Mysoline

Anticonvulsants, Barbiturates

A MedGuide that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications will be available.

Oral Administration

Administer with meals to minimize indigestion or GI irritation.

Oral Solid Formulations

NOTE: In June 2008, the FDA approved the use of an alternate manufacturer of the Mysoline brand 250 mg tablet. The new tablet differs in appearance from the previously approved tablet; therefore, Valeant Pharmaceuticals will be distributing a notification letter to healthcare professionals as well as patient advocacy groups and other relevant organizations.
For patients with difficulty swallowing, the tablets may be crushed and mixed with foods or fluids prior to administration.

Severe

suicidal ideation / Delayed / 0-1.0
coma / Early / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
serum sickness / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
porphyria / Delayed / Incidence not known
megaloblastic anemia / Delayed / Incidence not known
seizures / Delayed / Incidence not known
neonatal abstinence syndrome / Early / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

depression / Delayed / Incidence not known
confusion / Early / Incidence not known
nystagmus / Delayed / Incidence not known
tolerance / Delayed / Incidence not known
impaired cognition / Early / Incidence not known
ataxia / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
respiratory depression / Rapid / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
bullous rash / Early / Incidence not known
jaundice / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known
osteomalacia / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
hypoprothrombinemia / Delayed / Incidence not known
physiological dependence / Delayed / Incidence not known
psychological dependence / Delayed / Incidence not known
withdrawal / Early / Incidence not known
folate deficiency / Delayed / Incidence not known
vitamin D deficiency / Delayed / Incidence not known

Mild

drowsiness / Early / Incidence not known
libido decrease / Delayed / Incidence not known
vertigo / Early / Incidence not known
irritability / Delayed / Incidence not known
insomnia / Early / Incidence not known
lethargy / Early / Incidence not known
dizziness / Early / Incidence not known
agitation / Early / Incidence not known
emotional lability / Early / Incidence not known
nightmares / Early / Incidence not known
nausea / Early / Incidence not known
vomiting / Early / Incidence not known
anorexia / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
photosensitivity / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
asthenia / Delayed / Incidence not known
purpura / Delayed / Incidence not known
ecchymosis / Delayed / Incidence not known
weakness / Early / Incidence not known
fatigue / Early / Incidence not known
diplopia / Early / Incidence not known
mydriasis / Early / Incidence not known
miosis / Early / Incidence not known
ptosis / Delayed / Incidence not known

Mysoline

Rx

Oral anticonvulsant related to barbiturates; metabolized to phenobarbital and another active metabolite; effective in all seizure disorders except absence; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

For the treatment of generalized tonic-clonic seizures or complex partial seizures (e.g., psychomotor seizures). For the treatment of generalized tonic-clonic seizures or complex partial seizures in persons who have not received prior treatment. Oral dosage Adults

100 to 125 mg PO once daily at bedtime for 3 days, then 100 to 125 mg PO twice daily for 3 days, then 100 to 125 mg PO 3 times daily for 3 days, and then 250 mg PO 3 times daily. Usual dose: 250 mg PO 3 to 4 times daily. Max: 2,000 mg/day.[28597]

Children and Adolescents 8 to 17 years

100 to 125 mg PO once daily at bedtime for 3 days, then 100 to 125 mg PO twice daily for 3 days, then 100 to 125 mg PO 3 times daily for 3 days, and then 250 mg PO 3 times daily. Usual dose: 250 mg PO 3 to 4 times daily. Max: 2,000 mg/day.[28597]

Infants and Children 1 month to 7 years

50 mg PO once daily at bedtime for 3 days, then 50 mg PO twice daily for 3 days, then 100 mg PO twice daily for 3 days, then 125 to 250 mg PO 3 times daily. Usual dose: 125 to 250 mg PO 3 times daily or 10 to 25 mg/kg/day in divided doses.[28597]

Neonates†

Not generally recommended; neonates cannot convert primidone to phenobarbital.[52123] 12 to 20 mg/kg/day PO in 2 to 4 divided doses has been used.[63503] [63508]

For the treatment of generalized tonic-clonic seizures or complex partial seizures in persons already receiving other anticonvulsants. Oral dosage Adults

100 to 125 mg PO once daily at bedtime, initially. Gradually increase the dose as the other drug is gradually decreased. Usual dose: 250 mg PO 3 to 4 times daily. Max: 2,000 mg/day. If primidone monotherapy is the goal, complete transition from concomitant therapy over 2 weeks or longer.[28597]

Children and Adolescents 8 to 17 years

100 to 125 mg PO once daily at bedtime, initially. Gradually increase the dose as the other drug is gradually decreased. Usual dose: 250 mg PO 3 to 4 times daily. Max: 2,000 mg/day. If primidone monotherapy is the goal, complete transition from concomitant therapy over 2 weeks or longer.[28597]

For the treatment of essential tremor†. Oral dosage Adults

Clinical practice guidelines of the American Academy of Neurology consider primidone effective for the treatment of essential tremor (Level A, established). Give 25 to 62.5 mg/day PO initially, usually at night to increase tolerability. Increase as tolerated and needed by titrating the daily dose by 25 mg every 3 days. Titration to optimal dosing may take several weeks to limit intolerance. In clinical trials, the effective target dose range was 250 to 750 mg/day PO, given in divided doses. Mean effective dose average: 481.7 mg/day PO. Maximum suggested dose: 750 mg/day PO (i.e., 250 mg PO 3 times daily). Early side effects (e.g., nausea, dizziness, ataxia, confusion, sedation) attenuate after a few months of treatment; mild sedation may remain at higher daily doses.

†Indicates off-label use

Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

CrCl 50 mL/minute or more: No dose adjustment is necessary.
CrCl 10 to 50 mL/minute: Consider increasing the dosage interval to 12 to 24 hours. Adjust the dose as needed based on clinical response, serum concentrations, and tolerability.
CrCl less than 10 mL/minute: Consider increasing the dosage interval to 24 hours. Adjust the dose as needed based on clinical response, serum concentrations, and tolerability.
 
Intermittent hemodialysis
A supplemental dose after hemodialysis may be required; more than 30% of the administered primidone dose is expected to be removed during a 4-hour hemodialysis session in the average uremic person.

Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with primidone, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Primidone is metabolized to phenobarbital, which is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Abemaciclib: (Major) Avoid coadministration of primidone with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and primidone, which is metabolized to phenobarbital, is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.
Abiraterone: (Major) Avoid coadministration of abiraterone with primidone if possible due to decreased plasma concentrations of abiraterone. If concomitant use is unavoidable, increase the dosing frequency of abiraterone to twice daily. Reduce the dose back to the previous dose and frequency if primidone is discontinued. Abiraterone is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and primidone. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
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%.
Afatinib: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with primidone is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of primidone. Afatinib is a P-glycoprotein (P-gp) substrate and primidone is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
Albuterol; Budesonide: (Moderate) Coadministration may result in decreased exposure to budesonide. Primidone is a CYP3A4 inducer; budesonide is a CYP3A4 substrate. Monitor for decreased response to budesonide during concurrent use.
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.
Alosetron: (Minor) Alosetron is metabolized by CYP1A2 and CYP3A4. Primidone, which is metabolized to phenobarbital, can induce the activity of these enzymes and increase the metabolism of alosetron. Concomitant administration of these drugs has not been formally evaluated.
Alpelisib: (Major) Avoid coadministration of alpelisib with primidone due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer.
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. (Major) Coadministration of primidone and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. Primidone is metabolized in the liver to produce phenobarbital and PEMA. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Amphetamine; Dextroamphetamine Salts: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
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.
Apixaban: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as primidone. Phenobarbital is a strong inducer of both CYP3A4 and P-gp. Because primidone is metabolized to phenobarbital, drug interactions occurring with phenobarbital must be considered when primidone is administered. Concomitant administration of apixaban and primidone results in decreased exposure to apixaban and an increase in the risk of stroke.
Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
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) Avoid the concurrent use of primidone with aprepitant due to substantially decreased exposure of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant. Primidone is a strong CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant 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. Additionally, aprepitant is a CYP2C9 inducer and primidone is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
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.
Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Atazanavir: (Major) Coadministration of primidone and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with primidone unless atazanavir is boosted with ritonavir. Primidone is metabolized to phenobarbital and coadministration may also result in decreased phenobarbital concentrations. If atazanavir and primidone are used together, the patient must be closely monitored for antiviral efficacy and decreased primidone efficacy; clinical monitoring of phenobarbital concentrations with dosage titration if necessary is also warranted.
Atazanavir; Cobicistat: (Contraindicated) Coadministration of primidone with cobicistat-containing regimens is contraindicated. Primidone is converted to phenobarbital, a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration of primidone and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with primidone unless atazanavir is boosted with ritonavir. Primidone is metabolized to phenobarbital and coadministration may also result in decreased phenobarbital concentrations. If atazanavir and primidone are used together, the patient must be closely monitored for antiviral efficacy and decreased primidone efficacy; clinical monitoring of phenobarbital concentrations with dosage titration if necessary is also warranted.
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 primidone due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, 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 primidone 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 primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
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. (Moderate) Coadministration may result in decreased exposure to fluticasone. Primidone is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
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.
Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with primidone. Belumosudil is a CYP3A4 substrate and primidone, which is metabolized to phenobarbital, is a strong CYP3A inducer; concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with another strong CYP3A inducer decreased belumosudil exposure by 72% in healthy subjects.
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.
Berotralstat: (Major) Avoid coadministration of berotralstat with primidone. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and primidone is a P-gp inducer.
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.
Betrixaban: (Major) Avoid the concomitant administration of betrixaban and primidone. Concomitant administration of betrixaban and primidone results in decreased plasma concentrations of betrixaban that may be insufficient to achieve the intended therapeutic effect. Betrixaban is a P-glycoprotein (P-gp) substrate and primidone is a P-gp inducer.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Consider an alternative anticonvulsant during treatment with bictegravir. Concomitant use of bictegravir and primidone may result in decreased bictegravir plasma concentrations, which may result in the loss of therapeutic efficacy and development of resistance. Bictegravir is a substrate of CYP3A4; primidone is a strong inducer of CYP3A4.
Biotin: (Moderate) Primidone use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like primidone, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.
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.
Brentuximab vedotin: (Moderate) Concomitant administration of brentuximab vedotin and primidone may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and primidone is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
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 primidone due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; primidone is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
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.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and primidone are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; phenobarbital, the active metabolite of primidone, is a strong inducer of CYP3A4.
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.
Budesonide: (Moderate) Coadministration may result in decreased exposure to budesonide. Primidone is a CYP3A4 inducer; budesonide is a CYP3A4 substrate. Monitor for decreased response to budesonide during concurrent use.
Budesonide; Formoterol: (Moderate) Coadministration may result in decreased exposure to budesonide. Primidone is a CYP3A4 inducer; budesonide is a CYP3A4 substrate. Monitor for decreased response to budesonide during concurrent use.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Coadministration may result in decreased exposure to budesonide. Primidone is a CYP3A4 inducer; budesonide is a CYP3A4 substrate. Monitor for decreased response to budesonide during concurrent use.
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: (Moderate) Concomitant use of systemic lidocaine and primidone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital, the active metabolite of primidone, induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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 co

deine 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: (Contraindicated) Coadministration of cabotegravir and primidone is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenobarbital, the active metabolite of primidone, is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%.
Cabotegravir; Rilpivirine: (Contraindicated) Coadministration of cabotegravir and primidone is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenobarbital, the active metabolite of primidone, is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (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.
Cabozantinib: (Major) Avoid coadministration of cabozantinib with primidone due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with primidone 2 to 3 days after discontinuation of primidone. Cabozantinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
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) Consider a dose increase of cannabidiol if coadministered with primidone. Consider a dosage reduction of primidone as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Additive sedation and somnolence may occur. Coadministration may decrease cannabidiol plasma concentrations resulting in a decrease in efficacy and increase primidone exposure resulting in adverse effects. Cannabidiol is metabolized by CYP3A4; in vitro data predicts inhibition of CYP2C9 by cannabidiol. Primidone is a strong inducer of CYP3A4 and is metabolized by CYP2C9.
Capmatinib: (Major) Avoid coadministration of capmatinib and primidone due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
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: (Major) Consider a dose reduction of primidone when coadministered with cenobamate due to the potential for increased phenobarbital exposure and adverse effects. Multiple doses of cenobamate increased phenobarbital (active metabolite of primidone) exposure by 37%. Also, concomitant use of cenobamate with primidone may increase the risk of neurological adverse reactions, including sedation and somnolence.
Ceritinib: (Major) Avoid concomitant use of ceritinib with primidone as ceritinib exposure may be decreased, which may reduce its efficacy. Ceritinib is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer decreased ceritinib exposure by 70%.
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 cytochrome 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.
Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Chloroquine: (Moderate) Monitor patients more frequently for signs of reduced chloroquine effects if administered with primidone. Coadministration may decrease the exposure of chloroquine. Chloroquine may be a CYP3A4 substrate in vitro, and primidone is a strong CYP3A4 inducer.
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.
Cisapride: (Moderate) Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. Inducers of CYP3A4, such as primidone, may increase the clearance of cisapride.
Clarithromycin: (Major) Coadministration of primidone and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. Primidone is metabolized in the liver to produce phenobarbital and PEMA. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
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.
Clindamycin: (Moderate) Monitor for loss of clindamycin efficacy with coadministration of primidone as concurrent use may decrease clindamycin exposure. Clindamycin is a CYP3A4 substrate; primidone is a strong inducer of CYP3A4.
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: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as primidone, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Primidone may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of primidone in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring is warranted when primidone is used with clozapine. Additive sedation may be noted with concurrent use of clozapine and primidone; enzyme induction by primidone may take several days to become clinically apparent.
Cobicistat: (Contraindicated) Coadministration of primidone with cobicistat-containing regimens is contraindicated. Primidone is converted to phenobarbital, a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with primidone due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; primidone is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong 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 bioavailability of primidone if coadministered. To minimize potential for interactions, consider administering oral anticonvulsants such as primidone 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.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and primidone; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; primidone is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
Crizotinib: (Major) Avoid coadministration of crizotinib with primidone due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
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.
Dabigatran: (Major) In general, avoid coadministration of dabigatran with primidone because of P-gp induction by phenobarbital, an active metabolite of primidone. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
Daclatasvir: (Contraindicated) Concomitant use of daclatasvir with primidone is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Primidone is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
Dapsone: (Moderate) Monitor for an increase in hemolysis if coadministration of dapsone with primidone is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and primidone is a strong CYP3A4 inducer. Strong CYP3A4 inducers may increase the formation of dapsone hydroxylamine, a metabolite associated with hemolysis. Coadministration with another strong CYP3A4 inducer decreased dapsone levels by 7-fold to 10-fold; in leprosy, this reduction has not required a change in dosage. Also, coadministration of dapsone with primidone may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Daridorexant: (Major) Avoid concomitant use of daridorexant and primidone. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and primidone is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
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.
Darolutamide: (Major) Avoid coadministration of darolutamide with primidone due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Primidone is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
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: (Contraindicated) Coadministration of primidone with cobicistat-containing regimens is contraindicated. Primidone is converted to phenobarbital, a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (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: (Contraindicated) Coadministration of primidone with cobicistat-containing regimens is contraindicated. Primidone is converted to phenobarbital, a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (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.
Dasatinib: (Major) Avoid coadministration of dasatinib and primidone due to the potential for decreased dasatinib exposure and reduced efficacy. Consider an alternative to primidone with less potential for enzyme induction. If coadministration cannot be avoided, consider an increased dose of dasatinib and monitor for toxicity. Dasatinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Concurrent use of another strong CYP3A4 inducer decreased the mean Cmax and AUC of dasatinib by 81% and 82%, respectively.
Deflazacort: (Major) Avoid concomitant use of deflazacort and primidone. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; phenobarbital, the active metabolite of primidone, is a strong inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
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.
Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with primidone due to the risk of decreased dexlansoprazole plasma concentrations which may decrease efficacy. Dexlansoprazole is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer.
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.
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.
Docetaxel: (Major) Avoid coadministration of docetaxel with primidone due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Concomitant use with other strong CYP3A4 inducers increased docetaxel metabolism by 2.6-fold to 32-fold.
Dolutegravir: (Major) Avoid concurrent use of dolutegravir with primidone, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Primidone is metabolized to phenobarbital, which is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with primidone, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Primidone is metabolized to phenobarbital, which is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Rilpivirine: (Major) Avoid concurrent use of dolutegravir with primidone, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Primidone is metabolized to phenobarbital, which is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. (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.
Doravirine: (Contraindicated) Concurrent administration of doravirine and primidone is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent administration of doravirine and primidone is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer.
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) Phenobarbital is a potent inducer of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Primidone and mephobarbital, both metabolized to phenobartital, are also potent CYP3A4 inducers. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenobarbital, primidone, and mephobarbital if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) Phenobarbital is a potent inducer of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Primidone and mephobarbital, both metabolized to phenobartital, are also potent CYP3A4 inducers. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenobarbital, primidone, and mephobarbital 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.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) High doses of folate may cause decreased serum concentrations of primidone resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with primidone. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
Duvelisib: (Major) Avoid coadministration of duvelisib with primidone. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; primidone is a strong CYP3A inducer. In drug interaction studies, coadministration of duvelisib with another strong CYP3A inducer for 7 days decreased duvelisib Cmax and AUC by 66% and 82%, respectively.
Edoxaban: (Moderate) Coadministration of edoxaban and primidone may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and primidone is a P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of primidone; monitor for decreased efficacy of edoxaban.
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%.
Elagolix: (Moderate) Concomitant use of elagolix and primidone may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; phenobarbital, the active metabolite of primidone, is a strong inducer of CYP3A.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Concomitant use of elagolix and primidone may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; phenobarbital, the active metabolite of primidone, is a strong inducer of CYP3A.
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.
Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with primidone is not recommended as concurrent use may decrease exposure of elexacaftor; tezacaftor; ivacaftor. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substr ates (ivacaftor is a sensitive CYP3A4 substrate). Primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer significantly decreased ivacaftor exposure by 89%; elexacaftor and tezacaftor exposures are expected to also decrease during coadministration of strong CYP3A4 inducers. (Major) Coadministration of ivacaftor with primidone is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, primidone is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to primidone leading to increased or prolonged therapeutic effects and adverse events. (Major) Do not administer tezacaftor; ivacaftor and primidone together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of primidone, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
Eliglustat: (Major) Coadministration of eliglustat and primidone significantly decreases eliglustat exposure and is not recommended in extensive, intermediate, or poor metabolizers of CYP2D6. Primidone is a strong CYP3A inducer, and eliglustat is a CYP3A substrate.
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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of primidone with cobicistat-containing regimens is contraindicated. Primidone is converted to phenobarbital, a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Primodine is converted to phenobarbital. Phenobarbital induces the CYP3A4 metabolism of elvitegravir. Consider an alternative anticonvulsant when using elvitegravir. The combination product cobicistat; elvitegravir; emtricitabine; tenofovir is contraindicated in combination with primidone as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of primidone with cobicistat-containing regimens is contraindicated. Primidone is converted to phenobarbital, a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Primodine is converted to phenobarbital. Phenobarbital induces the CYP3A4 metabolism of elvitegravir. Consider an alternative anticonvulsant when using elvitegravir. The combination product cobicistat; elvitegravir; emtricitabine; tenofovir is contraindicated in combination with primidone as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
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.
Encorafenib: (Major) Avoid coadministration of encorafenib and primidone due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
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.
Entrectinib: (Major) Avoid coadministration of entrectinib with primidone due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Enzalutamide: (Major) Avoid coadministration of primidone with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when primidone is discontinued. Enzalutamide is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Eravacycline: (Major) Increase the dose of eravacycline to 1.5 mg/kg IV every 12 hours when coadministered with a strong CYP3A4 inducer, such as primidone. Concomitant use of strong CYP3A4 inducers decreases the exposure of eravacycline, which may reduce its efficacy. When eravacycline was administered with a strong CYP3A4/3A5 inducer, the eravacycline AUC was decreased by 35% and its clearance was increased by 54%.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and primidone due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A4 substrate and primidone is a strong 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 coadministration of erlotinib with primidone if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
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.
Etravirine: (Major) Etravirine should not be coadministered with phenobarbital due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant mutations of HIV; substantial reductions in etravirine concentrations may occur. Primidone is metabolized to phenobarbital, therefore a similar interaction would be expected with primidone.
Everolimus: (Major) Avoid coadministration of everolimus with primidone due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of primidone and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
Exemestane: (Major) If coadministration of exemestane with primidone is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
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.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as primidone, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of primidone during coadministration with fenofibric acid.
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.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil with primidone in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of primidone due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Finerenone: (Major) Avoid concurrent use of finerenone and primidone due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased overall exposure to finerenone by 90%.
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.
Fluticasone: (Moderate) Coadministration may result in decreased exposure to fluticasone. Primidone is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Fluticasone; Salmeterol: (Moderate) Coadministration may result in decreased exposure to fluticasone. Primidone is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Coadministration may result in decreased exposure to fluticasone. Primidone is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Fluticasone; Vilanterol: (Moderate) Coadministration may result in decreased exposure to fluticasone. Primidone is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Folic Acid, Vitamin B9: (Minor) Concurrent use of folic acid, vitamin B9 and phenobarbital and primidone may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenobarbital and primidone. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenobarbital concentrations upon folic acid initiation, dose titration, and discontinuation. Adjust the anticonvulsant dosage as appropriate.
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.
Fostamatinib: (Major) Avoid the concomitant use of fostamatinib with primidone. Concomitant use of fostamatinib with a strong CYP3A4 inducer decreases exposure to the major active metabolite, R406. R406 is extensively metabolized by CYP3A4; primidone is a strong CYP3A4 inducer. Concomitant use of fostamatinib with another strong CYP3A4 inducer decreased R406 AUC by 75% and Cmax by 59%.
Fostemsavir: (Contraindicated) Concomitant use of fostemsavir and primidone is contraindicated. Use of these drugs together may significantly decrease the plasma concentrations of temsavir, the active moiety of fostemsavir, thereby increasing the risk for HIV treatment failure or development of viral resistance. Temsavir is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer.
Futibatinib: (Major) Avoid concurrent use of futibatinib and primidone. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; primidone is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
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%.
Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with primidone is necessary. If primidone is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
General anesthetics: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
Gilteritinib: (Major) Avoid coadministration of gilteritinib and primidone due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; primidone is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
Glasdegib: (Major) Avoid coadministration of glasdegib and primidone due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and primidone as decreased plasma concentrations of glecaprevir may occur resulting in the potential loss of efficacy of glecaprevir. Glecaprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp); phenobarbital, the active metabolite of primidone, is a CYP3A4/P-gp inducer. (Moderate) Caution is advised with coadministration of pibrentasvir and primidone due to the potential loss of efficacy of pibrentasvir. Coadministration may decrease plasma concentrations of pibrentasvir. Pibrentasvir is a substrate of P-glycoprotein (P-gp); phenobarbital, the active metabolite of primidone, is a P-gp inducer.
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.
Granisetron: (Minor) In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron. The clinical significance of this change is not known. Primidone is the prodrug of phenobarbital and therefore a similar interaction is expected.
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 primidone coadministration. Guanfacine plasma concentrations can be reduced by primidone, 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 primidone. 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.
Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and primidone; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
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.
Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as primidone, as idelalisib exposure may be significantly reduced and efficacy compromised.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with primidone is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; primidone is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
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.
Indocyanine Green: (Moderate) Primidone may increase the clearance indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
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.
Irinotecan Liposomal: (Major) Avoid administration of primidone during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Primidone is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Irinotecan: (Major) Avoid administration of primidone during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Primidone is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with primidone is contraindicated due to the potential for decreased isavuconazole serum concentrations and treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; primidone is a strong inducer of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inducers is contraindicated. There was a 97% decrease in isavuconazole serum concentrations when coadministered with rifampin, another strong CYP3A4 inducer.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) It may be necessary to adjust the dosage of primidone if given concurrently with rifampin. Primidone is metabolized to phenobarbital. Rifampin may induce the metabolism of phenobarbital; coadministration may result in decreased phenobarbital plasma concentrations. Phenobarbital is a CYP29 and CYP2C19 substrate, and rifampin is an inducer of these enzymes.
Isoniazid, INH; Rifampin: (Moderate) It may be necessary to adjust the dosage of primidone if given concurrently with rifampin. Primidone is metabolized to phenobarbital. Rifampin may induce the metabolism of phenobarbital; coadministration may result in decreased phenobarbital plasma concentrations. Phenobarbital is a CYP29 and CYP2C19 substrate, and rifampin is an inducer of these enzymes.
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.
Istradefylline: (Major) Avoid coadministration of istradefylline with primidone as istradefylline exposure and efficacy may be reduced. Primidone is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
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.
Ivacaftor: (Major) Coadministration of ivacaftor with primidone is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, primidone is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to primidone leading to increased or prolonged therapeutic effects and adverse events.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with primidone due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
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%.
Ixazomib: (Major) Avoid the concomitant use of ixazomib and primidone; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
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.
Labetalol: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver, such as labetaolol. Clinicians should monitor patients for loss of beta-blockade.
Lamotrigine: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant primidone use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and primidone induces glucuronidation. During concurrent use of lamotrigine with primidone, lamotrigine steady-state concentration decreased by approximately 40%.
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: (Major) Coadministration of primidone and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. Primidone is metabolized in the liver to produce phenobarbital and PEMA. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. (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.
Lapatinib: (Major) Avoid coadministration of lapatinib with primidone due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If primidone is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with primidone due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If primidone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of primidone. Larotrectinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and barbiturates. Concurrent use may result in additive CNS depression.
Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein, such as primidone. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Lefamulin: (Major) Avoid coadministration of lefamulin with primidone unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; primidone is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and primidone 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; primidone is a strong 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.
Letermovir: (Major) Concurrent administration of letermovir and primidone is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). Primidone induces P-gp.
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.
Levomefolate: (Moderate) High doses of folate may cause decreased serum concentrations of primidone resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with primidone. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
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.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and primidone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital, the active metabolite of primidone, induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and primidone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital, the active metabolite of primidone, induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Concomitant use of systemic lidocaine and primidone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenobarbital, the active metabolite of primidone, induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Linezolid: (Minor) Primidone is metabolized to phenobarbital, which is a strong inducer of the CYP450 enzyme system. The AUC and Cmax of linezolid were decreased when coadministered with another strong CYP450 inducer, rifampin. It is unknown if primidone could cause decreases in linezolid exposure if these drugs are coadministered.
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 conc urrently 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.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and primidone is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
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: (Contraindicated) Coadministration of lorlatinib with primidone is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue primidone for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
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.
Lumacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with primidone is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, primidone is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to primidone leading to increased or prolonged therapeutic effects and adverse events.
Lumacaftor; Ivacaftor: (Major) Concomitant use of primidone and lumacaftor; ivacaftor is not recommended. Primidone may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Ivacaftor is a substrate of CYP3A, and primidone is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor. In vitro studies suggest lumacaftor; ivacaftor has the potential to induce CYP2C9 and CYP2C19; inhibition CYP2C9 has also been observed. Because primidone is a substrate of these enzymes, altered primidone exposure may occur.
Lumateperone: (Major) Avoid coadministration of lumateperone and primidone as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of lumateperone with a strong CYP3A4 inducer decreased lumateperone overall exposure by greater than 30-fold.
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 primidone due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and primidone is a strong CYP3A inducer.
Macimorelin: (Major) Discontinue primidone and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. Drug interaction studies involving macimorelin have not been conducted; however, macimorelin is primarily metabolized by CYP3A4 and primidone is a CYP3A4 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.
Maraviroc: (Major) Coadministration of maraviroc, a CYP3A/P-glycoprotein (P-gp) substrate, and primidone, a strong CYP3A inducer and P-gp inducer, without a concomitant strong CYP3A inhibitor may decrease maraviroc concentrations, therefore, the adult maraviroc dose should be increased to 600 mg PO twice daily when coadministered with primidone without a concomitant strong CYP3A inhibitor. Coadministration of maraviroc and primidone is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with a strong CYP3A inducer, without a strong CYP3A inhibitor, is not recommended. If the patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of the inducer; overall, increased maraviroc concentrations are expected.
Maribavir: (Major) Increase maribavir dose to 1,200 mg PO twice daily when coadministered with primidone. Coadministration may decrease maribavir exposure resulting in reduced virologic response. Maribavir is a CYP3A substrate and primidone is a strong CYP3A inducer.
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.
Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Methylphenidate Derivatives: (Moderate) Psychostimulants, such as methylphenidate derivatives, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as primidone. Some human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of primidone, which is metabolized to phenobarbital. More frequent monitoring of drug concentrations may be required when initiating or discontinuing methylphenidate. The mechanism of the potential effect on primidone concentrations is not clear; methylphenidate is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body, and appears to have no known inhibitory effect on hepatic enzymes.
Methylprednisolone: (Moderate) Coadministration may result in decreased exposure to methylprednisolone. Primidone is a CYP3A4 inducer; methylprednisolone is a CYP3A4 substrate. Monitor for decreased response to methylprednisolone during concurrent use.
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: (Moderate) Barbiturates can enhance the hepatic metabolism of beta blockers that are significantly metabolized by the liver, such as metoprolol. Clinicians should monitor patients for loss of beta blockade.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates can enhance the hepatic metabolism of beta blockers that are significantly metabolized by the liver, such as metoprolol. Clinicians should monitor patients for loss of beta blockade. (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.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and primidone as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Mifepristone: (Major) Avoid the use of mifepristone and potent CYP3A inducers such as primidone. It is not known if lowered mifepristone serum levels would lead to reduced response or therapeutic failure. If use together is medically necessary, monitor the patient closely to ensure the proper therapeutic response is obtained.
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 barbiturates like primidone and cause additive CNS depression. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient taking primidone for epilepsy is required. Barbiturates should generally be given at a reduced dose with an MAOI.
Montelukast: (Minor) Primidione, which is metabolized to phenobarbital, may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Phenobarbital is a strong CYP inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
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.
Naldemedine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as primidone, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
Naloxegol: (Major) Coadministration of naloxegol with primidone is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; phenobarbital, the active metabolite of primidone, is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with primidone is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and primidone is a strong 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.
Nefazodone: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with primidone is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
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 primidone with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as primidone. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant.
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%.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and primidone; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and primidone is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
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%.
Niraparib; Abiraterone: (Major) Avoid coadministration of abiraterone with primidone if possible due to decreased plasma concentrations of abiraterone. If concomitant use is unavoidable, increase the dosing frequency of abiraterone to twice daily. Reduce the dose back to the previous dose and frequency if primidone is discontinued. Abiraterone is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
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 primidone due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and primidone is a strong CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with another strong CYP3A inducer decreased the olaparib Cmax by 71% and the AUC by 87%.
Oliceridine: (Major) Concomitant use of oliceridine with primidone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of oliceridine with primidone 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. Also monitor for reduced efficacy of oliceridine and signs of opioid withdrawal if coadministration with primidone is necessary; consider increasing the dose of oliceridine as needed. If primidone is discontinued, consider a dose reduction of oliceridine and frequently monitor for signs of respiratory depression and sedation. Oliceridine is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease the plasma concentrations of oliceridine; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
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.
Oritavancin: (Moderate) Primidone is metabolized by CYP2C9 and CYP2C19; oritavancin is a weak inhibitor of both isoenzymes. Coadministration may result in elevated primidone plasma concentrations. If these drugs are administered concurrently, monitor patients for signs of primidone toxicity, such as confusion, excessive drowsiness, falls, unsteadiness, or difficulty walking, or nystagmus.
Osilodrostat: (Major) Monitor cortisol concentration and patient's signs and symptoms during coadministration of osilodrostat and primidone. Concurrent use may decrease osilodrostat exposure and reduce its efficacy; an increase in osilodrostat dose may be necessary. After discontinuation of primidone, monitor cortisol concentration and patient's signs and symptoms; a reduction in osilodrostat dose may be needed. Osilodrostat is a CYP3A4 and CYP2B6 substrate and primidone is a strong CYP3A4 inducer and also induces CYP2B6.
Osimertinib: (Major) Avoid coadministration of primidone with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If primidone is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
Ospemifene: (Moderate) Primidone is metabolized to phenobarbital in the body and is expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. Phenobarbital induces CYP450 enzymes including CYP3A4, CYP2C9, and CYP2C19, the same enzymes that are responsible for the metabolism of ospemifene. In drug interaction studies, the use of another strong combined CYP inducer decreased the systemic exposure of ospemifene by 58%.
Oxazepam: (Moderate) Additive CNS and/or respiratory depression may occur with concurrent use.
Oxcarbazepine: (Moderate) Monitor MHD, the active metabolite of oxcarbazepine, concentrations during oxcarbazepine dosage titration if primidone and oxcarbazepine are used concurrently. A dose adjustment of oxcarbazepine may be required after initiation, dosage modification, or discontinuation of primidone. Additive CNS depression may also occur. Coadministration of oxcarbazepine (600 to 1,800 mg/day) with phenobarbital (100 to 150 mg/day), the active metabolite of primidone, decreased the plasma concentration of MHD by 25% and increased the plasma concentration of phenobarbital by 14%. Strong CYP3A4 inducers and UGT inducers have been shown to decrease plasma concentrations of MHD. Primidone is a strong CYP3A4 inducer, and phenobarbital is a strong CYP3A4 inducer and UGT inducer.
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.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with primidone is contraindicated due to decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased pacritinib exposure by 87%.
Palbociclib: (Major) Avoid coadministration of primidone with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and primidone is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Paliperidone: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as primidone. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp 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 inducer 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. Clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of primidone.
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%.
Panobinostat: (Major) Avoid the concomitant use of panobinostat and primidone; panobinostat levels may be significantly decreased and its efficacy reduced. Primidone is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
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 primidone due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pemigatinib exposure by 85%.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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) Patients should limit activity and not drive or operate machinery until they know how concomitant use of perampanel and CNS depressants, such as primidone, affects them. Coadministration of perampanel with primidone may increase CNS depression. The combination of perampanel with CNS depressants 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.
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.
Pexidartinib: (Major) Avoid coadministration of pexidartinib with primidone as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. Pexidartinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased pexidartinib exposure by 65%.
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.
Pindolol: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver, such as pindolol. Clinicians should monitor patients for loss of beta-blockade.
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%.
Pitolisant: (Major) Monitor for loss of pitolisant efficacy after initiation of primidone. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if primidone is discontinued. Pitolisant is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Polatuzumab Vedotin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of primidone due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; primidone is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
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.
Ponatinib: (Major) Avoid coadministration of ponatinib with primidone due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
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.
Pralsetinib: (Major) Avoid coadministration of primidone with pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is unavoidable, double the current dose of pralsetinib starting on day 7 of coadministration. After primidone has been discontinued for at least 14 days, resume the pralsetinib dose taken prior to initiating primidone. Pralsetinib is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the pralsetinib AUC by 68%.
Pramipexole: (Major) The use of barbiturates in combination with pramipexole may increase the risk of clinically significant sedation via a pharmacodynamic interaction.
Praziquantel: (Contraindicated) The concomitant use of primidone with praziquantel is contraindicated due to decreased exposure and efficacy of praziquantel. If treatment with praziquantel is necessary, treatment with primidone should be discontinued 4 weeks before administration of praziquantel. Treatment with primidone can then be restarted 1 day after completion of praziquantel treatment. Primidone is a strong CYP3A4 inducer and praziquantel is a CYP3A4 substrate. In a crossover study with a 2-week washout period, administration of praziquantel followed by another strong CYP3A inducer resulted in undetectable plasma concentrations of praziquantel in 7 out of 10 subjects. When praziquantel was administered two weeks after discontinuation of the strong inducer, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone.
Prednisolone: (Moderate) Coadministration may result in decreased exposure to prednisolone. Primidone is a CYP3A4 inducer; prednisolone is a CYP3A4 substrate. Monitor for decreased response to prednisolone during concurrent use.
Prednisone: (Moderate) Coadministration may result in decreased exposure to prednisone. Primidone is a CYP3A4 inducer; prednisone is a CYP3A4 substrate. Monitor for decreased response to prednisone during concurrent use.
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.
Pretomanid: (Major) Avoid coadministration of pretomanid with primidone as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pretomanid exposure by 66%.
Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver, such as propranolol. Clinicians should monitor patients for loss of beta-blockade.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver, such as propranolol. Clinicians should monitor patients for loss of beta-blockade. (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.
Raltegravir: (Major) Coadministration of primidone with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital, the active metabolite of primidone, is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
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.
Regorafenib: (Major) Avoid coadministration of regorafenib with primidone due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
Relugolix: (Major) Avoid concurrent use of relugolix and primidone. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If primidone is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and primidone is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concurrent use of relugolix and primidone. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If primidone is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and primidone is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%.
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.
Ribociclib: (Major) Avoid coadministration of primidone with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
Ribociclib; Letrozole: (Major) Avoid coadministration of primidone with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
Rifampin: (Moderate) It may be necessary to adjust the dosage of primidone if given concurrently with rifampin. Primidone is metabolized to phenobarbital. Rifampin may induce the metabolism of phenobarbital; coadministration may result in decreased phenobarbital plasma concentrations. Phenobarbital is a CYP29 and CYP2C19 substrate, and rifampin is an inducer of these enzymes.
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.
Rimegepant: (Major) Avoid coadministration of rimegepant with primidone; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration of rimegepant with another strong CYP3A4 inducer decreased rimegepant exposure by 80%.
Ripretinib: (Major) Avoid coadministration of ripretinib with primidone. Coadministration may decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A4 and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
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.
Rivaroxaban: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein (P-gp) and strong CYP3A4 inducers, such as primidone. Phenobarbital is a strong inducer of both CYP3A4 and P-gp. Because primidone is metabolized to phenobarbital, drug interactions occurring with phenobarbital must be considered when primidone is administered. In a drug interaction study, coadministration of a single dose of rivaroxaban 20 mg with food with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax of rivaroxaban. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
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 increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Rolapitant: (Major) Avoid the use of rolapitant with chronic administration of phenobarbital; this also applies to drugs that are metabolized to phenobarbital, such as mephobarbital and primidone. Rolapitant is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
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.
Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Rucaparib: (Moderate) Monitor for an increase in primidone-related adverse reactions if coadministration with rucaparib is necessary. Primidone is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of primidone.
Rufinamide: (Moderate) A population pharmacokinetic analysis showed a decrease in rufinamide concentrations during concurrent use of primidone.
Ruxolitinib: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with primidone; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
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.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and primidone due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selpercatinib exposure by 87%.
Selumetinib: (Major) Avoid coadministration of selumetinib and primidone due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
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: (Major) Concomitant use of siponimod and primidone is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; primidone is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
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.
Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein, such as primidone. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein, such as primidone. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as primidone. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a P-gp and CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein, such as primidone. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as primidone. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a P-gp and CYP3A4 substrate. (Major) Avoid coadministration of voxilaprevir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as primidone. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Voxilaprevir is a substrate of P-gp and CYP3A4.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and primidone; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and primidone is a CYP3A4 inducer. Primidone is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Sorafenib: (Major) Avoid coadministration of sorafenib with primidone due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
Sotorasib: (Major) Avoid concurrent use of sotorasib and primidone. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
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, such as primidone, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Barbiturates, such as primidone, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
Stiripentol: (Major) Avoid coadministration of stiripentol with primidone. If concurrent use is necessary, increase the dose of stiripentol and monitor for excessive sedation and somnolence. Coadministration may decrease stiripentol plasma concentrations resulting in a decrease in efficacy; the CNS depressant effects of stiripentol may also be increased by primidone. Stiripentol is metabolized by CYP3A4, CYP1A2, and CYP2C19; primidone is a strong inducer of CYP3A4, and an inducer of CYP1A2 and CYP2C19.
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.
Sunitinib: (Major) Avoid coadministration of primidone with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the daily dose of sunitinib to a maximum of 87.5 mg for patients with GIST or RCC, and to a maximum of 62.5 mg for patients with pNET; monitor carefully for toxicity. Sunitinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to sunitinib and its primary active metabolite by 46%.
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.
Tadalafil: (Major) Avoid coadministration of tadalafil with primidone in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of primidone due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Tamoxifen: (Major) Avoid coadministration of primidone with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
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.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with primidone as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer.
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.
Temsirolimus: (Major) Avoid coadministration of temsirolimus with primidone due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If primidone is discontinued, decrease the dose of temsirolimus to the dose used before initiation of primidone. Temsirolimus is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
Teniposide: (Moderate) Monitor for reduced teniposide efficacy if coadministration with primidone is necessary; the concomitant use of teniposide and primidone may increase the clearance of teniposide resulting in reduced teniposide efficacy. Teniposide is a CYP3A4 substrate and primidone is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration of teniposide and enzyme-inducing antiepileptic drugs resulted in teniposide clearance values that were 2- to 3-times higher than values with teniposide alone.
Tenofovir Alafenamide: (Moderate) Close clinical monitoring is advised when administering primidone with tenofovir alafenamide due to the potential for treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Primidone is an inducer of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in decreased tenofovir serum concentrations and impaired virologic response.
Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as primidone, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Tezacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with primidone is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, primidone is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to primidone leading to increased or prolonged therapeutic effects and adverse events. (Major) Do not administer tezacaftor; ivacaftor and primidone together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of primidone, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
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.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and primidone if possible; increased metabolism to the active thiotepa metabolite may result in increased thiotepa toxicity (e.g., infection, bleeding, skin toxicity). Consider an alternative agent with no or minimal potential to induce CYP3A4. If coadministration is necessary, monitor patients for signs and symptoms of thiotepa toxicity. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; primidone is a strong CYP3A4 inducer.
Thiothixene: (Moderate) Barbiturates such as primidone may have additive CNS depressant effects, such as sedation, with thiothixene. Antipsychotics, such as thiothixene, may lower the seizure threshold, resulting in an exacerbation of symptoms in patients with a seizure disorder. 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.
Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as primidone. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with primidone may substantially decrease ticagrelor exposure which may decrease the efficacy of ticagrelor.
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.
Tofacitinib: (Major) Coadministration of tofacitinib and primidone is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate. Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. Primidone is metabolized to phenobarbital, a potent CYP3A4 inducer. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
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.
Tolvaptan: (Major) Avoid concurrent use of tolvaptan and primidone due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
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.
Toremifene: (Major) Avoid coadministration of primidone with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with primidone due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% 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 primidone. Concurrent use may result in additive CNS depression. Additionally, concurrent use may decrease trazodone exposure; adjust dose as needed based on therapeutic response. Trazodone is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
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.
Triamcinolone: (Moderate) Coadministration may result in decreased exposure to triamcinolone. Primidone is a CYP3A4 inducer; triamcinolone is a CYP3A4 substrate. Monitor for decreased response to triamcinolone during concurrent use.
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.
Triclabendazole: (Moderate) Monitor primidone and phenobarbital concentrations if triclabendazole is initiated or discontinued in a patient taking primidone; primidone dose adjustments may be needed. Coadministration of triclabendazole and primidone may result in increased primidone and phenobarbital concentrations; however, this elevation may be transient due to the short treatment duration of triclabendazole. Triclabendazole is an inhibitor of CYP2C19 in vitro and phenobarbital is partially metabolized by CYP2C19.
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.
Tucatinib: (Major) Avoid coadministration of tucatinib and primidone due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and primidone is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Ubrogepant: (Major) Avoid the coadministration of ubrogepant and primidone as concurrent use may decrease ubrogepant exposure and reduce the efficacy. Ubrogepant is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer resulted in an 80% reduction in ubrogepant exposure.
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.
Upadacitinib: (Major) Coadministration of upadacitinib with primidone is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
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 inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Since primidone is metabolized to phenobarbital, similar precautions should be observed if this agent is used concurrently with valproic acid. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased when appropriate.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
Vandetanib: (Major) Avoid coadministration of vandetanib with primidone due to decreased plasma concentrations of vandetanib and increased concentrations of the active metabolite. Vandetanib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased the geometric mean AUC of vandetanib by 40%; the geometric mean AUC and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively.
Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and primidone; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with primidone cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If primidone is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last primidone dose. Vemurafenib is a CYP3A4 substrate; primidone is metabolized to phenobarbital and is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Venetoclax: (Major) Avoid the concomitant use of venetoclax and primidone; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and primidone is a strong CYP3A4 inducer and a P-gp inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
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.
Vilazodone: (Moderate) Consider increasing the dose of vilazodone up to 2-fold over 1 to 2 weeks (maximum, 80 mg per day) based on clinical response if coadministration with primidone is necessary for more than 14 days. After discontinuation of primidone, resume the previous vilazodone dose over 1 to 2 weeks. Vilazodone is primarily metabolized by CYP3A4 and primidone is a strong CYP3A4 inducer. Decreased plasma concentrations of vilazodone are expected if vilazodone is used concomitantly with strong CYP3A4 inducers.
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.
Voclosporin: (Major) Avoid coadministration of voclosporin with primidone. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased voclosporin exposure by 87%.
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. (Major) Coadministration of primidone and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. Primidone is metabolized in the liver to produce phenobarbital and PEMA. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and phenobarbital or primidone. Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Phenobarbital and primidone are strong CYP3A inducers. Other barbiturates also induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
Voriconazole: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as primidone. Primidone is a CYP3A4 inducer and may increase the metabolism and reduce the effective serum concentrations of voriconazole.
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.

ates 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.

Mysoline/Primidone Oral Tab: 50mg, 125mg, 250mg

Adults

2,000 mg/day PO.

Geriatric

2,000 mg/day PO.

Adolescents

2,000 mg/day PO.

Children

8 to 12 years: 2,000 mg/day PO.
1 to 8 years: 25 mg/kg/day or 750 mg/day PO.

Infants

25 mg/kg/day or 750 mg/day PO.

Neonates

Not generally recommended; maintenance doses up to 20 mg/kg/day PO have been used.

Mechanism of Action: The anticonvulsant activities of primidone are attributed to both the parent drug and to the active metabolites. Since primidone is metabolized to phenobarbital, it shares all the actions of this compound (see Phenobarbital mechanism of action). Like phenobarbital, primidone raises the seizure threshold and inhibits spread from a seizure focus. Phenylethylmalonamide (PEMA) is the major metabolite and is a less potent anticonvulsant than phenobarbital, but it may potentiate the effects of phenobarbital. PEMA is more toxic than primidone. Because of its close relationship to phenobarbital, primidone may be a potent inducer of the enzymes involved in the metabolism of other drugs.

Primidone is administered orally. Serum concentrations of 5 to 12 mcg/mL are necessary to control seizures and avoid adverse effects. Distribution into body fluids and tissues is extensive, with about 75% of maternal plasma concentrations appearing in breast milk. Metabolism of primidone occurs slowly in the liver to produce phenobarbital and PEMA. In adults, roughly 15% to 25% of primidone is metabolized into phenobarbital. Importantly, phenobarbital and primidone accelerate the clearance of other drugs metabolized via hepatic microsomal enzymes (e.g., UGT enzymes, CYP2C-family enzymes, CYP3A-family enzymes, and CYP1A2). PEMA and primidone are bound only minimally to plasma proteins; roughly 20% to 45% of phenobarbital is plasma protein-bound. Plasma half-life of primidone is 10 to 12 hours. Plasma half-life of PEMA is 29 to 36 hours, and both it and phenobarbital, which has a half-life of several days, accumulate during long-term therapy. Excretion is primarily renal, roughly 40% to 60% as unchanged drug, with smaller amounts as PEMA and phenobarbital. Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1, before renal excretion of the associated metabolites.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP3A4, CYP1A2, CYP2C19, CYP2E1, UGT, and P-glycoprotein (P-gp)
Primidone is metabolized in the liver to produce phenobarbital and PEMA. Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and CYP2E1. Importantly, primidone and phenobarbital may accelerate the clearance of other drugs metabolized via hepatic microsomal enzymes (e.g., UGT [UDP-glucuronosyltransferase]), CYP2C-family enzymes, CYP3A-family enzymes and, CYP1A2); coadministration may result in significant drug interactions.[22005] [57046] [57080] [28596] Phenobarbital is also a strong inducer of the P-glycoprotein (P-gp) drug transporter.[34452] [57104] [57105]

Oral Route

Oral absorption of primidone is rapid, although there may be individual variation. About 60% to 80% of an oral dose is absorbed. Peak serum levels are achieved in 3 to 4 hours following oral dosage.

Pregnancy

The effects of primidone in human pregnancy are unknown. Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause-and-effect relationship. The possibility exists that other factors leading to birth defects, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy. The great majority of mothers on anticonvulsant medication deliver normal infants. Do not discontinue anticonvulsant drugs in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorders are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered before and during pregnancy, although even minor seizures may pose some hazard to the developing embryo or fetus. Neonatal hemorrhage, with a coagulation defect resembling vitamin K deficiency, has been described in newborns whose mothers were taking primidone and other anticonvulsants. Administer prophylactic vitamin K1 therapy for 1 month before and during labor and obstetric delivery in pregnant women under anticonvulsant therapy. To monitor human fetal outcomes, pregnant women taking primidone are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must enroll themselves by calling the registry at 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.