Nembutal

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Nembutal

Classes

Barbiturates, Plain

Administration
Oral Administration

To increase the rate of absorption, administer on an empty stomach or as the elixir.

Injectable Administration

IV administration is restricted to conditions in which other routes are not feasible (unconscious or noncooperative patients; conditions may include cerebral hemorrhage, eclampsia, status epilepticus, and delirium) or because prompt action is imperative.
Parenteral solutions are very alkaline; avoid intra-arterial injection and extravasation.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use solutions for injection that show evidence of precipitation.

Intravenous Administration

IV Push
Do not admix with any other medication or solution.
Slow IV injection is essential; at least 1 minute is necessary to determine the full effect of intravenous pentobarbital. Give no faster than 50 mg/minute.
During injection, maintain blood pressure, respiration, and cardiac function; monitor vital signs, and have equipment for resuscitation and artificial ventilation readily available.
 
Continuous IV Infusion
Pentobarbital is not FDA-approved to be administered as an IV infusion.
ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 8 mg/mL or 50 mg/mL.
Pentobarbital 600 mg/L or 1,200 mg/L in either 0.9% Sodium Chloride Injection or 5% Dextrose Injection was stable for 12 hours, and use of a 0.45 micron filter did not affect the amount of pentobarbital that would be delivered to a patient. In another compatibility study, pentobarbital concentrations not greater than 8 mg/mL in either 0.9% Sodium Chloride Injection or 5% Dextrose Injection were stable for 24 hours; precipitation was noted at higher pentobarbital concentrations.

Intramuscular Administration

Inject deeply into a large muscle mass.
Inject no more than 250 mg or 5 mL at any site.

Rectal Administration

Do not divide suppositories.
Instruct patient on proper use of suppository.
Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.

Adverse Reactions
Severe

tissue necrosis / Early / Incidence not known
bronchospasm / Rapid / Incidence not known
apnea / Delayed / Incidence not known
bradycardia / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
serum sickness / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
megaloblastic anemia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
porphyria / Delayed / Incidence not known
seizures / Delayed / Incidence not known
intraventricular hemorrhage / Delayed / Incidence not known
lactic acidosis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known

Moderate

impaired cognition / Early / Incidence not known
confusion / Early / Incidence not known
ataxia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
erythema / Early / Incidence not known
respiratory depression / Rapid / Incidence not known
hypoventilation / Rapid / Incidence not known
phlebitis / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
thrombocytopenia / Delayed / Incidence not known
bullous rash / Early / Incidence not known
hepatitis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
constipation / Delayed / Incidence not known
osteomalacia / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
nystagmus / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
withdrawal / Early / Incidence not known
physiological dependence / Delayed / Incidence not known
tachypnea / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known

Mild

dizziness / Early / Incidence not known
anxiety / Delayed / Incidence not known
vertigo / Early / Incidence not known
nightmares / Early / Incidence not known
emotional lability / Early / Incidence not known
hyperkinesis / Delayed / Incidence not known
insomnia / Early / Incidence not known
headache / Early / Incidence not known
weakness / Early / Incidence not known
agitation / Early / Incidence not known
irritability / Delayed / Incidence not known
drowsiness / Early / Incidence not known
lethargy / Early / Incidence not known
psychomotor impairment / Early / Incidence not known
injection site reaction / Rapid / Incidence not known
syncope / Early / Incidence not known
purpura / Delayed / Incidence not known
ecchymosis / Delayed / Incidence not known
fever / Early / Incidence not known
photosensitivity / Delayed / Incidence not known
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
asthenia / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
vomiting / Early / Incidence not known
nausea / Early / Incidence not known
ptosis / Delayed / Incidence not known
miosis / Early / Incidence not known
mydriasis / Early / Incidence not known
libido decrease / Delayed / Incidence not known
diaphoresis / Early / Incidence not known

Common Brand Names

Nembutal

Dea Class

Rx, schedule II

Description

Short-acting oral and parenteral barbiturate; for preoperative anxiety, sedation, refractory seizures, or to induce coma for increased intracranial pressure; rarely used for insomnia due to rapid development of tolerance; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

Dosage And Indications
For procedural sedation or for use as a preanesthetic medication. Intramuscular dosage Adults

150 to 200 mg IM. Use a reduced dosage in debilitated or geriatric patients.

Infants, Children, and Adolescents

2 to 6 mg/kg/dose (Max: 100 mg/dose) IM; may give an additional 1 to 3 mg/kg/dose if adequate sedation is not achieved within 1 hour of administration.

Intravenous dosage Adults

100 mg IV is a common, initial dose for a 70-kg adult. Allow at least 1 minute to assess full effect of dose. Additional doses may be given up to a total of 200 to 500 mg. Use a reduced dosage in debilitated or geriatric patients.

Infants†, Children†, and Adolescents†

1 to 3 mg/kg/dose (Max: 100 mg/dose) IV every 1 to 5 minutes as needed; Max cumulative dose: 6 mg/kg or 200 mg, whichever is less. Supplementary doses of 1 to 3 mg/kg may be required to maintain adequate sedation for imaging procedures. Patients receiving barbiturates for medical therapy may receive as much as 9 mg/kg total dose.

Neonates†

Although neonatal-specific data are limited, 1 to 3 mg/kg/dose IV every 1 to 5 minutes as needed has been reported; Max cumulative dose: 2 to 6 mg/kg.

Oral dosage

NOTE: Oral capsules are no longer commercially available in the US. Although details regarding stability are not available, the parenteral solution has been mixed in a 3:1 ratio with cherry syrup and given orally. In these pediatric studies, oral pentobarbital was better tolerated and as effective as the comparator (IV pentobarbital or chloral hydrate).

Children and Adolescents 4 to 17 years

1.5 to 4 mg/kg/dose (Max: 100 mg/dose) PO once. Max cumulative dose: 6 mg/kg or 200 mg, whichever is less. FDA-approved labeling recommends 2 to 6 mg/kg/24 hours and dependent on age, weight, and degree of desired sedation.

Children 1 to 3 years

3 to 6 mg/kg/dose (Max: 100 mg/dose) PO once. Max cumulative dose: 6 mg/kg or 200 mg, whichever is less. FDA-approved labeling recommends 2 to 6 mg/kg/24 hours and dependent on age, weight, and degree of desired sedation.

Infants

4 mg/kg/dose PO once; may give additional doses of 2 to 4 mg/kg/dose every 30 minutes as needed for adequate sedation. Max cumulative dose: 6 to 8 mg/kg. FDA-approved labeling recommends 2 to 6 mg/kg/24 hours and dependent on age, weight, and degree of desired sedation.

For the treatment of acute convulsive episodes, including status epilepticus. Intravenous dosage Adults

5 to 15 mg/kg/dose IV as a single dose, then 0.5 to 5 mg/kg/hour continuous IV infusion, initially. Titrate by 0.5 to 1 mg/kg/hour every 12 hours for breakthrough status epilepticus; may also consider additional 5 to 10 mg/kg/dose IV as a single dose if needed. Maintain EEG burst suppression for 12 to 48 hours before tapering the infusion. Guidelines recommend pentobarbital for refractory status epilepticus.

Infants, Children, and Adolescents

5 to 15 mg/kg/dose IV as a single dose, then 1 mg/kg/hour continuous IV infusion, initially. Titrate by 0.5 to 1 mg/kg/hour every 12 hours for breakthrough status epilepticus; may also consider additional 5 to 10 mg/kg/dose IV as a single dose if needed. Usual dose: 0.5 to 5 mg/kg/hour. Maintain EEG burst suppression for 12 to 48 hours before tapering the infusion. Guidelines recommend continuous IV infusion of pentobarbital for refractory status epilepticus.

Neonates

5 to 15 mg/kg/dose IV as a single dose, then by 1 mg/kg/hour continuous IV infusion, initially. Titrate by 0.5 to 1 mg/kg/hour every 12 hours for breakthrough status epilepticus; may also consider additional 5 to 10 mg/kg/dose IV as a single dose if needed. Usual dose: 0.5 to 5 mg/kg/hour. Maintain EEG burst suppression for 12 to 48 hours before tapering the infusion.   Guidelines recommend continuous IV infusion of pentobarbital for refractory status epilepticus.

For the short-term treatment of insomnia. Intramuscular dosage Adults

150 to 200 mg IM at bedtime. Use a reduced dosage in debilitated patients as they may be more sensitive to barbiturates. Studies indicate there is a loss of effectiveness of barbiturates for sleep induction and sleep maintenance after 2 weeks. Barbiturates are not considered an acceptable treatment for insomnia due to a significant adverse effect profile, narrow therapeutic index, tolerance and dependence, and the availability of safer alternatives.

Geriatric Adults

150 to 200 mg IM at bedtime. Use a reduced dosage in geriatric adults as they may be more sensitive to barbiturates. Barbiturates may be associated with marked excitement, depression, or confusion in geriatric or debilitated patients. Studies indicate there is a loss of effectiveness of barbiturates for sleep induction and sleep maintenance after 2 weeks. Barbiturates are not considered an acceptable treatment for insomnia due to a significant adverse effect profile, narrow therapeutic index, tolerance and dependence, and the availability of safer alternatives. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of barbiturates in long-term care facilities (LTCFs). Barbiturates should not be used to treat insomnia in a LTCF resident since they are highly addictive and can cause multiple adverse effects (e.g., CNS effects, hypotension, fall risk), especially in geriatric patients.

Infants, Children, and Adolescents

2 to 6 mg/kg/dose IM at bedtime (Max: 100 mg/dose). Not considered an acceptable treatment for insomnia per guidelines.

For the reduction of increased intracranial pressure (ICP)† in patients with traumatic brain injury (i.e., head trauma)†. Continuous Intravenous Infusion dosage Adults

10 mg/kg IV load over 30 minutes, then 5 mg/kg/dose IV every 3 hours for 3 doses, then a continuous infusion of 1 mg/kg/hour IV. Mechanical ventilation required. Titrate infusion to clinical response; dosage range 1 to 2 mg/kg/hour. In general, barbiturate coma is reserved for hemodynamically stable patients with persistent elevations of ICP greater than 20 to 25 mmHg. The goal is an induced coma state characterized by absent brainstem reflexes and suppression of the EEG. Monitor ICP, mean arterial pressure, cerebral perfusion pressure, and EEG burst suppression. To minimize the risk of cerebral hypoxia, monitor arteriovenous oxygen saturation. Taper pentobarbital after 24 hours of controlled ICP.

Children and Adolescents

10 mg/kg IV load over 30 minutes, then 5 mg/kg/dose IV every 3 hours for 3 doses, then a continuous infusion of 1 mg/kg/hour IV. Titrate infusion to clinical response; dosage range = 1 to 2 mg/kg/hour. Mechanical ventilation required. The goal is an induced coma state characterized by absent brainstem reflexes and suppression of the EEG. Monitor ICP, mean arterial pressure, cerebral perfusion pressure, and EEG burst suppression. Taper pentobarbital after 24 hours of controlled ICP. Traumatic brain injury guidelines recommend high-dose barbiturate therapy in hemodynamically stable patients with refractory ICP despite maximal medical and surgical management.

Intermittent Intravenous dosage Infants, Children, and Adolescents

5 mg/kg/dose IV every 4 to 6 hours has been suggested; titrate as needed to treat elevated ICP. Mechanical ventilation required. Some experts suggest this lower dose may be effective and avoid hypotensive effects; data suggests complete burst suppression on EEG may not be necessary for pentobarbital's protective effects.[53034] Of note, traumatic brain injury guidelines recommend high-dose barbiturate therapy in hemodynamically stable patients with refractory ICP despite maximal medical and surgical management.[64013]

For sedation maintenance† and to alleviate agitation† and anxiety† in patients refractory to standard therapy who are mechanically-ventilated. Continuos Intravenous Infusion dosage Infants, Children, and Adolescents

1 to 2 mg/kg IV load, then a continuous infusion of 1 to 2 mg/kg/hour IV. May administer bolus doses equivalent to the hourly rate of infusion every 2 hours as needed; if 4 to 6 boluses or more are needed in a 24-hour period, increase infusion rate by 1 mg/kg/hour. Titrate to adequate sedation; reported range is 1 to 6 mg/kg/hour (median range 2 mg/kg/hour). Monitor blood pressure. Gradually taper infusion or convert to an oral barbiturate (e.g., phenobarbital) after prolonged therapy to avoid symptoms of withdrawal. Pentobarbital therapy is an alternative option for sedation in those who fail standard therapy; significant complications including hypotension, oversedation, neurologic sequelae, and drug reaction limit its use.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Use with caution at reduced doses in hepatic impairment; specific guidelines for dosage adjustments are not available. Avoid use in patients with hepatic encephalopathy.

Renal Impairment

FDA-approved labeling recommends reduced dosage in renal impairment due to increased barbiturate sensitivity; specific guidelines for dosage adjustments are not available.

Drug Interactions

Abemaciclib: (Major) Avoid coadministration of pentobarbital with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 29% to 53%.
Acetaminophen: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Aspirin: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when dihydrocodeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of dihydrocodeine with a barbiturate can decrease dihydrocodeine concentrations, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Additive CNS depression may occur if barbiturates are used concomitantly with dichloralphenazone. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Diphenhydramine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Ibuprofen: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with a barbiturate may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; oxycodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Pamabrom; Pyrilamine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Phenylephrine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Pseudoephedrine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetazolamide: (Minor) Acetazolamide can induce osteomalacia in patients treated chronically with barbiturates. Potential mechanisms for this interaction include a carbonic anhydrase inhibitor induced increase in the urinary excretion of calcium and an increase in barbiturate effects resulting from metabolic acidosis. Acetazolamide can also increase the rate of excretion of weakly acidic drugs, such as barbiturates.
Acrivastine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with acrivastine.
Adagrasib: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
Alfentanil: (Major) Concomitant use of alfentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of alfentanil with a barbiturate may decrease alfentanil plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; alfentanil is a CYP3A4 substrate.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with barbiturates is necessary. Alprazolam is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Concomitant use with CYP3A4 inducers can decrease alprazolam concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, monitor for excessive sedation and somnolence during coadministration of alprazolam and barbiturates. Concurrent use may result in additive CNS depression.
Altretamine: (Minor) Because altretamine undergoes significant metabolism by the cytochrome P450 system, agents that stimulate CYP450 enzymes, such as barbiturates, increase the metabolism of altretamine and may result in decreased therapeutic effects.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Amlodipine: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Atorvastatin: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Amlodipine; Benazepril: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Celecoxib: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Olmesartan: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Valsartan: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Amoxapine: (Major) Monitor for excessive sedation and somnolence during coadministration of amoxapine and barbiturates. Concurrent use may result in additive CNS depression.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Anagrelide: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, such as barbiturates, could theoretically increase the elimination of anagrelide and decrease the efficacy of anagrelide.
Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
Apremilast: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
Aprepitant, Fosaprepitant: (Major) Use caution if barbiturates and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Barbiturates are CYP3A4 inducers and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
Aripiprazole: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.
Armodafinil: (Major) It is not clear how armodafinil interacts with barbiturates like phenobarbital. Armodafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased armodafinil efficacy. Barbiturates used for sleep could counteract the effect of armodafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining armodafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if armodafinil can affect seizure control.
Artemether; Lumefantrine: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
Asenapine: (Moderate) Barbiturates can cause CNS depression, and if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Aspirin, ASA: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Carisoprodol: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Dipyridamole: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Omeprazole: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with a barbiturate may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; oxycodone is a CYP3A4 substrate. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Atenolol; Chlorthalidone: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Atogepant: (Major) Avoid use of atogepant and barbiturates when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with barbiturates. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and barbiturates are strong CYP3A inducers. Coadministration with a strong CYP3A inducer resulted in a 60% reduction in atogepant overall exposure and a 30% reduction in atogepant peak concentration.
Atorvastatin: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Atorvastatin; Ezetimibe: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with barbiturates can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Avacopan: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Avanafil: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Avapritinib: (Major) Avoid coadministration of avapritinib with pentobarbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Axitinib: (Major) Avoid coadministration of axitinib with pentobarbital if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and pentobarbital is a moderate CYP3A4 inducer.
Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine, an antihistamine, is combined with CNS depressants including the barbiturates.
Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine, an antihistamine, is combined with CNS depressants including the barbiturates.
Azilsartan; Chlorthalidone: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Bedaquiline: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Belladonna; Opium: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Bendamustine: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of benzhydrocodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of benzhydrocodone with a barbiturate may decrease benzhydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; benzhydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
Betaxolol: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Clinicians should monitor patients for loss of beta-blockade.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Barbiturates may decrease the half-life and plasma concentrations of metronidazole. The clinical significance of this effect is uncertain.
Bismuth Subsalicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Barbiturates may decrease the half-life and plasma concentrations of metronidazole. The clinical significance of this effect is uncertain.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Bortezomib: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates and primidone, are added to brexpiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the brexpiprazole dose should be reduced over 1 to 2 weeks to the original level.
Brigatinib: (Major) Avoid coadministration of brigatinib with pentobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with pentobarbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of pentobarbital, resume the brigatinib dose that was tolerated prior to initiation of pentobarbital. Brigatinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including barbiturates.
Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including barbiturates.
Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including barbiturates.
Brivaracetam: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Brompheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Brompheniramine; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Brompheniramine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Lidocaine: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Meloxicam: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Buprenorphine: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenobarbital may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. It is likely that all barbiturates exert the same effect as phenobarbital. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if any of these agents are added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. Additive CNS depression may be the more important issue initially when barbiturates are given with buprenorphine; the induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Buprenorphine; Naloxone: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenobarbital may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. It is likely that all barbiturates exert the same effect as phenobarbital. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if any of these agents are added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. Additive CNS depression may be the more important issue initially when barbiturates are given with buprenorphine; the induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Bupropion: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Bupropion; Naltrexone: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Buspirone: (Moderate) Monitor for reduced anxiolytic effect of buspirone. Potent inducers of CYP3A4, such as the barbiturates, may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to maintain anxiolytic effect. There is also a risk of additive CNS depression (drowsiness) when buspirone is given concomitantly with barbiturates. In a study in healthy volunteers, co-administration of buspirone with a potent CYP3A4 inducer decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone.
Butalbital; Acetaminophen: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as barbiturates, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration.
Caffeine; Sodium Benzoate: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with barbiturates. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with barbiturates. Barbiturates stimulate microsomal hydroxylation and reduce the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
Calcitriol: (Moderate) Barbiturates can decrease the activity of vitamin D by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation may be required in patients with inadequate dietary intake of vitamin D who are receiving chronic treatment with barbiturates.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and pentobarbital. CNS depressants can potentiate the effects of cannabidiol.
Capmatinib: (Major) Avoid coadministration of capmatinib and pentobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Carbamazepine: (Moderate) Barbiturates can accelerate hepatic metabolism of carbamazepine due to induction of hepatic microsomal enzyme activity. Carbamazepine serum concentrations should be monitored closely if a barbiturate is added or discontinued during therapy.
Carbidopa; Levodopa; Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Carbinoxamine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as carbinoxamine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Cardiac glycosides: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
Cariprazine: (Major) Concomitant use of cariprazine and barbiturates is not recommended because the net effect on cariprazine and its equipotent active metabolites is unclear. CYP3A is responsible for both the formation and elimination of cariprazine's major active metabolites. Barbiturates are CYP3A inducers, however, concurrent use of cariprazine with CYP3A inducers has not been evaluated, and the net effect is unclear. In addition, due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
Celecoxib; Tramadol: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and pentobarbital. Concurrent use may result in additive CNS depression.
Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with barbiturates should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with barbiturates should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as dexchlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorambucil: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
Chloramphenicol: (Moderate) Chloramphenicol inhibits the cytochr

ome P-450 enzyme system and can affect the hepatic metabolism of phenobarbital. Phenobarbital levels rise modestly. It is also possible that plasma concentrations of chloramphenicol can be reduced by concomitant use of barbiturates, agents that are known to stimulate hepatic microsomal enzymes responsible for chloramphenicol metabolism.
Chlordiazepoxide: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Chlordiazepoxide; Amitriptyline: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Chlordiazepoxide; Clidinium: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Chlorothiazide: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Chlorpheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Dextromethorphan: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of dihydrocodeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when dihydrocodeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of dihydrocodeine with a barbiturate can decrease dihydrocodeine concentrations, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorthalidone: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Chlorthalidone; Clonidine: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Choline Salicylate; Magnesium Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Clemastine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as clemastine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Clobazam: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Clonazepam: (Moderate) Monitoring of clonazepam concentrations or dosage adjustment may be necessary if used concurrently with barbiturates due to decreased clonazepam concentrations. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with strong CYP3A4 inducers. Clonazepam is a CYP3A4 substrate. Barbiturates are strong CYP3A4 inducers. Additive CNS and/or respiratory depression may also occur.
Clorazepate: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate. N-desmethyldiazepam is a CYP3A4 and CYP2C19 substrate. Barbiturates are CYP3A4 and CYP2C19 inducers.
Clozapine: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with barbiturates due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and barbiturates are moderate inducers of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Codeine; Guaifenesin: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Codeine; Promethazine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Colesevelam: (Moderate) Colesevelam may decrease the absorption of anticonvulsants. To minimize potential for interactions, consider administering oral anticonvulsants at least 1 hour before or at least 4 hours after colesevelam.
COMT inhibitors: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Cyclosporine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Cyproheptadine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with cyproheptadine.
Darifenacin: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
Darunavir: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Darunavir; Cobicistat: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Delavirdine: (Major) Barbiturates may increase the metabolism of delavirdine, lead to substantial reductions in delavirdine concentrations and efficacy. The manufacturer recommends that delavirdine not be given with barbiturates when used as anticonvulsants due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant mutations of HIV. In addition, delavirdine may inhibit the metabolism of the barbiturates. If used concomitantly, the patient should be observed for changes in the clinical efficacy and concentrations of the antiretroviral and anticonvulsant regimens.
Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as barbiturates, may have additive effects and worsen drowsiness or sedation.
Dexamethasone: (Moderate) Monitor for decreased efficacy of dexamethasone if coadministration with barbiturates is necessary; consider increasing the dose of dexamethasone if clinically appropriate. Dexamethasone is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Dexchlorpheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as dexchlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as dexchlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with barbiturates is likely to lead to an enhancement of CNS depression.
Dextromethorphan; Bupropion: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Dextromethorphan; Quinidine: (Major) Quinidine is eliminated primarily via hepatic metabolism, primarily by the CYP3A4 isoenzyme. Administration of other hepatic enzyme inducers, such as barbiturates, can accelerate quinidine elimination and decrease its serum concentrations. Phenobarbital may decrease quinidine half-life and corresponding AUC by about 50 to 60%. Quinidine concentrations should be monitored closely after one of these agents is added. No special precautions appear necessary if these agents are begun several weeks before quinidine is added but quinidine doses may require adjustment if one of these agents is added or discontinued during quinidine therapy.
Diazepam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Diclofenac: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
Diclofenac; Misoprostol: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
Dicyclomine: (Moderate) Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like barbiturates.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diltiazem: (Major) Diltiazem is a CYP3A4 substrate. Coadministration of diltiazem with known CYP3A4 inducers, such as barbiturates, may significantly decrease the bioavailability of diltiazem. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure.
Dimenhydrinate: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with dimenhydrinate.
Diphenhydramine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Diphenhydramine; Ibuprofen: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Diphenhydramine; Naproxen: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Diphenhydramine; Phenylephrine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with barbiturates can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Disopyramide: (Moderate) Hepatic microsomal enzyme-inducing agents, such as barbiturates, have the potential to accelerate the hepatic metabolism of disopyramide, a CYP3A4 substrate. Serum disopyramide concentrations should be monitored closely if hepatic enzyme inducers are either added or discontinued during disopyramide therapy.
Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Donepezil: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP2D6 and CYP3A4, such as barbiturates (including primidone). The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
Donepezil; Memantine: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP2D6 and CYP3A4, such as barbiturates (including primidone). The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers, such as barbiturates, may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol.
Doxorubicin Liposomal: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxycycline: (Major) Phenobarbital has been shown to affect the pharmacokinetics of doxycycline. Doxycycline half-life was decreased from 15.3 hours to 11.1 hours. It is likely that other barbiturates may exert the same effect. Clinicians should keep in mind that larger doses of doxycycline may be necessary in patients receiving barbiturates. This interaction may not apply to other tetracyclines since they are less dependent on hepatic metabolism for elimination.
Doxylamine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Doxylamine; Pyridoxine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with barbiturates is necessary, and monitor for an increase in barbiturate-related adverse reactions and a decrease in the efficacy of dronabinol. Additive dizziness, confusion, somnolence, and other CNS effects may also occur. Dronabinol is a CYP2C9 and 3A4 substrate; barbiturates are moderate or strong (phenobarbital) inducers of CYP3A4; additionally phenobarbital is a moderate CYP2C9 inducer. Concomitant use may result in decreased plasma concentrations of dronabinol. Decreased clearance of barbiturates has also been reported with dronabinol use, possibly by competitive inhibition of metabolism. Published data show an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol.
Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Barbiturates induce CYP3A4. Coadministration of CYP3A4 inducers, such as barbiturates, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
Droperidol: (Major) Central nervous system depressants, such as barbiturates, have additive or potentiating effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant should be used.
Duvelisib: (Major) Avoid concomitant use of duvelisib with pentobarbital. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. When pentobarbital has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with pentobarbital. Duvelisib is a CYP3A substrate; pentobarbital is a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
Efavirenz: (Major) Complex interactions may occur when barbiturates (e.g., phenobarbital) are administered to patients receiving treatment for HIV infection; if treating seizure disorder, a different anticonvulsant should be used whenever possible. If a barbiturate must be used in a patient being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments to the barbiturate or the antiretroviral medications are unknown. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenobarbital is an inducer of CYP3A4, and a substrate and inducer of CYP2C9 and CYP2C19. Use caution if these drugs are to be coadministered, with increased monitoring of both efavirenz and barbiturate concentrations.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when barbiturates (e.g., phenobarbital) are administered to patients receiving treatment for HIV infection; if treating seizure disorder, a different anticonvulsant should be used whenever possible. If a barbiturate must be used in a patient being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments to the barbiturate or the antiretroviral medications are unknown. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenobarbital is an inducer of CYP3A4, and a substrate and inducer of CYP2C9 and CYP2C19. Use caution if these drugs are to be coadministered, with increased monitoring of both efavirenz and barbiturate concentrations.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when barbiturates (e.g., phenobarbital) are administered to patients receiving treatment for HIV infection; if treating seizure disorder, a different anticonvulsant should be used whenever possible. If a barbiturate must be used in a patient being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments to the barbiturate or the antiretroviral medications are unknown. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenobarbital is an inducer of CYP3A4, and a substrate and inducer of CYP2C9 and CYP2C19. Use caution if these drugs are to be coadministered, with increased monitoring of both efavirenz and barbiturate concentrations.
Elacestrant: (Major) Avoid concurrent use of elacestrant and barbiturates due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced elacestrant overall exposure by 86%.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inducers of CYP1A2, such as barbiturates, on the systemic exposure of eltrombopag has not been established. Monitor patients for a decrease in the efficacy of eltrombopag if these drugs are coadministered.
Empagliflozin; Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and barbiturates if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and barbiturates are strong CYP3A inducers. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and barbiturates if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and barbiturates are strong CYP3A inducers. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Erdafitinib: (Major) If coadministration of erdafitinib and pentobarbital is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If pentobarbital must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If pentobarbital is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer.
Ergotamine; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration.
Erlotinib: (Major) Avoid the coadministration of erlotinib with pentobarbital if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pentobarbital is a CYP3A4 and CYP1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
Escitalopram: (Moderate) Escitalopram is metabolized by CYP2C19 and CYP3A4. Barbiturates can induce the metabolism of various CYP 450 isoenzymes, including those involved in escitalopram metabolism. Although no clinical data are available to support a clinically significant interaction, escitalopram may need to be administered in higher doses in patients chronically taking barbiturates.
Esketamine: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Eslicarbazepine: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
Esomeprazole: (Major) Avoid coadministration of esomeprazole with barbiturates because it can result in decreased efficacy of esomeprazole. Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Estazolam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of estazolam. Estazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Eszopiclone: (Major) Barbiturates are potent inducers of CYP3A4 may increase the rate of eszopiclone metabolism. Additive CNS depression may also occur if barbiturates are used concomitantly with eszopiclone. Caution should be exercised during concomitant use of eszopiclone and any barbiturate; dosage reduction of one or both agents may be necessary.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethosuximide: (Moderate) Barbiturates induce hepatic microsomal enzymes and increase the hepatic metabolism of ethosuximide, leading to a decrease in ethosuximide plasma concentrations and half-life. To maintain a therapeutic dosage, serum concentrations of ethosuximide should be measured, especially if barbiturate therapy is added to or withdrawn from ethosuximide therapy.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with pentobarbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Fedratinib: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Felodipine: (Major) Barbiturates (e.g., phenobarbital, primidone) may significantly reduce systemic exposure of felodipine; consider alternative therapy. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. Felodipine is a CYP3A4 substrate, and these anticonvulsants are potent CYP3A4 inducers. In a pharmacokinetic study, felodipine's Cmax was considerably lower in epileptic patients on long-term anticonvulsant therapy than in healthy volunteers. In these patients, the mean AUC was reduced approximately 6% of that observed in healthy adults.
Fenfluramine: (Major) Avoid concurrent use of fenfluramine and barbiturates due to the risk of decreased fenfluramine plasma concentrations, which may reduce its efficacy. If concomitant use is necessary, monitor for decreased efficacy and consider increasing fenfluramine dose as needed. If barbiturates are discontinued during fenfluramine maintenance treatment, consider gradual reduction in the fenfluramine dosage to the dose administered prior to barbiturate initiation. Fenfluramine is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Fenoprofen: (Minor) Phenobarbital and possibly other barbiturates can decrease the plasma concentrations and half-life of fenoprofen. The clinical significance of this interaction has not been established, but dosage adjustments of fenoprofen may be necessary with concurrent administration of phenobarbital or following initiation or withdrawal of the drug.
Fentanyl: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and phenobarbital or other barbiturates, which are strong CYP3A4 inducers, is not recommended.
Fluconazole: (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Food: (Major) Advise patients to avoid cannabis use during barbiturate treatment due to the risk for additive CNS depression and other adverse reactions. Concomitant use may also decrease the concentration of some cannabinoids and alter their effects. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and barbiturates are strong CYP3A inducers. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inducer decreased THC, 11-OH-THC, and CBD peak exposures by 36%, 87%, and 52% respectively.
Fosamprenavir: (Moderate) Monitor for decreased fosamprenavir efficacy if coadministered with barbiturates. Concurrent use may decrease the plasma concentrations of fosamprenavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Fosamprenavir is a CYP3A substrate and barbiturates are strong CYP3A inducers. Coadministration with another strong CYP3A inducer decreased the fosamprenavir overall exposure by 82%.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Gabapentin: (Major) Concomitant use of barbiturates with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and barbiturates due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and barbiturates are a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ganaxolone overall exposure by 68%.
General anesthetics: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
Glasdegib: (Major) Avoid coadministration of glasdegib and pentobarbital due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided and pentobarbital will be used chronically, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after pentobarbital has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; pentobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
Glimepiride: (Minor) Barbiturates may induce the CYP2C9 metabolism of glimepiride. Blood glucose concentrations should be monitored and possible dose adjustments of glimepiride may need to be made.
Green Tea: (Minor) Some green tea products contain caffeine. The metabolism of xanthines, such as caffeine, can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
Griseofulvin: (Minor) Barbiturates can impair the oral absorption of griseofulvin, resulting in decreased serum concentrations and, potentially, decreased antifungal efficacy. The clinical significance of this interaction is uncertain, but the manufacturer recommends that these drugs not be co-administered.
Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Guanfacine: (Major) Monitor patients for guanfacine efficacy and for excess sedation during pentobarbital coadministration. Guanfacine plasma concentrations can be reduced by pentobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as barbiturates. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Hemin: (Major) Hemin works by inhibiting the enzyme (delta)-aminolevulinic acid synthetase. Drugs which increase the activity of this enzyme, such as barbiturates should not be used with hemin.
Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Hydantoins: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Hydromorphone: (Major) Concomitant use of hydromorphone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as pentobarbital. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Hydroxyzine: (Major) Because hydroxyzine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including barbiturates.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with barbiturates. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with a barbiturate may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; oxycodone is a CYP3A4 substrate.
Iloperidone: (Moderate) Barbiturates can cause CNS depression, and if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. In theory, the use of barbiturates and iloperidone may also result in an increase in iloperidone elimination as a result of the CYP inducing effects of barbiturates.
Imatinib: (Major) Avoid coadministration of imatinib and barbiturates if possible due to decreased plasma concentrations of imatinib. If concomitant use is unavoidable, increase the dose of imatinib by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers. Imatinib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib.
Indinavir: (Major) Barbiturates may increase the metabolism of indinavir and lead to decreased antiretroviral efficacy. In addition, indinavir may inhibit the CYP metabolism of barbiturates, resulting in increased barbiturate concentrations. Appropriate dose adjustments necessary to ensure optimum levels of both anti-retroviral agent and the barbiturate are unknown. Anticonvulsant serum concentrations should be monitored closely if these agents are added; the patient should be observed for changes in the clinical efficacy of the antiretroviral or anticonvulsant regimen.
Infigratinib: (Major) Avoid concurrent use of infigratinib and barbiturates. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the AUC of infigratinib by 56%.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Isavuconazonium: (Major) Concomitant use of isavuconazonium with pentobarbital should be undertaken with great caution due to the potential for treatment failure. Coadministration may result in reduced systemic exposure to isavucaonazole, the active moiety of isavuconazoium. Isavuconazole is a sensitive substrate of hepatic isoenzyme CYP3A4. Barbituates are known to induce hepatic CYP isoenzymes; phenobarbital, a potent inducer of CYP3A4, is contraindicated for use with isavuconazole.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) It may be necessary to adjust the dosage of pentobarbital if given concurrently with rifampin. Rifampin may induce the metabolism of pentobarbital; coadministration may result in decreased pentobarbital plasma concentrations.
Isoniazid, INH; Rifampin: (Moderate) It may be necessary to adjust the dosage of pentobarbital if given concurrently with rifampin. Rifampin may induce the metabolism of pentobarbital; coadministration may result in decreased pentobarbital plasma concentrations.
Isradipine: (Major) Because isradipine is a substrate of CYP3A4, the concomitant use of drugs that strongly induce CYP3A4, such as barbiturates, may cause a reduction in the bioavailability and thus decreased therapeutic effect of isradipine. Consider alternative therapy; if co-use is necessary, patients should be monitored for potential loss of therapeutic effect when hepatic enzyme inducers are added to isradipine therapy.
Itraconazole: (Major) Use of barbiturates is not recommended for 2 weeks before or during itraconazole therapy. Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of itraconazole. Monitor for breakthrough fungal infections.
Ivabradine: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and barbiturates due to decreased plasma concentrations of ixabepilone, which may reduce its efficacy. If concomitant use is unavoidable, gradually increase the dose of ixabepilone as tolerated from 40 mg/m2 to 60 mg/m2 and infuse over 4 hours; monitor carefully for ixabepilone-related toxicities. Ixabepilone is a CYP3A substrate and barbiturates are strong CYP3A inducers. Coadministration with another strong CYP3A inducer decreased ixabepilone exposure by 43%.
Ketoconazole: (Major) Avoid barbiturates for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Lansoprazole: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and barbiturates. Concurrent use may result in additive CNS depression.
Lemborexant: (Major) Avoid coadministration of lemborexant and pentobarbital as concurrent use may decrease lemborexant exposure which may reduce efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Lemborexant is a CYP3A4 substrate; pentobarbital is a moderate CYP3A4 inducer.
Lenacapavir: (Contraindicated) Concurrent use of lenacapavir and barbiturates is contraindicated due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced lenacapavir overall exposure by 84%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and barbiturates. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced leniolisib overall exposure by 78%.
Lesinurad: (Moderate) Barbiturates may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Barbiturates induce the CYP2C9 isoenzyme, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Barbiturates may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Barbiturates induce the CYP2C9 isoenzyme, and lesinurad is a CYP2C9 substrate.
Leucovorin: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Levamlodipine: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with barbiturates should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Levoketoconazole: (Major) Avoid barbiturates for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Levoleucovorin: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Levorphanol: (Major) Concomitant use of levorphanol with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial dose of levorphanol by approximately 50% or more. Educate patients about the risks and symptoms of respiratory depression and sedation.
Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and barbiturates if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and barbiturates are strong CYP3A inducers. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and barbiturates if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and barbiturates are strong CYP3A inducers. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Lisdexamfetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use lisdexamfetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Lithium: (Moderate) Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including anxiolytics, sedatives, and hypnotics.
Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of lopinavir; ritonavir and barbiturates. If concomitant use is necessary, do not use once daily dosing of lopinavir; ritonavir. Concomitant use may decrease lopinavir plasma concentrations, resulting in reduced efficacy. Lopinavir is a CYP3A substrate and barbiturates are CYP3A inducers. (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Lorazepam: (Moderate) Additive CNS and/or respiratory depression may occur with concurrent use.
Lorlatinib: (Major) Avoid concomitant use of lorlatinib and pentobarbital due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and pentobarbital is a moderate CYP3A inducer. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Lovastatin: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with HMG-CoA reductase inhibitors metabolized by CYP3A4 including lovastatin.
Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants, such as barbiturates. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inducers, such as barbiturates, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Decreased blood concentrations of lurasidone are expected when the drug is co-administered with strong inducers of CYP3A4.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and pentobarbital due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and pentobarbital is a moderate CYP3A inducer.
Magnesium Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Mannitol: (Minor) Mannitol promotes the urinary excretion of barbiturates, and it may be used as an adjunct in patients with barbiturate toxicity.
Maprotiline: (Major) Monitor for excessive sedation and somnolence during coadministration maprotiline and barbiturates. Concurrent use may result in additive CNS depression.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with barbiturates due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP2C19 and CYP3A substrate and barbiturates are a moderate CYP2C19 inducer and strong CYP3A inducer. The impact that a CYP3A inducer may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a strong CYP3A inducer is predicted to decrease mavacamten overall exposure by 69% and 87% in poor and normal CYP2C19 metabolizers, respectively.
Mebendazole: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the metabolism of mebendazole if given concomitantly. This effect can cause decreased levels of plasma mebendazole but is probably important only in the treatment of extraintestinal infections, such as hydatid cyst disease, and not in the treatment of intestinal helminths.
Meclizine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with meclizine.
Mefloquine: (Moderate) The barbiturates induce CYP3A4 and may increase the metabolism of mefloquine if coadministered. Concomitant administration can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria. Coadministration of mefloquine and barbiturates that are used as anticonvulsants may also result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors.
Melatonin: (Major) Use caution when combining melatonin with other traditional sedatives and hypnotics, including the sedative barbiturates. Use of more than one agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. If a barbiturate is taken for seizure control, watch for changes in anticonvulsant activity. Be alert for unusual changes in moods or behaviors. Patients reporting unusual sleep-related behaviors likely should discontinue melatonin use. Additionally, melatonin exposure and efficacy may be reduced when combined with barbiturates such as phenobarbital, as barbiturates induce many CYP450 isoenzymes, including CYP1A2, the primary metabolic pathway for melatonin.
Meperidine: (Major) Concomitant use of meperidine with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of meperidine with a barbiturate may decrease meperidine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; meperidine is a CYP3A4 substrate.
Meprobamate: (Major) Additive CNS depression may occur if barbiturates are used concomitantly with other anxiolytics, sedatives, and hypnotics like meprobamate. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate; dosage reduction of one or both agents may be necessary.
Metformin; Repaglinide: (Major) Coadministration of barbiturates and repaglinide may decrease the serum concentration of repaglinide; if coadministration is necessary, a dose increase of repaglinide may be necessary and increased frequency of blood glucose monitoring. Barbiturates are CYP3A4 inducers and repaglinide is a CYP3A4 substrate. Monitor for the possibility of reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Methadone: (Major) Concomitant use of methadone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of methadone with a barbiturate may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, CYP2C9, and CYP2C19, isoenzymes partially responsible for the metabolism of methadone.
Methazolamide: (Minor) Methazolamide can induce osteomalacia in patients treated chronically with barbiturates. Potential mechanisms for this interaction include a carbonic anhydrase inhibitor induced increase in the urinary excretion of calcium and an increase in barbiturate effects resulting from metabolic acidosis. Methazolamide can also increase the rate of excretion of weakly acidic drugs, such as barbiturates.
Methenamine; Sodium Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Methocarbamol: (Moderate) Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants such as barbiturates. Dosage reduction of one or both agents may be necessary.
Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
Methsuximide: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Methyclothiazide: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
Metolazone: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Metronidazole: (Minor) Barbiturates may decrease the half-life and plasma concentrations of metronidazole. The clinical significance of this effect is uncertain.
Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as barbiturates, should be used with caution. Additive drowsiness and/or dizziness is possible.
Metyrosine: (Moderate) The concomitant administration of metyrosine with barbiturates can result in additive sedative effects.
Mexiletine: (Moderate) While other hepatic enzyme inducers have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Midazolam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of midazolam. Midazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as barbiturates. Caution should be exercised when using these agents concurrently.
Mirtazapine: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Mitapivat: (Major) Avoid coadministration of mitapivat with barbiturates due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. Mitapivat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Coadministration with another strong CYP3A inducer decreased mitapivat overall exposure by 91% to 95%.
Mitotane: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants may cause additive CNS effects. Mitotane should be used cautiously with other drugs that may cause CNS depression including barbiturates.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and barbiturates. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Use of a strong CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 92%.
Modafinil: (Major) It is not clear how modafinil interacts with barbiturates like phenobarbital. Modafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased modafinil efficacy. Barbiturates used for sleep could counteract the effect of modafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining modafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if modafinil can affect seizure control.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Monoamine oxidase inhibitors: (Major) Monoamine oxidase inhibitors (MAOIs) may prolong the effect of some barbiturates, which may increase CNS depression. Additionally, MAOIs may increase the risk of hypotension after barbiturates are used for sedation induction. When possible, MAOIs should be discontinued for at least 10 days prior to elective surgery due to potential interactions with anesthetic agents. Barbiturates should generally be given at a reduced dose with an MAOI.
Morphine: (Major) Concomitant use of morphine with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of respiratory depression and sedation.
Morphine; Naltrexone: (Major) Concomitant use of morphine with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of respiratory depression and sedation.
Nabilone: (Major) Nabilone should not be taken with barbiturates or other sedative/hypnotic agents because these substances can potentiate the central nervous system effects of nabilone. Additive drowsiness and CNS depression can occur.
Nalbuphine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with nalbuphine. Caution should be exercised during concomitant use of nalbuphine and any barbiturate. Dosage reduction of one or both agents may be necessary.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with pentobarbital is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and pentobarbital is a CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers.
Naproxen; Esomeprazole: (Major) Avoid coadministration of esomeprazole with barbiturates because it can result in decreased efficacy of esomeprazole. Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Nelfinavir: (Major) Coadministration with phenobarbital and, potentially, other barbiturates may increase the metabolism of nelfinavir and lead to decreased nelfinavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If nelfinavir and barbiturates are used together, the patient must be closely monitored for antiviral efficacy.
Neratinib: (Major) Avoid concomitant use of pentobarbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
Nevirapine: (Moderate) Use caution and monitor for decreased efficacy of nevirapine if coadministered with barbiturates. Concurrent use may decrease the plasma concentrations of nevirapine leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Concomitant use may also decrease the barbiturate concentration. Monitor concentrations closely during coadministration of nevirapine; dose adjustments may be needed. Nevirapine is a CYP3A substrate and weak CYP3A inducer; barbiturates are strong CYP3A inducers. Coadministration with another strong CYP3A inducer decreased nevirapine exposure by greater than 50%.
Niacin; Simvastatin: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Nicardipine: (Major) Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
Nifedipine: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
Nimodipine: (Major) In epileptic patients taking phenobarbital with or without other enzyme-inducing anticonvulsants, there is a 7-fold decrease in the AUC of nimodipine due to hepatic enzyme induction. Patients receiving barbiturates and nimodipine concomitantly should be monitored closely for efficacy. Although no data are available, it is likely that nimodipine, a CYP3A4 substrate, may be affected by the coadministration of all barbiturates.
Nintedanib: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
Nirmatrelvir; Ritonavir: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering barbiturates; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following barbiturate discontinuation. Nirmatrelvir is a CYP3A substrate and barbiturates are strong CYP3A inducers. (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Nisoldipine: (Major) Coadministration of nisoldipine with CYP3A4 inducers like the barbiturates should be avoided and alternative antihypertensive therapy should be considered. Coadministration of a strong CYP3A4 inducer with nisoldipine in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Barbiturates (e.g., phenobarbital, primidone) may also decrease the oral bioavailability of nisoldipine via increased hepatic drug clearance.
Olanzapine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Olanzapine; Fluoxetine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Olanzapine; Samidorphan: (Major) Avoid the concurrent use of samidorphan and barbiturates; decreased samidorphan exposure and loss of efficacy may occur. Samidorphan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer reduced samidorphan exposure by 73%. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Olaparib: (Major) Avoid coadministration of olaparib with pentobarbital due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and pentobarbital is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
Oliceridine: (Major) Concomitant use of oliceridine with pentobarbital may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with pentobarbital to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and barbiturates due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced olutasidenib exposure by approximately 80%.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and barbiturates. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and barbiturates is a strong CYP3A inducer.
Omeprazole: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Omeprazole; Sodium Bicarbonate: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Ondansetron: (Minor) Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 patients with epilepsy who were maintained chronically on CYP3A4 inducers (e.g., barbiturates) a reduction in ondansetron AUC, Cmax, and half-life was observed, resulting in a significant increase in ondansetron clearance. However, these changes in ondansetron exposure are not thought to be clinically relevant; no dosage adjustment for ondansetron is recommended when CYP450 inducers are used concurrently.
Opicapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Oxazepam: (Moderate) Additive CNS and/or respiratory depression may occur with concurrent use.
Oxybutynin: (Moderate) Additive CNS depression may occur when oxybutynin is used concomitantly with other CNS-depressant drugs, including anxiolytics, sedatives, and hypnotics. In addition, because oxybutynin is metabolized by CYP3A4, administration with drugs that induce CYP3A4 (such as barbiturates) may reduce the serum concentration and effects of oxybutynin. Patients receiving these drugs concomitantly should be monitored for reduced efficacy.
Oxycodone: (Major) Concomitant use of oxycodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with a barbiturate may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; oxycodone is a CYP3A4 substrate.
Oxymorphone: (Major) Concomitant use of oxymorphone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxymorphone dosage by 1/3 to 1/2. Educate patients about the risks and symptoms of respiratory depression and sedation.
Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including barbiturates.
Paliperidone: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Palovarotene: (Major) Avoid concomitant use of palovarotene and barbiturates. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced palovarotene overall exposure by 11%.
Papaverine: (Moderate) Concurrent use of papaverine with potent CNS depressants such as barbiturates could lead to enhanced sedation.
Paroxetine: (Moderate) Barbiturates may induce various hepatic CYP450 isoenzymes, including those responsible for the metabolism of paroxetine. Clinicians should be aware of the potential for reduced SSRI efficacy with concurrent administration of a barbiturate, especially in chronic use.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and pentobarbital due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving these agents, which may include barbiturates.
Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving these agents, which may include barbiturates.
Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
Perindopril; Amlodipine: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
Phenothiazines: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the barbiturates. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Phenothiazines can also lower the seizure threshold, which may be important in patients taking a barbiturate for the treatment of seizures. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with the use of sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
Phentermine; Topiramate: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), an interaction with barbiturates via hepatic isoenzyme activity is possible. In patients receiving either phenobarbital or primidone in combination with topiramate, there was a < 10% change in phenobarbital or primidone plasma concentrations; the effects on topiramate plasma concentrations were not evaluated. Barbiturates may cause additive sedation or other CNS depressive effects when used concurrently with topiramate. When topiramate is combined with phentermine for the treatment of obesity, a greater risk of CNS depression exists. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as the barbiturates, may also increase the risk of bleeding; monitor patients appropriately.
Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
Pioglitazone; Glimepiride: (Minor) Barbiturates may induce the CYP2C9 metabolism of glimepiride. Blood glucose concentrations should be monitored and possible dose adjustments of glimepiride may need to be made.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Pomalidomide: (Moderate) Use pomalidomide and barbiturates together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Ponesimod: (Major) Avoid concurrent use of ponesimod and barbiturates and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and barbiturates are strong CYP3A inducers that may decrease ponesimod exposure. Additionally, phenobarbital is known to also induce UGT1A1; ponesimod is also an UGT1A1 substrate.
Pralidoxime: (Major) The action of barbiturates is potentiated by the acetylcholinesterase inhibitors, which should be considered when using pralidoxime. Barbiturates should be used with caution to treat convulsions produced by acetylcholinesterase inhibitors.
Pramipexole: (Major) The use of barbiturates in combination with pramipexole may increase the risk of clinically significant sedation via a pharmacodynamic interaction.
Pregabalin: (Major) Concomitant use of barbiturates with pregabalin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Procarbazine: (Moderate) Use procarbazine and barbiturates together with caution; additive CNS depression may occur.
Progestins: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Pseudoephedrine; Triprolidine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with triprolidine.
Quazepam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of quazepam. Quazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Quetiapine: (Major) Coadministration of barbiturates, potent CYP3A4 inducers, with quetiapine, a CYP3A4 substrate, may result in decreased exposure to quetiapine. The dose of quetiapine should be increased by up to 5-fold when combined with chronic administration (7 to 14 days) of a potent CYP3A4 inducer. Adjust the dose based on patient response and tolerability. When the potent CYP3A4 inducer is discontinued, the quetiapine dose should be reduced to the original dose within 1 to 2 weeks. Also, somnolence is a commonly reported adverse effect of quetiapine; coadministration of quetiapine with barbiturates may result in additive sedative effects.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Quinidine: (Major) Quinidine is eliminated primarily via hepatic metabolism, primarily by the CYP3A4 isoenzyme. Administration of other hepatic enzyme inducers, such as barbiturates, can accelerate quinidine elimination and decrease its serum concentrations. Phenobarbital may decrease quinidine half-life and corresponding AUC by about 50 to 60%. Quinidine concentrations should be monitored closely after one of these agents is added. No special precautions appear necessary if these agents are begun several weeks before quinidine is added but quinidine doses may require adjustment if one of these agents is added or discontinued during quinidine therapy.
Quinine: (Major) If concomitant administration of barbiturates and quinine cannot be avoided, frequently monitor the barbiturate concentration. Also, monitor closely for increased barbiturate-associated adverse events such as excessive drowsiness, difficulty breathing, or confusion. A single quinine 600 mg dose increased the mean plasma Cmax and AUC of a barbiturate by 53% and 81%, respectively, in 8 healthy subjects. In addition, barbiturates are CYP3A4 inducers and may decrease plasma quinine concentrations.
Quizartinib: (Major) Avoid concomitant use of barbiturates with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Quizartinib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Rabeprazole: (Moderate) Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
Ramelteon: (Major) Barbiturates can induce CYP1A2, the major metabolic pathway for ramelteon, and may eventually accelerate the clearance (and, thus, reduce the sedative properties) of ramelteon. Administration of multiple doses of a potent CYP inducer (rifampin) resulted in a mean decrease of approximately 80% in total exposure to ramelteon and its metabolite M-II. Additive CNS depression may also occur. The induction of ramelteon metabolism would likely require several days of barbiturate administration while additive drowsiness would appear immediately. Caution should be exercised during concomitant use of any CNS-depressant drugs and any barbiturate; dosage reduction of one or both agents may be necessary. If the medications must be used together, monitor for the effectiveness of ramelteon. Hypnotic barbiturates are best avoided during ramelteon therapy; the manufacturer warns against using other medications for sleep concurrently with ramelteon.
Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including barbiturates. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including buprenorphine, butorphanol, dronabinol, THC, nabilone, nalbuphine, and anxiolytics, sedatives, and hypnotics. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inducers, such as barbiturates, can theoretically reduce the effectiveness of HMG-CoA reductase activity via induction of CYP3A4 metabolism.
Remifentanil: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Remimazolam: (Major) The sedative effect of remimazolam can be accentuated by barbiturates. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
Repaglinide: (Major) Coadministration of barbiturates and repaglinide may decrease the serum concentration of repaglinide; if coadministration is necessary, a dose increase of repaglinide may be necessary and increased frequency of blood glucose monitoring. Barbiturates are CYP3A4 inducers and repaglinide is a CYP3A4 substrate. Monitor for the possibility of reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Rifampin: (Moderate) It may be necessary to adjust the dosage of pentobarbital if given concurrently with rifampin. Rifampin may induce the metabolism of pentobarbital; coadministration may result in decreased pentobarbital plasma concentrations.
Rilpivirine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Riluzole: (Moderate) Coadministration of riluzole with barbiturates may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Risperidone: (Moderate) Monitor for a decrease in risperidone efficacy during concomitant use of risperidone and barbiturates and increase risperidone dosage as appropriate based on response. For patients receiving long-acting risperidone dosage forms, supplemental oral risperidone may be required. Additionally, monitor for unusual drowsiness and sedation during coadministration due to the risk for additive CNS depression. Concomitant use may decrease risperidone exposure and increase the risk for CNS depression. Risperidone is a CYP3A substrate, and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced risperidone overall exposure by 50%.
Ritlecitinib: (Moderate) Monitor for a decrease in ritlecitinib efficacy during concomitant use of ritlecitinib and barbiturates. Concomitant use may decrease ritlecitinib exposure. Ritlecitinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced ritlecitinib overall exposure by 0.56-fold.
Ritonavir: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Roflumilast: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increa sed Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, like barbiturates, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
Ropinirole: (Moderate) Coadministration of ropinirole and barbiturates may result in decreased concentrations of ropinirole. If therapy with barbiturates is initiated or discontinued during treatment with ropinirole, adjustment of ropinirole dose may be required. Ropinirole is primarily metabolized by CYP1A2; barbiturates are inducers of CYP1A2. Also, somnolence is a commonly reported adverse effect of ropinirole; coadministration of ropinirole with barbiturates may result in additive sedative effects.
Rotigotine: (Major) Concomitant use of rotigotine with other CNS depressants, such as pentobarbital, can potentiate the sedation effects of rotigotine.
Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as barbiturates.
Salicylates: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Salsalate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Saquinavir: (Major) Coadministration with phenobarbital and, potentially, other barbiturates may increase the metabolism of saquinavir and lead to decreased saquinavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If saquinavir and barbiturates are used together, the patient must be closely monitored for antiviral efficacy.
Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline and barbiturates. Concurrent use may result in additive CNS depression. Although barbiturates are CYP3A4 inducers and selegiline is a CYP3A4 substrate, adequate studies have not been conducted to evaluate their effect, if any, on the effectiveness of selegiline.
Sildenafil: (Minor) Sildenafil is metabolized principally by the hepatic CYP3A4 and CYP2C9 isoenzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of sildenafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Simvastatin: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Siponimod: (Moderate) Concomitant use of siponimod and pentobarbital is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with pentobarbital is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; pentobarbital is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Sirolimus: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Skeletal Muscle Relaxants: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
Sodium Oxybate: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
Sparsentan: (Major) Avoid concomitant use of sparsentan and barbiturates due to the risk for decreased sparsentan exposure which may reduce its efficacy. Sparsentan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to decrease sparsentan overall exposure by 47%.
Spironolactone: (Moderate) Barbiturates may potentiate orthostatic hypotension when given concomitantly with spironolactone.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when given concomitantly with spironolactone. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and pentobarbital. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Major) Concomitant use of sufentanil with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if barbiturates must be administered. If concurrent use of sufentanil injection is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of sufentanil with barbiturates may decrease sufentanil plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; sufentanil is a CYP3A4 substrate.
Suvorexant: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with a barbiturate is necessary. Suvorexant is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Dosage adjustments of suvorexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of suvorexant with other drugs to treat insomnia is not recommended. The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with other CNS depressants. Patients should be cautioned against driving and other activities requiring complete mental alertness.
Tacrolimus: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Tapentadol: (Major) Concomitant use of tapentadol with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as barbiturates or primidone, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%. Barbiturates also induce CYP1A2, a secondary metabolic pathway of tasimelteon.
Telmisartan; Amlodipine: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Temazepam: (Moderate) Additive CNS and/or respiratory depression may occur with concurrent use.
Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as pentobarbital, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Thalidomide: (Major) The use of barbiturate anxiolytics, sedatives, or hypnotics with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
Theophylline, Aminophylline: (Moderate) The metabolism of aminophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to aminophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by aminophylline. (Moderate) The metabolism of theophylline can be increased by concurrent use with barbiturates. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to theophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by theophylline.
Thiazide diuretics: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as pentobarbital. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. The pre-anesthesia administration of thiothixene may increase the hypotensive effects of barbiturate anesthetics. Due to a lowering of seizure threshold by thiothixene, adequate barbiturate therapy should be maintained, if administered for anticonvulsant purposes, when thiothixene is added.
Thyroid hormones: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Tipranavir: (Moderate) Monitor for decreased efficacy of tipranavir if coadministered with barbiturates. Concurrent use may decrease the plasma concentrations of tipranavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Tipranavir is a CYP3A substrate and barbiturates are CYP3A inducers.
Tivozanib: (Major) Avoid concomitant use of tivozanib with barbiturates due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
Tolcapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Topiramate: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), an interaction with barbiturates via hepatic isoenzyme activity is possible. In patients receiving either phenobarbital or primidone in combination with topiramate, there was a < 10% change in phenobarbital or primidone plasma concentrations; the effects on topiramate plasma concentrations were not evaluated. Barbiturates may cause additive sedation or other CNS depressive effects when used concurrently with topiramate. When topiramate is combined with phentermine for the treatment of obesity, a greater risk of CNS depression exists. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as the barbiturates, may also increase the risk of bleeding; monitor patients appropriately.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with pentobarbital due to the potential for significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate. Barbiturates are known to induce hepatic CYP isoenzymes; most data describing barbiturate drug interactions have been documented with phenobarbital, a strong CYP3A inducer. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
Tramadol: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate.
Tramadol; Acetaminophen: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Trandolapril; Verapamil: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Trazodone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of trazodone and pentobarbital. Concurrent use may result in additive CNS depression.
Tretinoin, ATRA: (Moderate) Barbiturates may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Triazolam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of triazolam. Triazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with barbiturates may potentiate the CNS effects of either trimethobenzamide or the barbiturate.
Triprolidine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with triprolidine.
Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and barbiturates (such as phenobarbital or primidone) are CYP3A4 inducers. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
Valbenazine: (Major) Co-administration of strong CYP3A4 inducers, such as barbiturates, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Valerian, Valeriana officinalis: (Major) Patients who are taking barbiturates should generally avoid concomitant administration of valerian. Any substances that act on the CNS, including sedatives and hypnotics, may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. These interactions are probably pharmacodynamic in nature. There is a possibility of interaction with valerian at normal prescription dosages of sedatives and hypnotics.
Valproic Acid, Divalproex Sodium: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like pentobarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Verapamil: (Major) Barbiturates have been shown to enhance the hepatic clearance of verapamil. The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate. Patients receiving verapamil should be monitored for loss of therapeutic effect if barbiturates are added.
Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with barbiturates.
Vincristine Liposomal: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
Vincristine: (Major) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including barbiturates. Patients receiving these drugs concurrently should be monitored for possible loss of vincristine efficacy.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
Voriconazole: (Major) Coadministration may result in decreased exposure to voriconazole and increased exposure to pentobarbital. Per the manufacturer, voriconazole is contraindicated for use with long-acting barbiturates; caution is advised when coadministering with short-acting barbiturates, such as pentobarbital. Barbiturates are CYP3A4 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates.
Vortioxetine: (Major) Patients should be monitored for a decreased response to vortioxetine when barbiturates are co-administered. Vortioxetine is extensively metabolized by CYP isoenzymes, primarily CYP2D6 and by CYP3A4 and other isoenzymes to a lesser extent. The manufacturer recommends that the practitioner consider an increase in dose of vortioxetine when a strong CYP inducer is co-administered for more than 14 days. In such cases, the maximum recommended dose of vortioxetine should not exceed three times the original dose. When the inducer is discontinued, the dose of vortioxetine should be reduced to the original level within 14 days.
Voxelotor: (Major) Avoid coadministration of voxelotor and barbiturates as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; barbiturates are strong CYP3A inducers. Coadministration of voxelotor with a strong CYP3A inducer is predicted to decrease voxelotor exposure by up to 40%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Zaleplon: (Major) Coadministration of zaleplon and barbiturates may result in additive CNS depression. Caution should be exercised during concomitant use of anxiolytics, sedatives, and hypnotics and any barbiturate. In addition, zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inducers, such as barbiturates, may increase the clearance of zaleplon. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
Zanubrutinib: (Major) Avoid concurrent use of zanubrutinib and barbiturates due to the risk of decreased zanubrutinib exposure which may reduce its efficacy. Zanubrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer decreased zanubrutinib exposure by 93%.
Ziconotide: (Moderate) CNS depressant medications, such as barbiturates, may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Dosage adjustments may be necessary if ziconotide is used with a barbiturate.
Ziprasidone: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
Zolpidem: (Major) Concurrent use of zolpidem with barbiturates should be avoided if possible due to additive CNS depression. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than zolpidem alone. Concurrent use of zolpidem with other sedative-hypnotics at bedtime or in the middle of the night is not recommended. Dosage reduction may be required for co-use in some patients. For example, a dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended when used with another CNS depressant. Barbiturates are CYP3A4 enzyme inducers and may cause decreased plasma concentrations of zolpidem; in some patients efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration of a potent CYP3A4 inducer.
Zonisamide: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.

How Supplied

Nembutal/Pentobarbital Sodium Intramuscular Inj Sol: 1mL, 50mg
Nembutal/Pentobarbital Sodium Intravenous Inj Sol: 1mL, 50mg

Maximum Dosage
Adults

Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations.

Geriatric

Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations.

Adolescents

Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For procedural sedation, doses above 6 mg/kg/dose IM/IV/PO (Max: 100 mg/dose and 200 mg cumulative) are not usually necessary.

Children

Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For procedural sedation, doses above 6 mg/kg/dose IM/IV/PO (Max: 100 mg/dose and 200 mg cumulative) are not usually necessary.

Infants

Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For procedural sedation, doses above 6 mg/kg/dose IM/IV and 8 mg/kg/dose PO (Max: 100 mg/dose and 200 mg cumulative) are not usually necessary.

Neonates

Specific maximum dosage information not available; individualize dosage based on clinical parameters and serum pentobarbital concentrations. For procedural sedation, doses above 6 mg/kg/dose IV are not usually necessary.

Mechanism Of Action

Mechanism of Action: Pentobarbital suppresses the spread of seizure activity in the cortex, thalamus, and limbic systems. The exact mechanism by which pentobarbital exerts its effects is not known. In general, the drug has a nonselective depressant effect throughout the CNS due to a decrease in both pre- and postsynaptic excitability. The sedative-hypnotic effects of pentobarbital are related to its inhibition of ascending conduction in the reticular formation, which controls CNS arousal. This inhibition depresses the sensory cortex; decreases motor activity; alters cerebral function; and produces drowsiness, sedation, and hypnosis. In the motor cortex, pentobarbital increases the threshold for electrical stimulation, which contributes to its anticonvulsant properties. Unlike most other barbiturates, high doses of pentobarbital protects the brain from ischemia and intracranial pressure, possibly by exerting an anesthetic action in the brain. It has been suggested that the sedative-hypnotic and anticonvulsant effects of barbiturates may be due to their ability to mimic the inhibitory synaptic action of gamma-aminobutyric acid.

Pharmacokinetics

Pentobarbital is administered orally, parenterally, and rectally. Pentobarbital is a weak acid that is rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys. The drug distributes throughout the body, with about 35% to 45% of a dose bound to plasma proteins in the blood. In adults, the volume of distribution of the central compartment (Vdc) is approximately 0.45 L/kg and the volume of distribution (Vd) at steady state is approximately 1 L/kg. Due to the small Vdc, initial concentrations following IV bolus administration or rapid infusions are relatively high, which can result in significant hypotension or cardiac arrhythmias. Metabolism takes place in the liver via oxidation and glucuronidation. Microsomal enzymes involved in the metabolism of other drugs may be induced by pentobarbital, but there is no clear evidence that it accelerates its own metabolism. Plasma clearance appears to be variable among subjects and may increase during prolonged therapy; mean clearance during high dose continuous infusion was 0.72 mL/kg/minute, as demonstrated in adult brain injury patients. Mean plasma half-life is approximately 22 hours in adults; range of 15 to 50 hours have been reported. Half-life appears to be dose-dependent. Excretion occurs through the urine, mainly as glucuronide conjugates of metabolites, with negligible amounts excreted as unchanged drug.

Oral Route

Oral pentobarbital is approximately 95% bioavailable. The onset of action of pentobarbital is 15 to 60 minutes after oral administration. Duration of sedative effect is 30 minutes to 4 hours. Food may reduce the rate but not the extent of pentobarbital absorbed, delaying the onset of action.

Intravenous Route

The onset of action of pentobarbital is almost immediate, within 1 to 5 minutes after intravenous administration. Duration of sedative effect is 15 to 45 minutes.

Intramuscular Route

The onset of action of pentobarbital is 10 to 15 minutes after intramuscular administration. Duration of sedative effect is 1 to 2 hours.

Other Route(s)

Rectal Route
The onset of action of pentobarbital is 15 to 60 minutes after rectal administration. Duration of sedative effect is 1 to 4 hours.

Pregnancy And Lactation
Pregnancy

Pentobarbital is classified as FDA pregnancy category D. Pentobarbital should be used during pregnancy only if the benefits clearly outweigh the risks. Chronic use of barbiturates during pregnancy may cause major fetal malformations, hemorrhage at birth, and addiction. Females should be warned of the potential adverse effects on the fetus should pregnancy occur. A retrospective study revealed that in utero exposure to barbiturates was associated with intelligence deficits. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver, and brain. Fetal blood concentrations approach maternal blood concentrations following parenteral administration. Repeated use of pentobarbital during the third trimester can also cause physical dependence in the neonate. If pentobarbital is used during labor and obstetric delivery, neonates should be carefully observed for signs of respiratory depression, particularly if the infant is premature, and resuscitation equipment should be available. Anesthetic doses of pentobarbital may inhibit uterine activity, reducing the force and frequency of uterine contractions. Physicians are advised to recommend that pregnant patients receiving pentobarbital enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.