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  • CLASSES

    Anticonvulsants, Barbiturates

    DEA CLASS

    Rx

    DESCRIPTION

    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.

    COMMON BRAND NAMES

    Mysoline

    HOW SUPPLIED

    Mysoline/Primidone Oral Tab: 50mg, 250mg

    DOSAGE & INDICATIONS

    For use as an alternative to other anticonvulsants for the management of generalized tonic-clonic seizures, or for the management of complex partial seizures (e.g., psychomotor seizures).
    Oral dosage (in patients who have not received prior treatment)
    Adults, Adolescents, and Children >= 8 years

    Initially, 125 to 250 mg/day PO at bedtime; increase by 125 to 250 mg/day every 3 to 7 days. The usual dose is 750 to 1,500 mg/day in 3 to 4 divided doses with a maximum dose of 2 g/day.

    Children < 8 years and Infants

    Initially, 50 to 125 mg/day PO given at bedtime. Increase dose by 50 to 125 mg/day every 3 to 7 days. Usual doses range from 10 to 25 mg/kg/day PO given in 3 to 4 divided doses. Maximum dosage of 25 mg/kg/day administered in 4 divided doses, or up to a maximum dosage of 1,000 mg/day.

    Neonates

    12 to 20 mg/kg/day PO in 2 to 4 divided doses. Start at lower doses and titrate.

    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

    MAXIMUM DOSAGE

    As with all anticonvulsant-type medications, primidone dosage must be individualized. The following are the maximum dosage limits recommended by the manufacturer:

    Adults

    2000 mg/day PO.

    Elderly

    2000 mg/day PO.

    Adolescents

    2000 mg/day PO.

    Children

    >= 8 years: 2000 mg/day PO.
    < 8 years: 25 mg/kg/day PO or 1000 mg/day PO.

    Infants

    25 mg/kg/day PO.

    Neonates

    20 mg/kg/day PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Modify initial dose depending on degree of hepatic impairment; no quantitative recommendations are available. Initiate dose cautiously and adjust based on clinical response and serum concentrations.

    Renal Impairment

    CrCl > 50 ml/min: No dosage adjustment needed.
    CrCl 10—50 ml/min: Consider decreasing the dosage by increasing the interval between doses to 8—12 hours. Follow clinical response and serum concentrations.
    CrCl < 10 ml/min: Decrease the dosage by increasing the interval between doses to 12—24 hours. Follow clinical response and serum concentrations.
     
    Intermittent hemodialysis
    Primidone is partially removed by hemodialysis. Some experts recommend supplementing with 1/3 of a dose after a session.
     
    Peritoneal dialysis
    Data are not available for CAPD.

    ADMINISTRATION

    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.

    STORAGE

    Mysoline:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Agranulocytosis, barbiturate hypersensitivity, carbamazepine hypersensitivity, exfoliative dermatitis, hydantoin hypersensitivity

    Primidone is contraindicated in patients with a hypersensitivity to phenobarbital (i.e., barbiturate hypersensitivity). Barbiturates can cause severe and potentially fatal reactions that are preceded by skin eruptions. Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of adverse hematologic (i.e., agranulocytosis), hypersensitivity, or other adverse reactions to barbiturates or other anticonvulsants. Hypersensitivity reactions to anticonvulsants may present as various organ system problems, including cardiac, liver, renal, and skin disorders. Skin reactions can precede potentially fatal hypersensitivity reactions; exfoliative dermatitis has resulted in a few fatalities. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. Hypersensitivity reactions have been reported in patients who previously experienced hydantoin hypersensitivity (e.g., phenytoin) or carbamazepine hypersensitivity. Estimates of cross-sensitivity vary, but may range from 30—80%. Phenytoin, carbamazepine, and phenobarbital (and primidone) are all metabolized to hydroxylated aromatic compounds via the cytochrome P450 hepatic oxidative enzymes; arene oxide intermediates are formed during metabolism and are thought to be responsible for cross-sensitivity among these anticonvulsants in susceptible individuals. Some individuals may have a reduced ability to detoxify the intermediate toxic metabolites (e.g., arene oxides) of these anticonvulsants, which may be genetically mediated. However, studies of familial reactions have also shown that allergies to one anticonvulsant may not translate to allergies to others. There is no way to predict with certainty which patients will exhibit cross-sensitivity.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), corresponding to an estimated 2.1 per 1000 (95% CI: 0.7—4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Chronic obstructive pulmonary disease (COPD), pulmonary disease, respiratory depression, sleep apnea

    Because primidone can cause dose-dependent respiratory depression, it should be used cautiously in patients with pulmonary disease states causing respiratory depression, dyspnea, severe pulmonary insufficiency or airway obstruction. Barbiturates should be avoided in patients with bronchopneumonia. Use primidone with close supervision in patients with sleep apnea or chronic obstructive pulmonary disease (COPD).

    Abrupt discontinuation, seizure disorder, seizures, status epilepticus

    Primidone is considered to have a low potential for abuse. However, avoid abrupt discontinuation of primidone after prolonged use to limit drug withdrawal. Sudden, abrupt discontinuation of primidone in epileptic patients may precipitate a seizure disorder, acute seizures, or status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually when possible.

    Alcoholism, CNS depression, coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Primidone may cause blurred vision, drowsiness, dizziness, or mental status changes, especially with initial use. Because primidone can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. Patients should use caution when driving or operating machinery until they are aware of the effects of the drug. Coadministration with other CNS depressants, including alcohol, can magnify CNS depression. Ethanol ingestion should be avoided during use of barbiturates due to the potential for additive CNS depressant effects; the lethal dose of a barbiturate is significantly less if alcohol is also ingested. Use in patients with alcoholism is not advisable. Since primidone is used as an anticonvulsant, alcohol use may reduce seizure control.

    Geriatric

    Primidone is metabolized to phenobarbital, a barbiturate, and should be used with caution in the geriatric or debilitated patient. The geriatric or debilitated adult is generally more sensitive to the sedative effects of barbiturates and may react to these drugs with marked excitement, depression, or confusion. Because primidone can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries.[28597] [28596] Barbiturates should not be used for the treatment of insomnia. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If primidone must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs); barbiturates should not be initiated in any dose to treat anxiety or insomnia since they are highly addictive and can cause multiple adverse effects and increase the risk for falls, especially in the elderly. During use for any other condition, the need for the drug should be based on confirmation of the condition and its potential cause(s). Periodic monitoring of drug concentrations and evaluation of symptoms should be used to adjust doses, along with monitoring for adverse effects. Barbiturate anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Barbiturates may increase the metabolism of many drugs, such as antipsychotics or other anticonvulsants, potentially leading to decreased effectiveness and worsening of symptoms or decreased control of an underlying condition. When a medication is used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined by the OBRA guidelines.[60742]

    Hepatic disease, hepatic encephalopathy

    Primidone is extensively metabolized in the liver to active metabolites. Those with hepatic disease may be at increased risk for developing drug toxicity and may require lower dosage and slower dosage titration. Because barbiturates are sedative and also may impair the ability of the liver to metabolize ammonia, barbiturates are best avoided in patients with hepatic encephalopathy. Note that barbiturates are hepatic enzyme inducers and patients should be monitored for altered serum drug levels and/or therapeutics effects as indicated (see Drug Interactions).

    Anuria, dialysis, renal failure, renal impairment

    Barbiturates should be used cautiously in patients with renal impairment. The kidneys excrete metabolites and unchanged drug. Renal failure or anuria can lead to toxicity. The chronic use of primidone should generally be avoided in patients with renal failure; dosages need to be adjusted and administered less frequently. Close monitoring of levels is necessary in dialysis patients since the drug is partially removed by hemodialysis.

    Porphyria

    Primidone, like other barbiturates, is contraindicated in patients with porphyria. Barbiturates can exacerbate this disease. Barbiturates can stimulate the activity of enzymes like ALA synthetase, causing a buildup of porphyrin precursors and enhancing porphyrin synthesis.

    Anticoagulant therapy

    Primidone may decrease the effect of oral coumarin (e.g., warfarin) anticoagulant therapy (see Drug Interactions) and necessitate upward dosage adjustment of the anticoagulant for optimal effect. Conversely, when the drug is discontinued, the dose of the anticoagulant may have to be decreased.

    Osteomalacia, osteoporosis

    Use primidone with caution in patients with low bone density. There may be an increased risk of osteopenia/osteoporosis with long-term therapy. Osteomalacia has been noted in patients using phenobarbital who have end-stage renal disease.

    Neonates, premature neonates

    Primidone is not commonly used as an anticonvulsant in infants; phenobarbital is more commonly used. Due to immature hepatic and renal function (particularly in the first few weeks of life), neonates (especially premature neonates) must be carefully monitored during primidone use via serum concentrations and clinical status.

    Labor, obstetric delivery, pregnancy

    Primidone is an anticonvulsant that is metabolized to phenobarbital. Primidone should be used during pregnancy only if the benefits clearly outweigh the risks. Females should be warned of the potential adverse effects on the fetus if pregnancy occurs. Seizures themselves can be equally harmful to both the fetus and the mother and maintenance of anticonvulsant therapy may be essential to the mother. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations in the placenta, fetal liver, and brain. Fetal blood concentrations approach maternal blood concentrations after parenteral administration. According to the Practice Parameter of the American Academy of Neurology (AAN) and American Epilepsy Society (AES), avoidance of primidone during pregnancy may be considered due to the possible association of phenobarbital with reduced cognitive outcomes in the exposed fetus. If treatment with any anticonvulsant is required during pregnancy, monotherapy versus polytherapy should be considered to decrease the risk of major congenital malformations. Close clinical monitoring is often needed to guide dose adjustments during pregnancy. The Practice Parameter additionally states that newborns of women with epilepsy who received anticonvulsants during pregnancy probably have an increased risk of being small for gestational age and possibly having an increased risk of a 1-minute Apgar score of less than 7. Tests to detect birth defects using currently accepted procedures should be considered as a part of routine prenatal care. There are other risks to neonates; neonates with a history of in utero exposure to primidone should be monitored carefully. If primidone is used during labor and obstetric delivery, neonates should be carefully observed for signs of respiratory depression, particularly if the infant is premature. Consistent in utero exposure during the third trimester may cause physical dependence and respiratory depression in the neonate, and a neonatal abstinence syndrome has been reported. Acute symptoms of withdrawal and seizures may occur any time during the first 14 days of life. In addition, hypoprothrombinemia with hemorrhage has been observed within the first 24 hours in neonates and appears to result from drug-induced vitamin K deficiency in the fetus. Administration of vitamin K to the mother before obstetric delivery and to the neonate at birth has been shown to prevent or correct this defect. Physicians are advised to recommend that pregnant patients receiving primidone enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.  

    Breast-feeding

    Primidone should be given to nursing mothers with caution. According to the manufacturer, primidone is excreted and concentrated in breast milk, and the effects in the nursing infant are unknown. In one small study, the milk to plasma ratio was 0.8. An evidence-based review conducted by subcommittees of the American Academy of Neurology and American Epilepsy Society indicates that primidone probably penetrates into breast milk in potentially clinically significant amounts. Because infants (especially neonates) have slower drug elimination mechanisms than adults, accumulation may occur; drug levels in the infant could potentially exceed those in the mother. If primidone is continued during breast-feeding, observe the infant for sedation or other symptoms, like poor feeding, irritability, or poor weight gain. Plasma concentration monitoring is recommended in such infants. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    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

    DRUG INTERACTIONS

    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) 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. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Butalbital: (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; Butalbital; Caffeine: (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. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Butalbital; 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. (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. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Caffeine: (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. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    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. (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. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (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. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    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; Phenyltoloxamine: (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; 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; 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; 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; 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. (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; Propoxyphene: (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.
    Acetaminophen; 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. (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.
    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%.
    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; 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.
    Aliskiren; 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.
    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) Additive CNS and/or respiratory depression may occur. Additionally, the oral clearance of alprazolam (0.8 mg single dose) was increased in the presence of another CYP3A4 inducer for 10 days from 0.9 +/- 0.21 mL/minute/kg to 2.13 +/- 0.54 mL/minute/kg and the elimination half-life was shortened from 17.1 +/- 4.9 to 7.7 +/- 1.7 hours. Alprazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
    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.
    Amitriptyline; 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.
    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; Hydrochlorothiazide, HCTZ; 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. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amlodipine; Hydrochlorothiazide, HCTZ; 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. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    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; Telmisartan: (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.
    Amoxapine: (Major) Monitor for excessive sedation and somnolence during coadministration of amoxapine and barbiturates. Concurrent use may result in additive CNS depression.
    Amoxicillin; Clarithromycin; Lansoprazole: (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.
    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.
    Amprenavir: (Major) Coadministration with phenobarbital and, potentially, other barbiturates may increase the metabolism of amprenavir and lead to decreased amprenavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If amprenavir and barbiturates are used together, the patient must be closely monitored for antiviral efficacy.
    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) 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) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Aspirin, ASA; Butalbital; 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) 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) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Aspirin, ASA; 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) 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) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Aspirin, ASA; Caffeine; Orphenadrine: (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) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    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.
    Aspirin, ASA; Pravastatin: (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: (Severe) 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.
    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; 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.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with barbiturates can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with barbiturates can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    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.
    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 primarily metabolized by CYP3A4. 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.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Bendamustine: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Bendroflumethiazide; Nadolol: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of benzhydrocodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of benzhydrocodone with a barbiturate may decrease benzhydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; benzhydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
    Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
    Betaxolol: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Clinicians should monitor patients for loss of beta-blockade.
    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.
    Bicalutamide: (Moderate) Bicalutamide is metabolized by CYP3A4. Barbiturates induce CYP3A4 activity and will decrease the plasma concentrations of bicalutamide.
    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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering primidone with boceprevir due to the potential for boceprevir treatment failure. If primidone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of primidone and boceprevir. Primidone is an inducer of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may decrease.
    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.
    Bosentan: (Minor) Although this interaction has not been specifically studied, drugs which induce both CYP2C9 and CYP3A4 isoenzymes such as primidone may affect the metabolism of bosentan and may necessitate dosage adjustments of bosentan.
    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; Carbetapentane; 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. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Brompheniramine; Dextromethorphan; Guaifenesin: (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; 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. (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; 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. (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.
    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.
    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; 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.
    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.
    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.
    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: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration. (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Caffeine; Ergotamine: (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine 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.
    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.
    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.
    Carbetapentane; 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. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; 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. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; 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. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
    Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors, like entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression due to the possibility of additive sedation. Agents that may cause additive sedation when given concurrently with tolcapone include the barbiturates. The risk for adverse effects may increase, and patients should use caution in driving or other hazardous tasks until the effects of the drugs 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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (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.
    Carbinoxamine; Hydrocodone; Phenylephrine: (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 carbinoxamine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
    Carbinoxamine; 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. (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.
    Carbinoxamine; Phenylephrine: (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.
    Carbinoxamine; Pseudoephedrine: (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) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as primidone or barbiturates, has not been evaluated and is not recommended because the net effect on active drug and metabolites 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.
    Ceritinib: (Major) Avoid coadministration of ceritinib with primidone due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    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.
    Cevimeline: (Moderate) Inducers of cytochrome P450 3A4 and/or CYP 2D6, such as the barbiturates, may cause a reduction in cevimeline plasma concentrations.
    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; 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.
    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; 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; Dihydrocodeine; Pseudoephedrine: (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; Guaifenesin; 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. (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; Hydrocodone; Phenylephrine: (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; 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. (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.
    Cinacalcet: (Moderate) Coadministration of cinacalcet with a CYP3A4 enzyme inducer, such as a barbiturate, may result in a decreased effect of cinacalcet.
    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.
    Citalopram: (Moderate) Citalopram is metabolized by CYP2C19 and CYP3A4. Barbiturates can induce the metabolism of various CYP 450 isoenzymes, including those involved in citalopram metabolism. Although no clinical data are available to support a clinically significant interaction, citalopram may need to be administered in higher doses in patients chronically taking barbiturates.
    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) Concomitant use of clindamycin and primidone may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; primidone is a strong inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    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: (Severe) 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; 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: (Moderate) COMT inhibitors, like entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression due to the possibility of additive sedation. Agents that may cause additive sedation when given concurrently with tolcapone include the barbiturates. The risk for adverse effects may increase, and patients should use caution in driving or other hazardous tasks until the effects of the drugs are known.
    Conjugated Estrogens: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Conjugated Estrogens; Bazedoxifene: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    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.
    Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    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: (Severe) 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.
    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) Closely monitor for decreased primidone efficacy during coadministration; clinical monitoring of phenobarbital concentrations (active metabolite of primidone) with dosage titration if necessary is also warranted. Coadministration of darunavir and primidone may result in decreased phenobarbital concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenobarbital.
    Darunavir; Cobicistat: (Severe) 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) Closely monitor for decreased primidone efficacy during coadministration; clinical monitoring of phenobarbital concentrations (active metabolite of primidone) with dosage titration if necessary is also warranted. Coadministration of darunavir and primidone may result in decreased phenobarbital concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenobarbital.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) 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) Closely monitor for decreased primidone efficacy during coadministration; clinical monitoring of phenobarbital concentrations (active metabolite of primidone) with dosage titration if necessary is also warranted. Coadministration of darunavir and primidone may result in decreased phenobarbital concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenobarbital.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with primidone is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Primidone is converted to phenobarbital in vivo, and phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir, and ritonavir are substrates. (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with primidone is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Primidone is converted to phenobarbital in vivo, and phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir, and ritonavir are substrates. (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
    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) Coadministration may result in decreased exposure to dexamethasone. Primidone is a CYP3A4 inducer; dexamethasone is a CYP3A4 substrate. Monitor for decreased response to dexamethasone during concurrent use.
    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 barbiturates because it may result in decreased efficacy of dexlansoprazole. Dexlansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with barbiturates is likely to lead to an enhancement of CNS depression.
    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.
    Dienogest; Estradiol valerate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Diethylstilbestrol, DES: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (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.
    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; Hydrocodone; 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. (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.
    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.
    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: (Severe) 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: (Severe) 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: (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; Estradiol: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Drospirenone; Ethinyl Estradiol: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. (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: (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.
    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.
    Elbasvir; Grazoprevir: (Severe) 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 substrates (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: (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 Alafenamide: (Severe) 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: (Severe) 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: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    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; 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.
    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: (Moderate) COMT inhibitors, like entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression due to the possibility of additive sedation. Agents that may cause additive sedation when given concurrently with tolcapone include the barbiturates. The risk for adverse effects may increase, and patients should use caution in driving or other hazardous tasks until the effects of the drugs 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.
    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.
    Esomeprazole; Naproxen: (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.
    Esterified Estrogens: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Esterified Estrogens; Methyltestosterone: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estradiol: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estradiol; Levonorgestrel: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estradiol; Norethindrone: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estradiol; Norgestimate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estradiol; Progesterone: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estrogens: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Estropipate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    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) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Ethinyl Estradiol: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Desogestrel: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. (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. (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.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Norethindrone: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Norgestimate: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Ethinyl Estradiol; Norgestrel: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    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.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide, VP-16 when coadministered with phenobarbital, as concomitant use is associated with increased etoposide clearance and reduced efficacy. Phenobarbital is a strong inducer of CYP3A4 and P-glycoprotein (P-gp), and etoposide is a CYP3A4 and P-gp substrate.
    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) Depending on the indication, coadministration of primidone with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of primidone with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); primidone is a strong inducer of CYP3A4 and a P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased everolimus exposure by 63%.
    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 primidone as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    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.
    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.
    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.
    Fluoxetine; 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.
    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: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with barbiturates. Barbiturates are inducers of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with barbiturates, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be increased. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Major) Coadministration with phenobarbital and, potentially, other barbiturates may increase the metabolism of fosamprenavir and lead to decreased fosamprenavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If fosamprenavir and barbiturates are used together, the patient must be closely monitored for antiviral efficacy.
    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%.
    Galantamine: (Moderate) Monitor for reduced efficacy of galantamine during concurrent use of barbiturates. Galantamine is a substrate for CYP3A4 and CYP2D6. The effectiveness of the drug could theoretically be reduced by the concomitant administration of strong CYP3A4 inducers such as barbiturates.
    Gallium Ga 68 Dotatate: (Minor) Mannitol promotes the urinary excretion of barbiturates, and it may be used as an adjunct in patients with barbiturate toxicity.
    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.
    Glimepiride; Pioglitazone: (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.
    Glimepiride; Rosiglitazone: (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.
    Guaifenesin; 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.
    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.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Losartan: (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; 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. (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.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; 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. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Spironolactone: (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.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: (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; Phenylephrine: (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; Potassium Guaiacolsulfonate: (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; Potassium Guaiacolsulfonate; 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.
    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.
    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: (Severe) 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) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    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.
    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 is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. 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 is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Isavuconazonium: (Severe) 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) Ixabepilone is a CYP3A4 substrate and concomitant use with CYP3A4 inducers such as barbiturates may lead to reduced and subtherapeutic concentrations of ixabepilone. Caution should be utilized when CYP3A4 inducers are coadministered with ixabepilone, and alternative therapies with low enzyme induction potential should be considered.
    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.
    Kava Kava, Piper methysticum: (Major) Kava kava should be avoided when possible in patients taking barbiturates. Additive sedation or other CNS-related side effects are possible. Kava may inhibit CYP enzymes, increasing barbiturate exposure. When available, therapeutic drug monitoring for the specific barbiturate (e.g., phenobarbital) may be advisable. Liver injury may occur with Kava, which may be an additive side effect with some barbiturate treatments.
    Ketoconazole: (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of ketoconazole. Clinicians should be alert for lack of efficacy of these antifungals in concurrent use.
    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; Naproxen: (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.
    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.
    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.
    Levobupivacaine: (Minor) Barbiturates may induce the metabolism of levobupivacaine resulting in a decreased serum half-life. Dosage adjustments of levobupivacaine may be necessary.
    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.
    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.
    Linagliptin: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Linagliptin; Metformin: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    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.
    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.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with primidone. Loperamide is metabolized by the hepatic enzyme CYP3A4, and is a substrate for the drug transporter P-glycoprotein (P-gp). Primidone is an inducer of both CYP3A4 and P-gp.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with primidone. Loperamide is metabolized by the hepatic enzyme CYP3A4, and is a substrate for the drug transporter P-glycoprotein (P-gp). Primidone is an inducer of both CYP3A4 and P-gp.
    Lopinavir; Ritonavir: (Major) Barbiturates may increase the metabolism of lopinavir and lead to decreased antiretroviral efficacy. In addition, coadministration of lopinavir boosted with ritonavir may induce the CYP metabolism of barbiturates, resulting in decreased barbiturate concentrations. Appropriate dose adjustments necessary to ensure optimum levels of both anti-retroviral agent and the barbiturate are unknown; however, once daily lopinavir; ritonavir should not be used. 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. (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
    Lorazepam: (Moderate) Additive CNS and/or respiratory depression may occur with concurrent use.
    Lorlatinib: (Severe) Coadministration of lorlatinib with primidone is contraindicated due to the potential for serious hepatotoxicity; the efficacy of lorlatinib may also be decreased. Discontinue primidone for 3 plasma half-lives prior to initiating lorlatinib. Lorlatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Severe hepatotoxicity indicated by increased AST/ALT (grade 2, 8%; grade 3 or 4, 83%) occurred in healthy subjects receiving a single 100-mg dose of lorlatinib with multiple daily doses of another strong CYP3A4 inducer (n = 12); ALT and AST returned to normal limits after a median of 15 days. Additionally, the mean AUC and Cmax of lorlatinib were decreased by 85% and 76%, respectively.
    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.
    Lovastatin; Niacin: (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.
    Lurasidone: (Severe) 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.
    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.
    Magnesium Salts: (Minor) 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.
    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.
    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.
    Meperidine; Promethazine: (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.
    Mepivacaine; Levonordefrin: (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.
    Mestranol; Norethindrone: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    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.
    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: (Moderate) Psychostimulants, such as methylphenidate, 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.
    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 significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; phenobarbital, the active metabolite of primidone, is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    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.
    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.
    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) can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. MAOIs may prolong the effect of barbiturates like primidone and cause additive CNS depression.
    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: (Moderate) Concomitant use of nabilone with other CNS depressants, like barbiturates, can potentiate the effects of nabilone on respiratory depression.
    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%.
    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) Coadministration of nevirapine with barbiturates, which induce the activity of CYP3A, would be expected to increase the clearance of nevirapine, thereby decreasing nevirapine plasma concentrations. However, since nevirapine also induces CYP3A enzymes, decreases in anticonvulsant serum concentrations may be noted with the possibility of new seizure activity. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and barbiturates are unknown. If used concomitantly, the patient should be observed for changes in the clinical efficacy and concentrations of the antiretroviral and anticonvulsant regimens.
    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%.
    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.
    Olaparib: (Major) Avoid the coadministration of olaparib with primidone due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with primidone is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Primidone is converted to phenobarbital in vivo, and phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir, and ritonavir are substrates. (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
    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; 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.
    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.
    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.
    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.
    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.
    Pemoline: (Moderate) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents.
    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%.
    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.
    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.
    Pralidoxime: (Major) The action of barbiturates is potentiated by the acetylcholinesterase inhibitors, which should be considered when using pralidoxime. Barbiturates should be used with caution to treat convulsions produced by acetylcholinesterase inhibitors.
    Pramipexole: (Major) The use of barbiturates in combination with pramipexole may increase the risk of clinically significant sedation via a pharmacodynamic interaction.
    Praziquantel: (Severe) 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: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    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.
    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.
    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.
    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: (Severe) 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.
    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.
    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.
    Reserpine: (Moderate) Administration of reserpine can potentiate the depressant effects of CNS depressants such as barbiturates.
    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.
    Rifapentine: (Moderate) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by these enzymes, like barbiturates, may require dosage adjustments when administered concurrently with rifapentine.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Riluzole: (Moderate) Coadministration of riluzole with barbiturates may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
    Risperidone: (Major) Potent inducers of CYP3A4, such as barbiturates, may decrease plasma concentrations of risperidone and its active metabolite. Therefore, the manufacturer of oral risperidone recommends a slow upward titration of the risperidone dose as needed up to double the patient's usual dose during use of a 3A4 inducer. When using Risperdal Consta, the patient will require close monitoring for 4 to 8 weeks when starting an inducer. A lower dose of Risperdal Consta may be prescribed between 2 to 4 weeks before the planned discontinuation of the inducer to adjust for the expected increase in plasma concentrations of risperidone and its active metabolite. For patients treated with the recommended dose of Risperdal Consta 25 mg and discontinuing the inducer, it is recommended to continue the 25 mg dose unless a reduction to 12.5 mg or discontinuation of treatment is indicated. The efficacy of the 12.5 mg dose has not been studied in clinical trials.
    Ritonavir: (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
    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.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Barbiturates can accelerate the hepatic clearance of estrogens. 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. 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 estrogens for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Sertraline: (Moderate) Sertraline is a substrate for CYP3A4 and CYP2C19. Drugs that induce hepatic isoenzymes, such as barbiturates could decrease sertraline plasma concentrations, potentially causing decreased effectiveness of this SSRI.
    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.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and primidone as induction of CYP3A4 by phenobarbital (active metabolite) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    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.
    Simvastatin; Sitagliptin: (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) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Skeletal Muscle Relaxants: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Sodium Oxybate: (Severe) 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%.
    Spironolactone: (Moderate) Barbiturates, such as primidone, may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    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 dose of sunitinib in 12.5 mg increments based on individual safety and tolerability to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily; monitor carefully for toxicity. The maximum daily dose administered in the pNET study was 50 mg. 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.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering primidone with telaprevir due to the potential for telaprevir treatment failure. If primidone dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of primidone and telaprevir. Primidone is an inducer of the hepatic isoenzyme CYP3A4; telaprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of telaprevir may decrease.
    Telithromycin: (Major) Concomitant administration of CYP3A4 inducers such as primidone, which is metabolized to phenobarbital, are expected to cause subtherapeutic concentrations of telithromycin and loss of efficacy.
    Telotristat Ethyl: (Moderate) Use caution if primidone is coadministered with telotristat ethyl, and monitor for a decrease in the efficacy of telotristat ethyl. Telotristat, the active metabolite of telotristat ethyl, is a substrate of P-glycoprotein (P-gp) and primidone is a P-gp inducer. Exposure to telotristat ethyl may decrease.
    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.
    Terbinafine: (Moderate) Due to the risk for breakthrough fungal infections, caution is advised when administering terbinafine with barbiturates. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may decrease the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenzymes, with major contributions coming from CYP1A2, CYP2C9, CYP2C19 and CYP3A4; barbiturates induce these enzymes. Monitor patients for breakthrough fungal infections.
    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: (Major) Barbiturates increase the metabolism of tipranavir, and may lead to decreased efficacy of tipranavir. In addition, tipranavir 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
    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; primidone is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. 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: (Moderate) COMT inhibitors, like entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression due to the possibility of additive sedation. Agents that may cause additive sedation when given concurrently with tolcapone include the barbiturates. The risk for adverse effects may increase, and patients should use caution in driving or other hazardous tasks until the effects of the drugs are known.
    Tolvaptan: (Major) Avoid coadministration of tolvaptan with primidone due to decreased plasma concentrations of tolvaptan. If concomitant use of primidone is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 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 significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Tramadol: (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate.
    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: (Major) 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.
    Triazolam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of triazolam. Triazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with barbiturates may potentiate the CNS effects of either trimethobenzamide or the barbiturate.
    Trimetrexate: (Minor) Drugs such as barbiturates can increase the metabolism of trimetrexate by induction of the hepatic cytochrome P-450 system. This can lead to lower plasma concentrations of trimetrexate.
    Triprolidine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with triprolidine.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and barbiturates (such as phenobarbital or primidone) are CYP3A4 inducers. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    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) Any substances that act on the CNS, including psychoactive drugs and drugs used as anesthetic adjuvants (e.g., barbiturates, benzodiazepines), 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 anxiolytics, sedatives, and hypnotics (including barbiturates and benzodiazepines). Patients who are taking barbiturates or other sedative/hypnotic drugs should avoid concomitant administration of valerian. Patients taking medications such as tricyclic antidepressants, lithium, MAOIs, skeletal muscle relaxants, SSRIs and serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) should discuss the use of herbal supplements with their health care professional prior to consuming valerian; combinations should be approached with caution in the absence of clinical data. Patients should not abruptly stop taking their prescribed psychoactive medications.
    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.
    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.
    Vardenafil: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as barbiturates, will decrease plasma levels of vardenafil.
    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.
    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: (Severe) 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 primidone 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. Voxelotor is a substrate of CYP3A4; primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 77%.
    Warfarin: (Major) A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead 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 the concomitant use of zanubrutinib and primidone. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. The AUC of zanubrutinib was decreased by 93% when coadministered with another strong CYP3A4 inducer.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Primidone is an anticonvulsant that is metabolized to phenobarbital. Primidone should be used during pregnancy only if the benefits clearly outweigh the risks. Females should be warned of the potential adverse effects on the fetus if pregnancy occurs. Seizures themselves can be equally harmful to both the fetus and the mother and maintenance of anticonvulsant therapy may be essential to the mother. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations in the placenta, fetal liver, and brain. Fetal blood concentrations approach maternal blood concentrations after parenteral administration. According to the Practice Parameter of the American Academy of Neurology (AAN) and American Epilepsy Society (AES), avoidance of primidone during pregnancy may be considered due to the possible association of phenobarbital with reduced cognitive outcomes in the exposed fetus. If treatment with any anticonvulsant is required during pregnancy, monotherapy versus polytherapy should be considered to decrease the risk of major congenital malformations. Close clinical monitoring is often needed to guide dose adjustments during pregnancy. The Practice Parameter additionally states that newborns of women with epilepsy who received anticonvulsants during pregnancy probably have an increased risk of being small for gestational age and possibly having an increased risk of a 1-minute Apgar score of less than 7. Tests to detect birth defects using currently accepted procedures should be considered as a part of routine prenatal care. There are other risks to neonates; neonates with a history of in utero exposure to primidone should be monitored carefully. If primidone is used during labor and obstetric delivery, neonates should be carefully observed for signs of respiratory depression, particularly if the infant is premature. Consistent in utero exposure during the third trimester may cause physical dependence and respiratory depression in the neonate, and a neonatal abstinence syndrome has been reported. Acute symptoms of withdrawal and seizures may occur any time during the first 14 days of life. In addition, hypoprothrombinemia with hemorrhage has been observed within the first 24 hours in neonates and appears to result from drug-induced vitamin K deficiency in the fetus. Administration of vitamin K to the mother before obstetric delivery and to the neonate at birth has been shown to prevent or correct this defect. Physicians are advised to recommend that pregnant patients receiving primidone enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.  

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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-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. Phenobarbital is also a strong inducer of the P-glycoprotein (P-gp) drug transporter.

    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.