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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 to treat status epilepticus, generalised tonic-clonic, 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: 2 to 3 divided dosages of 30 to 120 mg per 24 hours.
maximum: 400 mg per 24 hours.
Preoperative sedation:
- IM: 60 to 90 minutes before operation, 100 to 200 mg.

Phenobarbital Dose in the treatment of Status epilepticus: IV:

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

Note: When sedation is present or the loading dose is increased, extra breathing support may be needed. If repeat doses are given before 10 to 15 minutes and produce CNS depression, adequate time may not be allowed for establishing peak CNS concentration.

Phenobarbital (Luminal) Dose in the treatment of Seizures:

Maintenance dose:
- Oral, IV: The typical dosage range (statistics are few) is 2 mg/kg over the course of a day in divided doses.
- Note: The dosage should be adjusted for each person based on their clinical response and serum concentration; normally, a dose of 2 mg/kg per 24 hours will result in a steady-state level of 20 mg/l.
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: 260 mg as the initial dose, followed by 130 mg as needed in following doses.
Note: Clinical Institute Withdrawal Assessment (CIWA) results were assessed every half-hour throughout clinical trials.
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: Clonazepam was replaced with phenobarbital in the study at a dose equivalent to that of the baseline drug (clonazepam 1 mg = phenobarbital 60 mg). The computed baseline total dose should be divided into 4 doses and given every 6 hours for 48 hours. Then, over the course of the following 10 days, the daily requirement should be reduced by 10%.
Fixed dose taper:
- Start with 200 mg, then administer 100 mg every four hours for five doses, then 60 mg every four hours for four doses, and finally 60 mg every eight hours for three doses.

Phenobarbital (Luminal) Dose in Children

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

Infants, Children, and Adolescents:
- IV: Initial: 15-20 mg per kg.
- Max dose: 1000 mg; if necessary, repeat once after 10-15 minutes.
- Maximum cumulative dose: 40 mg/kg; if repeat doses are given before 10 to 15 minutes have passed and produce CNS depression, appropriate time may not be allowed for establishing peak CNS concentration.

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.
- Typical dosage range: Note: Vary the dosage dependent on the patient's clinical reaction and serum concentration; OD doses are typically given to children and adolescents before bed. A few facilities have utilised:
  - 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 more recent, faster-acting drugs.

Manufacturer's labeling:
- Children and Adolescents: Oral: 2 mg/kg/dose thrice a day.
- maximum dose: 40 mg.
Alternate dosing: Limited data available:
- Children and infants: IM, 2-4 mg/kg/day, divided, orally (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: Some facilities have used: 2-3 mg/kg/dose; dose may be repeated after 12–24 hours depending on requirement 3-5 mg/kg via IM or IV at night.

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

Infants and Children:
- Oral: The usual dosage range is 3–8 mg/kg/day divided into 2–3 doses; case reports mention doses as high as 10 mg/kg/day.
- A dose of 5 mg/kg/day has been used to treat hyperbilirubinemia and lower serum bilirubin concentrations in patients with Crigler Najjar syndrome. Due to sedation and other negative effects, it should not be taken in cases of biliary cirrhosis.

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:
- When switching from pentobarbital to phenobarbital, the following strategy has been described: After stopping the pentobarbital infusion, half of the phenobarbital IV loading dose (see table) should be administered over an hour, and the other half should be administered over an hour six hours later.
- Six hours after the loading dose has been finished, provide an IV maintenance phenobarbital dose. The maintenance phenobarbital dose should be administered every 12 hours and be equal to 1/3 of the loading dose. After the patient has stabilised, oral medication should be started with a weekly 10% to 20% taper.

Note: This conversion technique is supported by preliminary patient data who were mechanically ventilated. It is important to keep a watchful eye on respiratory condition. It is important to evaluate 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

The placenta is not a barrier to phenobarbital.
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.
Maternal use may contribute to an increase in the prevalence of foetal malformations.
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:
- They can sign up for the North American Antiepileptic Drug (AED) Pregnancy Registry by calling 888-233-2334 or visiting http://www.aedpregnancyregistry.org throughout pregnancy.

Use of phenobarbital while breastfeeding

Phentabarbital can be found in breast milk.
The desire in nursing may be delayed as a result of in utero exposure.
The abrupt cessation of breastfeeding may result in infantile spasms or other withdrawal symptoms.
When giving phenobarbital to breastfeeding moms, the manufacturer advises caution

Phenobarbital (Luminal) Dose in Kidney Disease:

The manufacturer's labelling does not provide any precise dosage modifications; dosage decrease is advised. The following recommendations have been made by certain clinicians.
- CrCl less than 10 mL/min: No dosage change is required.
- Dose should be given every 12 to 16 hours if CrCl is less than 10 mL/minute.
- Hemodialysis (moderately dialyzable [20%–50%]): 50% dose to be administered prior to and 50% dose following dialysis.
- 35% to 40% of the peritoneum should be removed; 50% of the usual dose should be administered.
- Continuous renal replacement treatment (CRRT): A typical dose should be administered coupled with ongoing medication level monitoring.

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 with 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
- Use with caution in people who have heart disease or hemodynamically unstable people (hypotension and shock).
Depression
- In patients who are depressed, exercise caution.
Diabetes:
- Diabetes sufferers should be watched out for.
Use of drugs:
- Be cautious as you may become dependent on drugs.
- Prolonged use may lead to tolerance, psychological reliance, and/or physical dependence.
Hepatic impairment
- Be careful. Patients with premonitory signs or symptoms of hepatic impairment should be avoided.
Hyperthyroidism:
- In people with hyperthyroidism, exercise caution.
Hypoadrenalism
- In patients with adrenal insufficiency, exercise caution.
Renal impairment
- In patients with kidney dysfunction, exercise caution.

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 lower serum levels of albendazole's active metabolite(s).
Alcohol (Ethyl)	Alcohol's CNS depressing effect may be amplified by CNS depressants (Ethyl).
Alizapride	CNS depressants may have an enhanced CNS depressant impact.
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 lower the level of beta-blockers in the blood. Atenolol, Levobunolol, Metipranolol, and Nadolol are exceptions.
Blood Pressure Lowering Agents	The hypotensive effects of blood pressure lowering medications may be strengthened by barbiturates.
Brentuximab Vedotin	The serum concentration of Brentuximab Vedotin may decrease when CYP3A4 Inducers (Strong) are present. Particularly, levels of the active monomethyl auristatin E (MMAE) constituent could drop.
Brexanolone	Brexanolone's CNS depressing effects may be amplified by other CNS depressants.
Brimonidine (Topical)	CNS depressants may have an enhanced CNS depressant impact.
Bromopride	CNS depressants may have an enhanced CNS depressant impact.
Calcifediol	The serum concentration of calcifediol may drop in response to CYP3A4 Inducers (Strong).
Calcium Channel Blockers	Calcium Channel Blockers' metabolism may be accelerated by barbiturates. Management: Keep an eye out for any diminished therapeutic effects of barbiturate medication when concurrently using calcium channel blockers. There may need to be dose modifications with calcium channel blockers. The concurrent use of phenobarbital and nimodipine is not recommended. Clevidipine is an exception.
Cannabidiol	The serum concentration of cannabidiol may drop in response to CYP3A4 Inducers (Strong).
Cannabidiol	CNS depressants may have an enhanced CNS depressant impact.
Cannabis	Cannabis serum concentrations may be reduced by strong CYP3A4 inducers. Serum concentrations of tetrahydrocannabinol and cannabidiol may fall, to be more precise.
Cannabis	CNS depressants may have an enhanced CNS depressant impact.
CarBAMazepine	CarBAMazepine's serum levels may drop if CYP3A4 Inducers (Strong) are present.
Chlorphenesin Carbamate	CNS depressants' harmful or toxic effects could be increased.
ChlorproPAMIDE	ChlorproPAMIDE's serum levels may be reduced by CYP3A4 Inducers (Strong).
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	PHENobarbital serum concentration can rise.
Diethylstilbestrol	Diethylstilbestrol levels in the serum may be reduced by CYP3A4 Inducers (Strong).
Dimethindene (Topical)	CNS depressants may have an enhanced CNS depressant impact.
Disopyramide	Disopyramide's serum levels may drop when PHENobarbital is used.
Doxercalciferol	The active metabolite(s) of doxercalciferol may be present in higher serum concentrations when CYP3A4 Inducers (Strong) are present.
Doxylamine	CNS depressants may have an enhanced CNS depressant impact. Management: The producer of the pregnancy-safe drug Diclegis (doxylamine/pyridoxine) particularly advises against combining it with other CNS depressants.
Dronabinol	The serum concentration ofdronabinol may drop in response to CYP3A4 Inducers (Strong).
Dronabinol	CNS depressants may have an enhanced CNS depressant impact.
Elagolix	Elagolix's serum levels may be reduced by CYP3A4 Inducers (Strong).
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	The blood concentration of Gestrinone may drop when PHENobarbital is used.
Glecaprevir and Pibrentasvir	Glecaprevir and Pibrentasvir's serum concentrations may be lowered by CYP3A4 Inducers (Strong).
Griseofulvin	Barbiturates may lower the level of gliseofulvin in the blood.
Hydrocortisone (Systemic)	CYP3A4 Inducers (Strong) may lower the level of hydrocortisone in the blood (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 lower the level of PHENobarbital in the serum.
LevETIRAcetam	LevETIRAcetam's serum levels may drop when PHENobarbital is used.
Levomefolate	May lower the level of PHENobarbital in the serum.
Levomethadone	Levomethadone's serum levels may drop when PHENobarbital is used.
Local Anesthetics	The harmful or toxic effects of local anaesthetics may be increased by methemoglobinemia associated agents. In particular, there may be an elevated risk for methemoglobinemia.
Lofexidine	CNS depressants may have an enhanced CNS depressant impact. Management: Separate drug interaction monographs go into further detail about the medications indicated as exceptions to this book.
Lumacaftor	May lower the serum level 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 lower the level of barbiturates in the blood.
Nabilone	CNS depressants may have an enhanced CNS depressant impact.
Nalmefene	PHENobarbital may lower the level of nalmefene in the blood.
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)	PrednisoLONE serum levels may be decreased by CYP3A4 Inducers (Strong) (Systemic).
PredniSONE	The blood concentration of PredniSONE may drop when CYP3A4 Inducers (Strong) are taken.
Prilocaine	The harmful or toxic effects of Prilocaine may be increased by methemoglobinemia associated agents. Combinations of these medications may make substantial methemoglobinemia more likely. Monitoring patients for methemoglobinemia symptoms (such as hypoxia and cyanosis) is necessary when prilocaine is used with other medications that can cause methemoglobinemia in patients. When giving these medicines to newborns, avoid using lidocaine or prilocaine.
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 intensify QuiNIDine's hepatotoxic effects.QuiNIDine's serum levels may drop when PHENobarbital is used.
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	The sedative effects of CNS depressants may increase those of ROPINIRole.
Rotigotine	Rotigotine's sedative effects may be boosted by CNS depressants.
Rufinamide	PHENobarbital serum concentration can rise. PHENobarbital may lower the level of rufinamide in the blood.
Ruxolitinib	Ruxolitinib's serum levels may drop when CYP3A4 Inducers (Strong) are present.
SAXagliptin	The blood concentration of SAXagliptin may decrease in response to CYP3A4 Inducers (Strong).
Selective Serotonin Reuptake Inhibitors	Selective serotonin reuptake inhibitors may have a worsened or more hazardous effect when taken with CNS depressants. Particularly, there may be an increased risk of psychomotor impairment.
Sertraline	CYP3A4 Inducers (Strong) may lower the level of sertraline in the blood.
Sodium Nitrite	Methemoglobinemia Associated Agents might make sodium nitrite more harmful or hazardous. Combinations of these medications may make substantial methemoglobinemia more likely.
Sulthiame	May intensify PHENobarbital's harmful or toxic effects.
Tetrahydrocannabinol	Tetrahydrocannabinol's serum levels may be reduced by CYP3A4 Inducers (Strong).
Tetrahydrocannabinol	CNS depressants may have an enhanced CNS depressant impact.
Tetrahydrocannabinol and Cannabidiol	CNS depressants may have an enhanced CNS depressant impact.
Tetrahydrocannabinol and Cannabidiol	Tetrahydrocannabinol and cannabidiol serum concentrations may be lowered by CYP3A4 Inducers (Strong).
Theophylline Derivatives	Theophylline derivatives' serum levels may be reduced by barbiturates. Exceptions: Dyphylline.
Thiazide and Thiazide-Like Diuretics	Thiazide and Thiazide-Like Diuretics may have an enhanced orthostatic hypotensive effect when used with barbiturates.
Thiothixene	Thiothixene's serum levels may drop when PHENobarbital is used.
Trimeprazine	CNS depressants may have an enhanced CNS depressant impact.
Tropisetron	Tropisetron's serum levels may drop when taken with CYP3A4 Inducers (Strong).
Udenafil	CYP3A4 Inducers (Strong) may lower the level of udenafil in the blood.
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	Afatinib's serum levels may drop when PHENobarbital is used. Management: In accordance with US labelling, if persistent phenobarbital usage is necessary, raise the dose of afatinib by 10 mg as tolerated; then decrease it to the original amount 2-3 days after ceasing phenobarbital. Avoid mixing, as per Canadian labelling.
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 intensify Benzhydrocodone's CNS depressive effects. PHENobarbital may lower serum levels of Benzhydrocodone's active metabolite(s). Particularly, phenobarbital may lower hydrocodone serum concentrations. Treatment: When at all possible, stay away from benzhydrocodone and phenobarbital. Check for sedation or respiratory depression. When taken with phenobarbital, which is a potent CYP3A4 inducer, keep an eye out for withdrawal and decreased benzhydrocodone efficacy.
Bictegravir	PHENobarbital may lower the level of bictegravir in the blood. Management: When combining bictegravir, emtricitabine, and tenofovir alafenamide, consider using a different anticonvulsant. If the combination must be taken, keep a cautious eye out for signs of diminished antiviral efficacy.
Blonanserin	Blonanserin's CNS depressing effects may be enhanced by other CNS depressants.
Brexpiprazole	Brexpiprazole's serum levels may be reduced by CYP3A4 Inducers (Strong). Treatment: The dose of brexpiprazole should be progressively increased over the course of one to two weeks if it is combined with a potent CYP3A4 inducer.
Buprenorphine	The CNS depressive effects of buprenorphine may be strengthened by phenobarbital. Buprenorphine's serum concentration may drop when PHENobarbital is used. Management: When at all feasible, stay away from phenobarbital and buprenorphine. Check for sedation or respiratory depression. When taken with phenobarbital, which is a potent CYP3A4 inducer, keep an eye out for withdrawal symptoms and decreased buprenorphine efficacy.
BusPIRone	BusPIRone serum levels may be decreased by CYP3A4 Inducers (Strong). Management: Take into account alternatives to this fusion. Monitor patients for diminished buspirone effects if coadministration of these medications is judged necessary.
Cabozantinib	The serum concentration of Cabozantinib may fall in response to CYP3A4 Inducers (Strong). Management: If at all feasible, stay away from taking cabozantinib with potent CYP3A4 inducers. Depending on the cabozantinib product used and the intended use, cabozantinib dose modifications are advised if taken in conjunction. Monograph for more information.
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	CNS depressants may have an enhanced CNS depressant impact. Management: Keep a close eye out for signs of severe CNS depression. If such a combination is required, it should be taken at a dose that has been suitably lowered, according to the instructions for chlormethiazole.
Cholestyramine Resin	May lower the level of PHENobarbital in the serum. To reduce the chance of any major interactions, provide phenobarbital at least one hour before or four to six hours after giving cholestyramine.
Clarithromycin	The serum concentrations of the active metabolite(s) of clarithromycin may rise in response to CYP3A4 Inducers (Strong). Clarithromycin may raise the level of CYP3A4 inducers in the serum (Strong). CYP3A4 Inducers (Strong) may lower the level of clarithromycin in the blood. If a patient is receiving a CYP3A inducer, other antimicrobial therapy should be considered. Drugs that speed up the conversion of clarithromycin into 14hydroxyclarithromycin may change the drug's therapeutic action and reduce its effectiveness.
Codeine	The effects of codeine's CNS depressant may be strengthened by phenobarbital. PHENobarbital may lower the level of codeine in the blood. Management: When feasible, refrain from using phenobarbital and codeine. Check for sedation or respiratory depression. As phenobarbital is a potent CYP3A4 inducer, keep an eye out for withdrawal symptoms if you mix it with codeine.
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)	Slows down the metabolism of CYP2C19 substrates (High risk with Inhibitors).
CYP3A4 Substrates (High risk with Inducers)	The metabolism of CYP3A4 Substrates may be increased by strong CYP3A4 Inducers (High risk with Inducers). Management: Take into account a substitute for one of the interfering medications. Specific contraindications may apply to some combinations. the relevant manufacturer's label. Benzhydrocodone, Buprenorphine, CarBAMazepine, Etizolam, Hydrocodone, Tramadol, and Zolpidem are examples of exclusions.
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)	Dexamethasone serum levels may be decreased by CYP3A4 Inducers (Strong) (Systemic). In patients taking potent CYP3A4 inducers, consider increasing the dose of dexamethasone, and watch out for signs of diminished steroid efficacy.
DOXOrubicin (Conventional)	Strong CYP3A4 Inducers may lower DOXOrubicin serum levels (Conventional). Treatment: In individuals receiving doxorubicin, look for alternatives to medications that are potent CYP3A4 inducers. Pfizer Inc., a U.S. manufacturer, advises against using certain mixtures.
Doxycycline	Barbiturates may lower Doxycycline's serum levels.
Droperidol	CNS depressants may have an enhanced CNS depressant impact. Consider lowering the dosage of droperidol or other CNS drugs (such as opioids or barbiturates) when they are used concurrently. In separate drug interaction monographs, exceptions to this monograph are covered in more detail.
Enzalutamide	Enzalutamide's serum levels may be reduced by CYP3A4 Inducers (Strong). Management: Whenever possible, choose an alternate agent with little to no ability to induce CYP3A4. Increase the dosage of enzalutamide from 160 mg daily to 240 mg if this combination cannot be avoided.
Enzalutamide	.May lower the serum level of CYP2C19 substrates (High risk with Inducers). For medications that CYP2C19 activates, active metabolite concentrations may decrease instead. Treatment: Enzalutamide should not be used concurrently with CYP2C19 substrates that have a limited therapeutic index. Enzalutamide use, along with the use of any other CYP2C19 substrate, should be done with caution and under close observation.
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 lower the level of felbamate in the serum. PHENobarbital's serum levels may rise with the use of felbamate. Management: Initiate felbamate at 1200 mg/day in divided doses three to four times daily and reduce phenobarbital dose by 20% in patients receiving phenobarbital. Keep an eye out for rising phenobarbital levels and their effects as well as falling felbamate levels and their effects.
FentaNYL	The CNS depressive action of FentaNYL may be strengthened by PHENobarbital. The serum concentration of FentaNYL may decrease when PHENobarbital is used. Management: When at all feasible, stay away from phenobarbital and fentanyl. Check for sedation or respiratory depression. When taken with phenobarbital, which is a potent CYP3A4 inducer, keep an eye out for withdrawal and decreased fentanyl efficacy.
Flunitrazepam	Flunitrazepam's CNS depressing effects may be enhanced by other CNS depressants.
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 intensify barbiturates' CNS depressive effects. When using hydroxyzine along with a barbiturate, consider lowering the dose as necessary. Patients should be constantly watched for an excessive reaction to the combination when using it concurrently.
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 lower the level of LamoTRIgine in the blood. Management: If taking a barbiturate concurrently with lamotrigine, consult its prescription literature for age-dependent dosage instructions and adjust lamotrigine dosage accordingly.
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 lower the level of lopinavir in the serum. When using these medications together, higher doses of lopinavir may be required for treatment. Do not combine phenobarbital with a once-daily lopinavir/ritonavir regimen. Using this combination, increase the monitoring of each patient's therapeutic response.
Manidipine	Manidipine's serum levels may drop when CYP3A4 Inducers (Strong) are taken. Treatment: Take into account avoiding the simultaneous use of manidipine and potent CYP3A4 inducers. If taken together, keep a watchful eye out for diminished manidipine effects and diminished efficacy. Manidipine dosages may need to be increased.
Maraviroc	It's possible that CYP3A4 Inducers (Strong) will lower the level of Maraviroc in your blood. Management: When used with potent CYP3A4 inducers, increase the adult dose of maraviroc to 600 mg twice daily. Patients who are also getting potent CYP3A4 inhibitors are not covered by this.
Mefloquine	May reduce an anticonvulsant's therapeutic impact. Anticonvulsant serum concentrations may be reduced by mefloquine. Treatment: Mefloquine should not be used to prevent malaria in those who have a history of convulsions. With concurrent use, closely monitor anticonvulsant concentrations and therapeutic response.
Meperidine	Meperidine's serum levels may drop if CYP3A4 Inducers (Strong) are present. When using strong CYP3A4 inducers concurrently, the dose of meperidine may need to be increased. Keep an eye out for the effects of opioid withdrawal.
Methotrimeprazine	The CNS depressing action of methotrimeprazine may be enhanced by CNS depressants. The CNS depressant action of CNS Depressants may be strengthened by methotrimeprazine. Management: Start concurrent methotrimeprazine therapy while reducing the adult dose of CNS depressants by 50%. Only once a clinically effective dose of methotrimeprazine has been established should additional CNS depressant dosage modifications be made.
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	Opioid agonists' CNS depressing effects may be amplified by CNS depressants. Management: When at all possible, refrain from using benzodiazepines or other CNS depressants concurrently with opioid agonists. Only in the event that other treatment choices are insufficient should these medications be combined. Limit the duration and dosage of each medicine when used together.
Osimertinib	Osimertinib's serum levels may be reduced by CYP3A4 Inducers (Strong).
OXcarbazepine	PHENobarbital may lower serum levels of OXcarbazepine's active metabolite(s). Particularly, levels of the main active 10-monohydroxy metabolite may drop. PHENobarbital's serum levels may rise in response to oxcarbazepine. Management: Take into account raising the starting dose of Oxtellar XR (oxcarbazepine extended release tablet) for adults to 900 mg per day. For additional oxcarbazepine formulations, there are no particular guidelines available.
OxyCODONE	PHENobarbital may intensify OxyCODONE's CNS depressive effects. PHENobarbital may lower the level of OxyCODONE in the blood. Management: When at all feasible, stay away from oxycodone and phenobarbital. Check for sedation or respiratory depression. If phenobarbital is taken with oxycodone, keep an eye out for withdrawal symptoms as phenobarbital is a potent CYP3A4 inducer.
Perampanel	CYP3A4 Inducers (Strong) may lower the level of Perampanel in the serum. When using perampanel alongside strong and moderate CYP3A4 inducers, the beginning dose should be increased to 4 mg/day.
Perampanel	CNS depressants may have an enhanced CNS depressant impact. Treatment: Until they have experience using the combination, patients taking perampanel along with any other medication that has CNS depressive effects should avoid complex and high-risk activities, especially those like driving that call for awareness and coordination.
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	PHENobarbital serum concentration can rise. PHENobarbital may lower the level of quinine in the blood.
Radotinib	The serum concentration of Radotinib may drop when CYP3A4 Inducers (Strong) are taken. Management: When possible, look into alternatives to this combination because there may be an increased chance of radotinib treatment failure.
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 lower the level of Sirolimus in the blood. Management: If at all feasible, refrain from using sirolimus and potent CYP3A4 inducers together. Check for decreased serum sirolimus concentrations if the two are combined. Increases in sirolimus dosage will probably be required to prevent subtherapeutic sirolimus levels.
Sodium Oxybate	CNS depressants may have an enhanced CNS depressant impact. Management: Take into account substitutes for combined use. Reduce the doses of one or more medications when simultaneous use is necessary. It is not advised to use sodium oxybate with alcoholic beverages or hypnotic sedatives.
SUFentanil	The CNS depressive action of SUFentanil may be strengthened by PHENobarbital. It's possible that PHENobarbital will lower SUFentanil's serum levels. Sufentanil and phenobarbital should be avoided whenever possible in treatment. Check for sedation or respiratory depression. In cases when sufentanil is taken with phenobarbital, watch for decreased efficacy and withdrawal because phenobarbital is a potent CYP3A4 inducer.
SUNItinib	The serum concentration of SUNItinib may decrease in response to CYP3A4 Inducers (Strong). Management: Avert wherever you can. It is advised to raise sunitinib dosage, which varies depending on the indication, if such a combination cannot be avoided. For information, see the entire monograph.
Suvorexant	Suvorexant's CNS depressing effects may be amplified by other CNS depressants. Treatment: Suvorexant and/or any other CNS depressant dosage reduction may be required. Suvorexant should not be combined with any other drugs to treat insomnia, including alcohol.
Tadalafil	Tadalafil's serum levels may be lowered by CYP3A4 Inducers (Strong). Management of erectile dysfunction: no usual dose modifications are advised; monitor for diminished effectiveness. Tadalafil should not be used to treat pulmonary arterial hypertension in patients taking a potent CYP3A4 inducer.
Tamoxifen	The active metabolite(s) of tamoxifen's serum concentrations may be reduced by CYP3A4 Inducers (Strong). Tamoxifen's serum levels may drop when CYP3A4 Inducers (Strong) are taken. Management: Look at alternatives to using tamoxifen and potent CYP3A4 inducers together. If the combination cannot be avoided, keep an eye out for diminished tamoxifen therapeutic benefits.
Tapentadol	CNS depressants may have an enhanced CNS depressant impact. Treatment: When feasible, refrain from using tapentadol and benzodiazepines or other CNS depressants simultaneously. Only in the event that other treatment choices are insufficient should these medications be combined. Limit the dosages if used together.
Temsirolimus	Temsirolimus' serum levels may drop if you use CYP3A4 Inducers (Strong). If a concurrent strong CYP3A4 inducer is required, consider raising the dose of temsirolimus from 25 mg IV/week to 50 mg IV/week.
Teniposide	Teniposide's serum levels may drop if you use barbiturates. Management: Because of the possibility of decreasing teniposide concentrations, consider alternatives to combined treatment with barbiturates and teniposide. If the combination must be used, keep a watchful eye on the teniposide response.
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	The CNS depressive effect of TraMADol may be strengthened by PHENobarbital. PHENobarbital may lower the level of TraMADol in the serum. Tramadol and phenobarbital should be avoided whenever possible in treatment. Check for sedation or respiratory depression. If tramadol is taken with phenobarbital, watch out for decreased effectiveness and withdrawal because phenobarbital is also a potent CYP3A4 inducer.
Tricyclic Antidepressants	Tricyclic Antidepressants' metabolism may be accelerated by barbiturates.
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 speed up the metabolism of substances that block vitamin K. Management: Pay closer attention to INR. After a barbiturate is started or given at a higher dose, it could be necessary to raise the dosage of an anticoagulant. Following barbiturate withdrawal or dose reduction, anticoagulant dose reductions may be required.
Vortioxetine	It's possible that CYP3A4 Inducers (Strong) will lower Vortioxetine's serum levels. Management: When taken with a potent drug metabolism inducer for longer than 14 days, consider raising the vortioxetine dose to no more than three times the original dose. After quitting the potent inducer, the vortioxetine dosage should be returned to normal within 14 days.
Zaleplon	Strong CYP3A4 Inducers may lower the level of zaleplon in the blood. Treatment: If a patient is taking a hypnotic that CYP3A4 cannot metabolise, consider using an alternative hypnotic.
Zolpidem	The CNS depressing action of zolpidem may be enhanced by CNS depressants. Men with additional CNS depressants should lower their sublingual zolpidem dose to 1.75 mg under the Intermezzo brand. For women, there should be no such dose adjustment. Avoid using other CNS depressants or alcohol right before bed.
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	The serum concentration of Daclatasvir may be reduced by CYP3A4 Inducers (Strong).
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	The active metabolite(s) of gemigliptin may be present in lower serum quantities when CYP3A4 Inducers (Strong) are present. Gemigliptin's serum levels may be reduced by CYP3A4 Inducers (Strong).
Glasdegib	Glasdegib's serum levels may be reduced by CYP3A4 Inducers (Strong).
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 lower the level of ledipasvir in the serum.
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	Methoxyflurane's nephrotoxic impact may be enhanced by CYP2A6 Inducers. Methoxyflurane metabolism may be increased by CYP2A6 inducing substances.
Mianserin	May intensify barbiturates' CNS depressive effects. Barbiturates' therapeutic effects may be lessened by minanserin. Barbiturates may lower the Mianserin serum levels.
Midostaurin	Midostaurin's serum levels may be reduced by CYP3A4 Inducers (Strong).
MiFEPRIStone	It's possible that CYP3A4 Inducers (Strong) will lower the level of MiFEPRIStone in the blood.
Naldemedine	The serum concentration of naldemedine may drop in response to CYP3A4 Inducers (Strong).
Naloxegol	Naloxegol's serum levels may be reduced by CYP3A4 Inducers (Strong).
Neratinib	The serum concentration of neratinib may decrease after taking CYP3A4 Inducers (Strong).
Netupitant	It's possible that CYP3A4 Inducers (Strong) will lower Netupitant's serum levels.
NIFEdipine	CYP3A4 Inducers (Strong) may lower the level of NIFEdipine in the serum.
Nilotinib	Nilotinib's serum levels may be reduced by CYP3A4 Inducers (Strong).
NiMODipine	The serum concentration of NiMODipine may drop in response to CYP3A4 Inducers (Strong).
Nisoldipine	Nisoldipine's serum levels may be reduced by CYP3A4 Inducers (Strong).
Olaparib	CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib.
Orphenadrine	The CNS depressing action of orphenadrine may be enhanced by CNS depressants.
Oxomemazine	CNS depressants may have an enhanced CNS depressant impact.
Palbociclib	It's possible that CYP3A4 Inducers (Strong) will lower palbociclib's serum levels.
Panobinostat	CYP3A4 Inducers (Strong) may lower the level of panobinostat in the blood.
Paraldehyde	The CNS depressing effects of paraldehyde may be enhanced by CNS depressants.
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 lower the level of sofosbuvir in the serum.
Somatostatin Acetate	May intensify the hazardous or harmful effects of barbiturates. Somatostatin Acetate in particular may intensify or extend the sedative effects of barbiturates.
Sonidegib	Sonidegib's serum levels may be reduced by CYP3A4 Inducers (Strong).
SORAfenib	The serum concentration of SORAfenib may drop when CYP3A4 Inducers (Strong) are taken.
Stiripentol	The serum concentration of Stiripentol may drop when PHENobarbital is used.
Tasimelteon	CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon.
Tenofovir Alafenamide	PHENobarbital may decrease the serum concentration of Tenofovir Alafenamide.
Thalidomide	The CNS depressing effect of thalidomide may be enhanced by CNS depressants.
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 orally, IV, or IM.
According to the manufacturer, a rapid IV infusion rate of more than 60 mg per minute should be avoided.
According to the Neurocritical Care Society, it should be delivered at a rate of 50 to 100 mg/minute in cases of status epilepticus.
Avoid administering SubQ and extravasation.
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 diminish motor activity, change cerebellar functioning, depress the sensory cortex, and induce lethargy, sleepiness, and hypnosis.
Due to their CNS depressive properties, barbiturates when administered in large amounts might result in respiratory depression.

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:

The primary method of metabolism in the liver is oxidation by CYP2C9, with minor contributions from CYP2C19 and CYP2E1 and 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.