticals (Pvt) Ltd
Phenomed	Medicraft Pharmaceuticals (Pvt) Ltd.
Phenosal	Universal Pharmaceuticals (Pvt) Ltd
Phenotab	Wilshire Laboratories (Pvt) Ltd.