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Primidone: Drug information

Primidone: Drug information
(For additional information see "Primidone: Patient drug information" and see "Primidone: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Mysoline
Pharmacologic Category
  • Anticonvulsant, Miscellaneous;
  • Barbiturate
Dosing: Adult

Seizure disorders (grand mal, psychomotor, and focal): Oral: Days 1 to 3: 100 to 125 mg/day at bedtime; days 4 to 6: 100 to 125 twice daily; days 7 to 9: 100 to 125 mg 3 times daily; usual dose: 750 to 1,500 mg/day in divided doses 3 to 4 times/day with maximum dosage of 2 g/day

Patients already receiving other antiseizure medications: Initial: 100 to 125 mg at bedtime; gradually increase to maintenance dose as other drug is gradually decreased, continue until desired level obtained or other drug completely withdrawn. If goal is monotherapy, conversion should be completed over ≥2 weeks.

Essential tremor (off-label use): Oral: Initial: 25 mg once daily; increase dose gradually (eg, every 3 to 7 days) based on response and tolerability in increments of 25 mg. Usual dosage: 150 to 250 mg/day in 1 or 2 divided doses. Doses of up to 750 mg/day have been studied, but some experts recommend a maximum of 250 to 500 mg/day due to dose-related adverse drug reactions (Abboud 2011; Deik 2022; Deuschl 2011; Findley 1985; Serrano-Duenas 2003; Shanker 2019).

Dosing: Kidney Impairment: Adult

No dosage adjustment provided in manufacturer's labeling. However, the following recommendations (based on a maximum of 750 mg twice daily in normal kidney function) have been used by some clinicians: Note: Avoid in renal failure if possible; due to active metabolites with long half-lives and complex kinetics (Aronoff 2007):

GFR ≥50 mL/minute: No dosage adjustment necessary.

GFR 10 to 50 mL/minute: Administer no more frequently than every 12 to 24 hours (Aronoff 2007).

GFR <10 mL/minute: Administer no more frequently than every 24 hours (Aronoff 2007).

Hemodialysis: Dialyzable (Lee 1982). Administer dose after dialysis due to high extraction during hemodialysis or may administer a supplemental dose prior to dialysis session that is 30% of the patient's usual dose (Aronoff 2007; Asconapé 2014; Lee 1982).

Dosing: Hepatic Impairment: Adult

No dosage adjustment provided in manufacturer’s labeling. However, increased side effects may occur in severe liver disease; monitor plasma levels and adjust dose accordingly.

Dosing: Pediatric

(For additional information see "Primidone: Pediatric drug information")

Seizure disorder (generalized tonic-clonic, psychomotor, and focal):

Weight-directed: Infants and Children <8 years: Oral: Usual maintenance range: 10 to 25 mg/kg/day in 2 to 3 divided doses; start with lower dosage and titrate upward; usual maximum dose: 500 mg/dose (Kliegman 2016)

Fixed dosing:

Children <8 years: Oral:

Initial: Days 1 to 3: 50 mg at bedtime; Days 4 to 6: 50 mg twice daily; Days 7 to 9: 100 mg twice daily

Maintenance (starting Day 10 of therapy): 125 to 250 mg three times daily

Patients already receiving other antiseizure medications: Specific recommendations in this age group are not available. However, in older pediatric patients (≥8 years of age), the usual initial starting dose is recommended, and then gradually increase primidone to maintenance dose as other drug is gradually decreased, continue until desired level obtained or other drug completely withdrawn. If goal is monotherapy, conversion should be completed over ≥2 weeks.

Children ≥8 years and Adolescents: Oral:

Initial: Days 1 to 3: 100 to 125 mg at bedtime; Days 4 to 6: 100 to 125 twice daily; Days 7 to 9: 100 to 125 mg 3 times daily

Maintenance (starting Day 10 of therapy): 250 mg 3 times daily; adjust dose to usual maintenance range: 750 to 1,000 mg/day in divided doses 3 to 4 times daily; some patients may require 1,500 mg/day in divided doses 4 times daily; maximum daily dose: 2,000 mg/day

Patients already receiving other antiseizure medications: Initial: 100 to 125 mg at bedtime; gradually increase to maintenance dose as other drug is gradually decreased, continue until desired level obtained or other drug completely withdrawn. If goal is monotherapy, conversion should be completed over ≥2 weeks.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in manufacturer’s labeling. Avoid in renal failure if possible; due to active metabolites with long half-lives and complex kinetics; based on experience in adult patients, dosing adjustment suggested

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in manufacturer’s labeling. However, increased side effects may occur in severe liver disease; monitor plasma levels and adjust dose accordingly.

Dosing: Older Adult

Use with extreme caution due to CNS effects and increased risk for falls (Bourdet 2001). In addition, there is potential for acute toxicity in certain patients upon initiation of relatively low doses; monitor older adults closely during initiation for toxicity and intolerance (Findley 1985; O'Brien 1981).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Mysoline: 50 mg, 250 mg [scored]

Generic: 50 mg, 250 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 125 mg, 250 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM222370.pdf, must be dispensed with this medication.

Administration: Pediatric

Oral: Administer without regard to food; may consider food to decrease GI upset

Use: Labeled Indications

Management of grand mal, psychomotor, and focal seizures

Use: Off-Label: Adult

Essential tremor

Medication Safety Issues
Sound-alike/look-alike issues:

Primidone may be confused with predniSONE, primaquine, pyridoxine

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined.

Central nervous system: Ataxia, drowsiness, emotional disturbance, fatigue, hyperirritability, suicidal ideation, vertigo

Dermatologic: Morbilliform rash

Gastrointestinal: Anorexia, nausea, vomiting

Genitourinary: Impotence

Hematologic & oncologic: Agranulocytosis, granulocytopenia, megaloblastic anemia (idiosyncratic), pure red cell aplasia, red cell hypoplasia

Ophthalmic: Diplopia, nystagmus

Contraindications

Hypersensitivity to phenobarbital; porphyria

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Suicidal ideation: Pooled analysis of trials involving various antiseizure medications (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.

Disease-related concerns:

• Depression: Use with caution in patients with depression or suicidal tendencies.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Hypoadrenalism: Use with caution in patients with hypoadrenalism.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution in patients with respiratory disease.

• Substance abuse: Use with caution in patients with a history of drug abuse; potential for drug dependency exists. Tolerance or psychological and physical dependence may occur with prolonged use.

Concurrent drug therapy issues:

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Special populations:

• Debilitated patients: Use with caution in patients who are debilitated; may cause paradoxical responses.

• Elderly: Use with caution in elderly patients due to sedating side effects and cognitive function declines. Primidone may cause paradoxical responses.

• Pediatric: Primidone's active metabolite, phenobarbital, has been associated with cognitive deficits in children receiving chronic therapy for febrile seizures.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Acute pain: Do not administer to patients in acute pain.

• Withdrawal: Antiseizure medications should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Warnings: Additional Pediatric Considerations

One of the active metabolites of primidone is phenobarbital. Phenobarbital may cause CNS depression and effects with other sedative drugs may be potentiated. Phenobarbital has been associated with cognitive deficits in children receiving therapy for complicated febrile seizures. Cognitive deficits observed with phenobarbital were further described in a retrospective chart review of 280 pediatric patients who had received either phenobarbital, levetiracetam, or both for treatment of neonatal seizures. A subset of the study group (n=67) had a Bayley Scales of Infant Development (BSID) completed at 24 months corrected age. Based on the analysis of cumulative exposures, the investigators observed that increased phenobarbital exposure was associated with a significant decrease in BSID cognitive (8 points) and motor (9 points) scores and an increased probability for the development of cerebral palsy (2.3-fold) for every 100 mg/kg of phenobarbital exposure (Maitre 2013).

Pediatric patients may be at increased risk for vitamin D deficiency; with chronic therapy, phenobarbital may cause catabolism of vitamin D; the daily vitamin D requirement may be increased in these patients (≥400 units/day); vitamin D status should be periodically monitored with laboratory data (Misra 2008; Wagner 2008).

Metabolism/Transport Effects

Substrate of CYP2C19 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP1A2 (weak), CYP2A6 (weak), CYP2B6 (weak), CYP2C9 (weak), CYP3A4 (strong), UGT1A1

Drug Interactions

Abemaciclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abemaciclib. Risk X: Avoid combination

Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid whenever possible. If such a combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during concomitant use. Risk D: Consider therapy modification

Acalabrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Risk D: Consider therapy modification

Acetaminophen: Primidone may increase the metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor therapy

Afatinib: Primidone may decrease the serum concentration of Afatinib. Management: Consider increasing the afatinib dose by 10 mg as tolerated in patients requiring chronic coadministration of phenobarbital with afatinib. Reduce afatinib dose back to the original afatinib dose 2 to 3 days after discontinuation of phenobarbital. Risk D: Consider therapy modification

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfacalcidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alfacalcidol. Risk C: Monitor therapy

Alfentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and strong CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Risk D: Consider therapy modification

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alpelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alpelisib. Risk X: Avoid combination

ALPRAZolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of ALPRAZolam. Risk C: Monitor therapy

Amiodarone: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Amiodarone. CYP3A4 Inducers (Strong) may decrease the serum concentration of Amiodarone. Risk C: Monitor therapy

AmLODIPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of AmLODIPine. Risk C: Monitor therapy

Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products. Risk X: Avoid combination

Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Management: Avoid concurrent use of apixaban with strong CYP3A4 inducers whenever possible. Use of a strong CYP3A4 inducer with apixaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Risk D: Consider therapy modification

Apremilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast. Risk X: Avoid combination

Aprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant. Risk X: Avoid combination

ARIPiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of ARIPiprazole. Management: For indications other than major depressive disorder: double the oral aripiprazole dose over 1 to 2 weeks and closely monitor. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Risk D: Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Risk D: Consider therapy modification

Artemether and Lumefantrine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether and Lumefantrine. Risk X: Avoid combination

Asunaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir. Risk X: Avoid combination

Atazanavir: Primidone may decrease the serum concentration of Atazanavir. Atazanavir may decrease the serum concentration of Primidone. Management: Coadministration of primidone and atazanavir without ritonavir is not recommended. If atazanavir and ritonavir are coadministered with primidone, primidone dose increases may be required. Risk D: Consider therapy modification

Atogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Atogepant. Management: The recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with strong or moderate CYP3A4 inducers. Risk D: Consider therapy modification

Atorvastatin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Atorvastatin. Risk C: Monitor therapy

Avacopan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avacopan. Risk X: Avoid combination

Avanafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avanafil. Risk X: Avoid combination

Avapritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avapritinib. Risk X: Avoid combination

Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Barbiturates: Primidone may enhance the adverse/toxic effect of Barbiturates. Primidone is converted to phenobarbital, and thus becomes additive with existing barbiturate therapy. Risk C: Monitor therapy

Barnidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Barnidipine. Risk C: Monitor therapy

Bazedoxifene: Primidone may decrease the serum concentration of Bazedoxifene. This may lead to loss of efficacy or, if bazedoxifene is combined with estrogen therapy, an increased risk of endometrial hyperplasia. Risk C: Monitor therapy

Bedaquiline: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Bedaquiline. CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Risk X: Avoid combination

Belumosudil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Belumosudil. Management: Increase the dose of belumosudil to 200 mg twice daily when coadministered with strong CYP3A4 inducers. Risk D: Consider therapy modification

Benidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benidipine. Risk C: Monitor therapy

Benperidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benperidol. Risk C: Monitor therapy

Benzhydrocodone: Primidone may enhance the CNS depressant effect of Benzhydrocodone. Primidone may decrease serum concentrations of the active metabolite(s) of Benzhydrocodone. Specifically, serum concentrations of hydrocodone may be decreased. Management: Avoid use of benzhydrocodone and primidonel when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased benzhydrocodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

Betamethasone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Betamethasone (Systemic). Risk C: Monitor therapy

Bictegravir: Primidone may decrease the serum concentration of Bictegravir. Management: When possible consider using an alternative antiseizure drug with concurrent bictegravir, emtricitabine, and tenofovir alafenamide. If the combination must be used, monitor closely for evidence of reduced antiviral effectiveness. Risk D: Consider therapy modification

Bisoprolol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bisoprolol. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: Barbiturates may enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Risk X: Avoid combination

Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. Risk X: Avoid combination

Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if the strong CYP3A4 inducer is discontinued. Risk D: Consider therapy modification

Brigatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brigatinib. Risk X: Avoid combination

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Brivaracetam: Primidone may decrease the serum concentration of Brivaracetam. Risk C: Monitor therapy

Bromocriptine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bromocriptine. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: Primidone may enhance the CNS depressant effect of Buprenorphine. Primidone may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider therapy modification

BuPROPion: CYP2B6 Inducers (Weak) may decrease the serum concentration of BuPROPion. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inducers (Strong) may decrease the serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed. Risk D: Consider therapy modification

Cabazitaxel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabazitaxel. Risk C: Monitor therapy

Cabotegravir: UGT1A1 Inducers may decrease the serum concentration of Cabotegravir. Risk X: Avoid combination

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, increase cabozantinib capsules (Cometriq) by 40 mg from previous dose, max 180 mg daily. Increase cabozantinib tablets (Cabometyx) by 20 mg from previous dose, max 80 mg daily Risk D: Consider therapy modification

Calcifediol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcifediol. Risk C: Monitor therapy

Calcitriol (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcitriol (Systemic). Risk C: Monitor therapy

Canagliflozin: Primidone may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Cannabidiol: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Cannabidiol. CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabidiol. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabis: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor therapy

Capmatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Capmatinib. Risk X: Avoid combination

CarBAMazepine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of Primidone. Specifically, osteomalacia and rickets. Carbonic Anhydrase Inhibitors may decrease the serum concentration of Primidone. Risk C: Monitor therapy

Cariprazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cariprazine. Risk X: Avoid combination

Ceritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib. Risk X: Avoid combination

Chloramphenicol (Systemic): May increase serum concentrations of the active metabolite(s) of Primidone. Specifically, the concentrations of phenobarbital may be increased. Primidone may decrease the serum concentration of Chloramphenicol (Systemic). Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

ChlorproPAMIDE: CYP3A4 Inducers (Strong) may decrease the serum concentration of ChlorproPAMIDE. Risk C: Monitor therapy

Cilnidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cilnidipine. Risk C: Monitor therapy

Citalopram: CYP3A4 Inducers (Strong) may decrease the serum concentration of Citalopram. Risk C: Monitor therapy

Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A4 inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Risk D: Consider therapy modification

Clindamycin (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Clindamycin (Systemic). Risk C: Monitor therapy

ClonazePAM: CYP3A4 Inducers (Strong) may decrease the serum concentration of ClonazePAM. Risk C: Monitor therapy

CloZAPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine. Management: Avoid use with strong CYP3A4 inducers when possible. If combined, monitor patients closely and consider clozapine dose increases. Clozapine dose reduction and further monitoring may be required when strong CYP3A4 inducers are discontinued. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Cobicistat: Primidone may decrease the serum concentration of Cobicistat. Risk X: Avoid combination

Cobimetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cobimetinib. Risk X: Avoid combination

Codeine: Primidone may enhance the CNS depressant effect of Codeine. Primidone may decrease the serum concentration of Codeine. Management: Avoid use of codeine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Risk D: Consider therapy modification

Copanlisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Copanlisib. Risk X: Avoid combination

Cosyntropin: May enhance the hepatotoxic effect of Primidone. Risk C: Monitor therapy

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Risk X: Avoid combination

CycloSPORINE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of CycloSPORINE (Systemic). Management: Monitor closely for reduced cyclosporine concentrations when combined with strong CYP3A4 inducers. Cyclosporine dose increases will likely be required to maintain adequate serum concentrations. Risk D: Consider therapy modification

Cyproterone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cyproterone. Risk C: Monitor therapy

Dabigatran Etexilate: Primidone may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy

Daclatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir. Risk X: Avoid combination

Dapsone (Systemic): May enhance the adverse/toxic effect of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Dapsone (Systemic). Risk C: Monitor therapy

Daridorexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daridorexant. Risk X: Avoid combination

Darunavir: May decrease the serum concentration of Primidone. Risk C: Monitor therapy

Dasabuvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasabuvir. Risk X: Avoid combination

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid concurrent use of dasatinib with strong CYP3A4 inducers when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification

Deflazacort: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Risk X: Avoid combination

Delamanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Delamanid. Risk X: Avoid combination

Delavirdine: Primidone may decrease the serum concentration of Delavirdine. Risk X: Avoid combination

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexAMETHasone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of DexAMETHasone (Systemic). Management: Consider dexamethasone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced dexamethasone efficacy. Consider avoiding this combination when treating life threatening conditions (ie, multiple myeloma). Risk D: Consider therapy modification

Dexmethylphenidate: May increase serum concentrations of the active metabolite(s) of Primidone. Specifically, phenobarbital concentrations could become elevated. Dexmethylphenidate may increase the serum concentration of Primidone. Risk C: Monitor therapy

DiazePAM: CYP3A4 Inducers (Strong) may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

DilTIAZem: CYP3A4 Inducers (Strong) may decrease the serum concentration of DilTIAZem. Management: Consider alternatives to this combination when possible. If combined, monitor for decreased diltiazem efficacy. Risk D: Consider therapy modification

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Disopyramide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Disopyramide. Risk C: Monitor therapy

Dolutegravir: Primidone may decrease the serum concentration of Dolutegravir. Specifically, the Primidone metabolite phenobarbital may decrease Dolutegravir serum concentrations. Risk X: Avoid combination

Domperidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Domperidone. Risk C: Monitor therapy

Doravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Doravirine. Risk X: Avoid combination

Doxercalciferol: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

Doxycycline: Barbiturates may decrease the serum concentration of Doxycycline. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol. Risk C: Monitor therapy

Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Risk X: Avoid combination

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Duvelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Duvelisib. Risk X: Avoid combination

Dydrogesterone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dydrogesterone. Risk C: Monitor therapy

Ebastine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ebastine. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ebastine. Risk C: Monitor therapy

Efavirenz: CYP3A4 Inducers (Strong) may decrease the serum concentration of Efavirenz. Risk C: Monitor therapy

Elagolix: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elagolix. Risk C: Monitor therapy

Elagolix, Estradiol, and Norethindrone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elagolix, Estradiol, and Norethindrone. Risk C: Monitor therapy

Elbasvir and Grazoprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk X: Avoid combination

Eliglustat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat. Risk X: Avoid combination

Elvitegravir: Primidone may decrease the serum concentration of Elvitegravir. Risk X: Avoid combination

Encorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Encorafenib. Risk X: Avoid combination

Enfortumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Entrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Entrectinib. Risk X: Avoid combination

Enzalutamide: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Enzalutamide. CYP3A4 Inducers (Strong) may decrease the serum concentration of Enzalutamide. Management: Consider using an alternative agent that has no or minimal CYP3A4 induction potential when possible. If this combination cannot be avoided, increase the dose of enzalutamide from 160 mg daily to 240 mg daily. Risk D: Consider therapy modification

Eplerenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eplerenone. Risk C: Monitor therapy

Eravacycline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers. Risk D: Consider therapy modification

Erdafitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erdafitinib. Risk X: Avoid combination

Erlotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erlotinib. Management: Avoid the combination of erlotinib and strong CYP3A4 inducers whenever possible. If this combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Risk D: Consider therapy modification

Escitalopram: CYP3A4 Inducers (Strong) may decrease the serum concentration of Escitalopram. Risk C: Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Eslicarbazepine: Primidone may decrease the serum concentration of Eslicarbazepine. (based on studies with phenobarbital) Risk C: Monitor therapy

Estazolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Estazolam. Risk C: Monitor therapy

Estrogen Derivatives: CYP3A4 Inducers (Strong) may decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Eszopiclone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eszopiclone. Risk C: Monitor therapy

Ethosuximide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ethosuximide. Risk C: Monitor therapy

Etizolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etizolam. Risk C: Monitor therapy

Etoposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. Risk D: Consider therapy modification

Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response. Risk D: Consider therapy modification

Etoricoxib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoricoxib. Risk C: Monitor therapy

Etravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etravirine. Risk X: Avoid combination

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers if possible. If coadministration cannot be avoided, monitor for decreased everolimus serum concentrations and effects, and adjust everolimus dose as needed. Risk D: Consider therapy modification

Evogliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Evogliptin. Risk C: Monitor therapy

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Increase the exemestane dose to 50 mg once daily in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity or inadequate clinical response. Risk D: Consider therapy modification

Fedratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fedratinib. Risk X: Avoid combination

Felbamate: May increase serum concentrations of the active metabolite(s) of Primidone. Specifically, phenobarbital concentrations may increase. Primidone may decrease the serum concentration of Felbamate. Management: Initiate felbamate at typical doses (1,200 mg/day in 3 or 4 divided doses for adults and children 14 years of age or older; 15 mg/kg/day in 3 or 4 divided doses in children 2 to 14 years of age) while reducing the primidone dose by 20%. Risk D: Consider therapy modification

Felodipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Felodipine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced felodipine efficacy and the need for felodipine dose increases. Risk D: Consider therapy modification

FentaNYL: Primidone may enhance the CNS depressant effect of FentaNYL. Primidone may decrease the serum concentration of FentaNYL. Management: Avoid use of fentanyl and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider therapy modification

Fesoterodine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

Fexinidazole: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Fexinidazole. Risk X: Avoid combination

Finerenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Finerenone. Risk X: Avoid combination

Flibanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Flibanserin. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Folic Acid: May decrease the serum concentration of Primidone. Additionally, folic acid may decrease concentrations of active metabolites of primidone (e.g., phenobarbital). Risk C: Monitor therapy

Fosamprenavir: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant. Risk X: Avoid combination

Fosnetupitant: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosnetupitant. Risk X: Avoid combination

Fosphenytoin: May increase the metabolism of Primidone. The ratio of primidone:phenobarbital is thus changed. Risk C: Monitor therapy

Fostamatinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostamatinib. Risk X: Avoid combination

Fostemsavir: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostemsavir. Risk X: Avoid combination

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase the gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Risk D: Consider therapy modification

Gemigliptin: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Gemigliptin. CYP3A4 Inducers (Strong) may decrease the serum concentration of Gemigliptin. Risk X: Avoid combination

Gestrinone: Primidone may decrease the serum concentration of Gestrinone. Risk C: Monitor therapy

Gilteritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gilteritinib. Risk C: Monitor therapy

Glasdegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glasdegib. Risk X: Avoid combination

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy

Griseofulvin: Barbiturates may decrease the serum concentration of Griseofulvin. Risk C: Monitor therapy

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Risk D: Consider therapy modification

Haloperidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Haloperidol. Risk C: Monitor therapy

Hemin: Barbiturates may diminish the therapeutic effect of Hemin. Risk X: Avoid combination

Hormonal Contraceptives: CYP3A4 Inducers (Strong) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a strong CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

HYDROcodone: Primidone may enhance the CNS depressant effect of HYDROcodone. Primidone may decrease the serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

Hydrocortisone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of Barbiturates. Management: Consider a decrease in the barbiturate dose, as appropriate, when used together with hydroxyzine. With concurrent use, monitor patients closely for excessive response to the combination. Risk D: Consider therapy modification

Ibrexafungerp: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrexafungerp. Risk X: Avoid combination

Ibrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrutinib. Risk X: Avoid combination

Idelalisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib. Risk X: Avoid combination

Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid use of imatinib and strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Doses up to 1200 mg/day (600 mg twice daily) have been used. Risk D: Consider therapy modification

Indinavir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and strong CYP3A4 inducers whenever possible due to the risk for decreased indinavir concentrations, reduced efficacy, and development of resistance. If combined, monitor for indinavir treatment failure Risk D: Consider therapy modification

Infigratinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination

Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Management: Avoid administration of strong CYP3A4 inducers during irinotecan treatment, and substitute non-CYP3A4 inducing agents at least 2 weeks prior to irinotecan initiation, whenever possible. If combined, monitor for reduced irinotecan efficacy. Risk D: Consider therapy modification

Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Risk X: Avoid combination

Isradipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Isradipine. Risk C: Monitor therapy

Istradefylline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Istradefylline. Risk X: Avoid combination

Itraconazole: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Itraconazole. CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole. Risk X: Avoid combination

Ivabradine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivabradine. Risk X: Avoid combination

Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor. Risk X: Avoid combination

Ivosidenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivosidenib. Risk X: Avoid combination

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Risk D: Consider therapy modification

Ixazomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixazomib. Risk X: Avoid combination

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ketamine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ketamine. Risk C: Monitor therapy

Ketoconazole (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Ketoconazole (Systemic). Management: The use of ketoconazole concurrently with or within 2 weeks of a strong CYP3A4 inducer is not recommended. If such a combination cannot be avoided, monitor patients closely for evidence of diminished clinical response to ketoconazole. Risk D: Consider therapy modification

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lacidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lacidipine. Risk C: Monitor therapy

LamoTRIgine: May enhance the adverse/toxic effect of Primidone. Specifically, the risk for hematologic toxicities may be increased. Primidone may decrease the serum concentration of LamoTRIgine. Management: For patients taking primidone without valproate, lamotrigine dose adjustments are recommended for lamotrigine initiation. Recommendations vary based on lamotrigine indication and age. See full interact monograph for details. Risk D: Consider therapy modification

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If concomitant use cannot be avoided, titrate lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk D: Consider therapy modification

Larotrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer's half-life. Risk D: Consider therapy modification

Ledipasvir: Primidone may decrease the serum concentration of Ledipasvir. Risk X: Avoid combination

Lefamulin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lemborexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lemborexant. Risk X: Avoid combination

Lercanidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lercanidipine. Risk C: Monitor therapy

Letermovir: May increase the serum concentration of UGT1A1 Inducers. Risk X: Avoid combination

Leucovorin Calcium-Levoleucovorin: May decrease the serum concentration of Primidone. Additionally, leucovorin/levoleucovorin may decrease concentrations of active metabolites of primidone (e.g., phenobarbital). Risk C: Monitor therapy

Leuprolide and Norethindrone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Leuprolide and Norethindrone. Specifically, norethindrone concentrations may be decreased. Risk C: Monitor therapy

Levamlodipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Levamlodipine. Risk C: Monitor therapy

LevETIRAcetam: May enhance the CNS depressant effect of Primidone. Primidone may decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

Levoketoconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Levoketoconazole. Risk X: Avoid combination

Levomefolate: May decrease serum concentrations of the active metabolite(s) of Primidone. Levomefolate may decrease the serum concentration of Primidone. Risk C: Monitor therapy

Levomethadone: May enhance the CNS depressant effect of Primidone. Primidone may decrease the serum concentration of Levomethadone. Management: Avoid concomitant use of levomethadone and primidone when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Levonorgestrel (IUD): CYP3A4 Inducers (Strong) may diminish the therapeutic effect of Levonorgestrel (IUD). CYP3A4 Inducers (Strong) may decrease the serum concentration of Levonorgestrel (IUD). Risk C: Monitor therapy

Lidocaine (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

LinaGLIPtin: CYP3A4 Inducers (Strong) may decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lonafarnib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lonafarnib. Risk X: Avoid combination

Lopinavir: Primidone may decrease the serum concentration of Lopinavir. Management: Avoid once-daily administration of lopinavir/ritonavir if used together with phenobarbital. If lopinavir/ritonavir twice daily is combined with phenobarbital, monitor closely for decreased efficacy of lopinavir/ritonavir. Risk D: Consider therapy modification

Lorlatinib: CYP3A4 Inducers (Strong) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib. Risk X: Avoid combination

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Risk X: Avoid combination

Lumateperone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumateperone. Risk X: Avoid combination

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Risk X: Avoid combination

Lurbinectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurbinectedin. Risk X: Avoid combination

Macimorelin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macimorelin. Risk X: Avoid combination

Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. Risk X: Avoid combination

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Manidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. Risk D: Consider therapy modification

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider therapy modification

Maribavir: Primidone may decrease the serum concentration of Maribavir. Management: Increase the dose of maribavir to 1,200 mg twice daily with concomitant use of primidone. Risk D: Consider therapy modification

Mefloquine: May diminish the therapeutic effect of Primidone. Primidone may decrease the serum concentration of Mefloquine. Mefloquine may decrease the serum concentration of Primidone. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If primidone is being used for another indication, monitor for decreased concentrations and efficacy of both primidone/phenobarbital and mefloquine. Risk D: Consider therapy modification

Meperidine: Primidone may enhance the CNS depressant effect of Meperidine. Primidone may increase serum concentrations of the active metabolite(s) of Meperidine. Management: Avoid concomitant use of meperidine and primidone when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Methadone: Primidone may enhance the CNS depressant effect of Methadone. Primidone may decrease the serum concentration of Methadone. Management: Avoid concomitant use of methadone and primidone when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Methoxyflurane: Barbiturates may enhance the nephrotoxic effect of Methoxyflurane. Barbiturates may increase the metabolism of Methoxyflurane. Risk X: Avoid combination

Methylergonovine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Methylergonovine. Risk C: Monitor therapy

Methylfolate: May decrease the serum concentration of Primidone. Risk C: Monitor therapy

Methylphenidate: May increase serum concentrations of the active metabolite(s) of Primidone. Specifically, phenobarbital concentrations could become elevated. Methylphenidate may increase the serum concentration of Primidone. Risk C: Monitor therapy

MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): Primidone may decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Mianserin: May enhance the CNS depressant effect of Barbiturates. Mianserin may diminish the therapeutic effect of Barbiturates. Barbiturates may decrease the serum concentration of Mianserin. Risk X: Avoid combination

Midazolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Midazolam. Risk C: Monitor therapy

Midostaurin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Midostaurin. Risk X: Avoid combination

MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Risk X: Avoid combination

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirabegron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirabegron. Risk C: Monitor therapy

Mirodenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Risk D: Consider therapy modification

Mirtazapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirtazapine. Risk C: Monitor therapy

Mitapivat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mitapivat. Risk X: Avoid combination

Mobocertinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Mobocertinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Mobocertinib. Risk X: Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Barbiturates. Risk C: Monitor therapy

Naldemedine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naldemedine. Risk X: Avoid combination

Naloxegol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol. Risk X: Avoid combination

Nateglinide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nateglinide. Risk C: Monitor therapy

Nelfinavir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nelfinavir. Risk C: Monitor therapy

Neratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Neratinib. Risk X: Avoid combination

Netupitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant. Risk X: Avoid combination

Nevirapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nevirapine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced nevirapine efficacy. Risk D: Consider therapy modification

NiCARdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiCARdipine. Risk C: Monitor therapy

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Management: Avoid coadministration of nifedipine with strong CYP3A4 inducers when possible and if combined, monitor patients closely for clinical signs of diminished nifedipine response. Risk D: Consider therapy modification

Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination

Nilvadipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilvadipine. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiMODipine. Risk X: Avoid combination

Nintedanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nintedanib. Risk C: Monitor therapy

Nirmatrelvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nirmatrelvir. Risk X: Avoid combination

Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination

Nitrendipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nitrendipine. Risk C: Monitor therapy

OLANZapine: CYP1A2 Inducers (Weak) may decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Olaparib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib. Risk X: Avoid combination

Olmutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olmutinib. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ondansetron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ondansetron. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orlistat: May decrease the serum concentration of Antiseizure Agents. Risk C: Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Osilodrostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osilodrostat. Risk C: Monitor therapy

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Management: Avoid coadministration of osimertinib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase osimertinib to 160 mg daily. Reduce osimertinib to 80 mg daily 3 weeks after discontinuation of the strong CYP3A4 inducer. Risk D: Consider therapy modification

OXcarbazepine: CYP3A4 Inducers (Strong) may decrease the serum concentration of OXcarbazepine. Specifically, the concentrations of the 10-monohydroxy active metabolite of oxcarbazepine may be decreased. Risk C: Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: Primidone may enhance the CNS depressant effect of OxyCODONE. Primidone may decrease the serum concentration of OxyCODONE. Management: Avoid use of oxycodone and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

PACLitaxel (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inducers (Strong) may decrease the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. Risk X: Avoid combination

Panobinostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat. Risk X: Avoid combination

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

PAZOPanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib. Risk X: Avoid combination

Pemigatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pemigatinib. Risk X: Avoid combination

Perampanel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with strong CYP3A4 inducers. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if the inducer is discontinued. Risk D: Consider therapy modification

Pexidartinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pexidartinib. Risk X: Avoid combination

Phenytoin: May increase the metabolism of Primidone. The ratio of primidone:phenobarbital is thus changed. Risk C: Monitor therapy

Pimavanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin. Risk X: Avoid combination

Piperaquine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Piperaquine. Risk X: Avoid combination

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pitolisant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: If on a stable pitolisant dose of 8.9 mg or 17.8 mg/day and starting a strong CYP3A4 inducer, double the pitolisant dose over 7 days (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Reduce pitolisant dose by 50% when the inducer is discontinued. Risk D: Consider therapy modification

Polatuzumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Risk C: Monitor therapy

PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. Management: Avoid coadministration of ponatinib with strong CYP3A4 inducers unless the potential benefit of concomitant treatment outweighs the risk of reduced ponatinib exposure. Monitor patients for reduced ponatinib efficacy if combined. Risk D: Consider therapy modification

Ponesimod: UGT1A1 Inducers may decrease the serum concentration of Ponesimod. Risk X: Avoid combination

Pralsetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pralsetinib. Management: Avoid concomitant use of pralsetinib with strong CYP3A4 inducers when possible. If combined, increase the starting dose of pralsetinib to double the current pralsetinib dosage starting on day 7 of coadministration. Risk D: Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Risk X: Avoid combination

PrednisoLONE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy

PredniSONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE. Risk C: Monitor therapy

Pretomanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pretomanid. Risk X: Avoid combination

Propacetamol: Primidone may increase the metabolism of Propacetamol. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor therapy

Propafenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Propafenone. Risk C: Monitor therapy

Pyridoxine: May decrease serum concentrations of the active metabolite(s) of Primidone. Specifically, concentrations of phenobarbital may be reduced. Risk C: Monitor therapy

QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: An increase in quetiapine dose (as much as 5 times the regular dose) may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7 to 14 days of discontinuing the inducer. Risk D: Consider therapy modification

QuiNIDine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

QuiNINE: May increase the serum concentration of Primidone. Primidone may decrease the serum concentration of QuiNINE. Management: Consider alternatives to this combination when possible. If coadministration of primidone and quinine cannot be avoided, monitor for reduced quinine efficacy and for increased phenobarbital (active metabolite) serum concentrations and toxicities. Risk D: Consider therapy modification

Radotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Risk D: Consider therapy modification

Ramelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ramelteon. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination

Reboxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Reboxetine. Risk C: Monitor therapy

Regorafenib: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Risk X: Avoid combination

Remdesivir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Remdesivir. Risk C: Monitor therapy

Repaglinide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

Ribociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ribociclib. Risk X: Avoid combination

Rifabutin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rifabutin. Risk C: Monitor therapy

Rilpivirine: Primidone may decrease the serum concentration of Rilpivirine. Risk X: Avoid combination

Rimegepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rimegepant. Risk X: Avoid combination

Riociguat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Riociguat. Risk C: Monitor therapy

Ripretinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ripretinib. Risk X: Avoid combination

RisperiDONE: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of RisperiDONE. CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Careful monitoring for reduced risperidone efficacy and possible dose adjustment are recommended when combined with strong CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider therapy modification

Ritonavir: May decrease the serum concentration of Primidone. Primidone may decrease the serum concentration of Ritonavir. Management: Consider avoiding this combination due to the potential for decreased ritonavir concentrations and the possible development of resistance. If combined, monitor for decreased phenobarbital and ritonavir concentrations and effects during coadministration. Risk D: Consider therapy modification

Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Management: Consider alternatives to use of rivaroxaban with strong CYP3A4 inducers. Use of a strong CYP3A4 inducer with rivaroxaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Risk D: Consider therapy modification

Roflumilast: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Roflumilast. CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Risk X: Avoid combination

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Risk X: Avoid combination

RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Risk X: Avoid combination

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May increase serum concentrations of the active metabolite(s) of Primidone. Specifically, phenobarbital concentrations may be increased. Primidone may decrease the serum concentration of Rufinamide. Risk C: Monitor therapy

Ruxolitinib (Systemic): CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ruxolitinib (Systemic). CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib (Systemic). Risk C: Monitor therapy

Sacituzumab Govitecan: UGT1A1 Inducers may decrease serum concentrations of the active metabolite(s) of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be decreased. Risk X: Avoid combination

Samidorphan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Samidorphan. Risk X: Avoid combination

Sapropterin: Primidone may decrease the serum concentration of Sapropterin. Risk C: Monitor therapy

Saquinavir: Primidone may decrease the serum concentration of Saquinavir. Risk X: Avoid combination

SAXagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of SAXagliptin. Risk C: Monitor therapy

Selpercatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Selpercatinib. Risk X: Avoid combination

Selumetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Selumetinib. Risk X: Avoid combination

Sertraline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sertraline. Risk C: Monitor therapy

Sildenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sildenafil. Risk C: Monitor therapy

Simeprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir. Risk X: Avoid combination

Sirolimus (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus (Conventional). Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Risk D: Consider therapy modification

Sirolimus (Protein Bound): CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

Sofosbuvir: Primidone may decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination

Solifenacin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Solifenacin. Risk C: Monitor therapy

Sonidegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sonidegib. Risk X: Avoid combination

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk X: Avoid combination

Sotorasib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sotorasib. Risk X: Avoid combination

Stiripentol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Stiripentol. Management: Avoid concomitant use of stiripentol and strong CYP3A4 inducers when possible. If combined, monitor for reduced stiripentol efficacy and increase the stiripentol dose as needed. Risk D: Consider therapy modification

SUFentanil: Primidone may enhance the CNS depressant effect of SUFentanil. Primidone may decrease the serum concentration of SUFentanil. Management: Avoid use of sufentanil and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased sufentanil efficacy and withdrawal if combined. Risk D: Consider therapy modification

Sulthiame: Primidone may enhance the adverse/toxic effect of Sulthiame. Risk C: Monitor therapy

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If combined, increase sunitinib dose to a max of 87.5 mg daily when treating GIST or RCC. Increase sunitinib dose to a max of 62.5 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Tacrolimus (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Tacrolimus (Systemic). Management: Monitor for decreased tacrolimus concentrations and effects when combined with strong CYP3A4 inducers. Tacrolimus dose increases will likely be needed during concomitant use. Risk D: Consider therapy modification

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction or benign prostatic hypertrophy: monitor for decreased effectiveness - no standard dose adjustment is recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Risk D: Consider therapy modification

Tamoxifen: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Strong) may decrease the serum concentration of Tamoxifen. Risk X: Avoid combination

Tasimelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon. Risk X: Avoid combination

Tazemetostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tazemetostat. Risk X: Avoid combination

Telithromycin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Telithromycin. Risk X: Avoid combination

Temsirolimus: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be decreased. CYP3A4 Inducers (Strong) may decrease the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inducers. If coadministration is unavoidable, increase temsirolimus dose to 50 mg per week. Resume previous temsirolimus dose after discontinuation of the strong CYP3A4 inducer. Risk D: Consider therapy modification

Teniposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Teniposide. Risk C: Monitor therapy

Tenofovir Alafenamide: Primidone may decrease the serum concentration of Tenofovir Alafenamide. Risk X: Avoid combination

Tepotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tepotinib. Risk X: Avoid combination

Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Management: Avoid use of the tetrahydrocannabinol/cannabidiol oromucosal spray and strong CYP3A4 inducers when possible. If combined use is necessary, careful titration is recommended, notably within the two weeks following discontinuation of the inducer. Risk D: Consider therapy modification

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tezacaftor and Ivacaftor. Risk X: Avoid combination

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Theophylline Derivatives: Barbiturates may decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Thiotepa: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Strong) may decrease the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects. Risk D: Consider therapy modification

Thiothixene: Primidone may decrease the serum concentration of Thiothixene. Risk C: Monitor therapy

Thyroid Products: Primidone may decrease the serum concentration of Thyroid Products. Risk C: Monitor therapy

TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Risk X: Avoid combination

Tipranavir: Primidone may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Primidone. Risk C: Monitor therapy

Tivozanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tivozanib. Risk X: Avoid combination

Tofacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib. Risk X: Avoid combination

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Risk X: Avoid combination

Toremifene: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Toremifene. CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination

Trabectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin. Risk X: Avoid combination

TraMADol: Primidone may enhance the CNS depressant effect of TraMADol. Primidone may decrease the serum concentration of TraMADol. Management: Avoid use of tramadol and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider therapy modification

TraZODone: CYP3A4 Inducers (Strong) may decrease the serum concentration of TraZODone. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers. Risk D: Consider therapy modification

Triamcinolone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Triamcinolone (Systemic). Risk C: Monitor therapy

Triazolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Triazolam. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced triazolam efficacy. Substantial triazolam dose increases will likely be required. Risk D: Consider therapy modification

Tricyclic Antidepressants: Barbiturates may increase the metabolism of Tricyclic Antidepressants. Management: Monitor for decreased efficacy of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. Tricyclic antidepressant dose adjustments are likely required. Risk D: Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tropisetron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tropisetron. Risk C: Monitor therapy

Tucatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tucatinib. Risk X: Avoid combination

Ubrogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ubrogepant. Risk X: Avoid combination

Udenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Udenafil. Risk C: Monitor therapy

Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Risk X: Avoid combination

Upadacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Upadacitinib. Risk X: Avoid combination

Valbenazine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valproate Products: May increase the serum concentration of Primidone. More specifically, the serum concentration of phenobarbital, primidone's primary active metabolite, may be increased. Primidone may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Vandetanib: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Vandetanib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Risk X: Avoid combination

Velpatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Risk X: Avoid combination

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Management: Avoid coadministration of vemurafenib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase the vemurafenib dose by 240 mg as tolerated. Resume prior vemurafenib dose 2 weeks after discontinuation of strong CYP3A4 inducer. Risk D: Consider therapy modification

Venetoclax: CYP3A4 Inducers (Strong) may decrease the serum concentration of Venetoclax. Risk X: Avoid combination

Verapamil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Verapamil. Management: Consider alternatives to this combination. If combined, monitor for reduced verapamil efficacy. Verapamil dose increases may be necessary. Risk D: Consider therapy modification

Vilazodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1 to 2 weeks after inducer discontinuation. Risk D: Consider therapy modification

VinCRIStine: CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine. Risk C: Monitor therapy

VinCRIStine (Liposomal): CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

Vinflunine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinflunine. Risk X: Avoid combination

Vinorelbine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinorelbine. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Barbiturates may increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. Anticoagulant dose increases of 30% to 60% may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction. Risk D: Consider therapy modification

Voclosporin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voclosporin. Risk X: Avoid combination

Vorapaxar: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar. Risk X: Avoid combination

Voriconazole: Primidone may decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Vortioxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Risk D: Consider therapy modification

Voxelotor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,500 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider therapy modification

Voxilaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxilaprevir. Risk X: Avoid combination

Zaleplon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zaleplon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Risk D: Consider therapy modification

Zanubrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zanubrutinib. Risk X: Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Zonisamide: May enhance the CNS depressant effect of Primidone. Primidone may decrease the serum concentration of Zonisamide. Risk C: Monitor therapy

Zopiclone: Primidone may enhance the CNS depressant effect of Zopiclone. Primidone may decrease the serum concentration of Zopiclone. Risk C: Monitor therapy

Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy

Food Interactions

Protein-deficient diets increase duration of action of primidone.

Pregnancy Considerations

Primidone and its metabolites (PEMA, phenobarbital, and p-hydroxyphenobarbital) cross the placenta; neonatal serum concentrations at birth are similar to those in the mother. Withdrawal symptoms may occur in the neonate and may be delayed due to the long half-life of primidone and its metabolites. Use may be associated with birth defects and adverse events; the use of folic acid throughout pregnancy and vitamin K during the last month of pregnancy is recommended. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of antiseizure therapy.

Patients exposed to primidone during pregnancy are encouraged to enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Breastfeeding Considerations

Primidone and its metabolites (PEMA, phenobarbital, and p-hydroxyphenobarbital) are found in breast milk (variable concentrations). The manufacturer recommends discontinuing breast-feeding if undue drowsiness and somnolence occur in the newborn.

Dietary Considerations

Folic acid: Low erythrocyte and CSF folate concentrations. Megaloblastic anemia has been reported. To avoid folic acid deficiency and megaloblastic anemia, some clinicians recommend giving patients on antiseizure medications prophylactic doses of folic acid and cyanocobalamin.

Vitamin B: Primidone use has been associated with low serum concentrations of vitamin B2 (riboflavin), B6 (pyridoxine), and B12 (cyanocobalamin), which may contribute to hyperhomocysteinemia. Hyperhomocysteinemia may contribute to cardiovascular disease, venous thromboembolic disease, dementia, neuropsychiatric symptoms, and poor seizure control. Some clinicians recommend administering riboflavin, pyridoxine, and cyanocobalamin supplements in patients taking primidone (Apeland 2003; Apeland 2008; Belcastro 2010; Bochyńska 2012).

Monitoring Parameters

Serum primidone and phenobarbital concentration, neurological status. Monitor CBC and comprehensive metabolic panel at 6-month intervals to compare with baseline obtained at start of therapy. Monitor for suicidality and depression.

Reference Range

Therapeutic: Children <5 years: 7-10 mcg/mL (SI: 32-46 micromole/L); Adults: 5-12 mcg/mL (SI: 23-55 micromole/L); toxic effects rarely present with levels <10 mcg/mL (SI: 46 micromole/L) if phenobarbital concentrations are low. Dosage of primidone is adjusted with reference mostly to the phenobarbital level; Toxic: >15 mcg/mL (SI: >69 micromole/L). There is no clear correlation between serum level and clinical benefit when used for essential tremor (Hedera 2013).

Mechanism of Action

Decreases neuron excitability, raises seizure threshold similar to phenobarbital; primidone has two active metabolites, phenobarbital and phenylethylmalonamide (PEMA); PEMA may enhance the activity of phenobarbital

Pharmacokinetics

Absorption: Well absorbed (Neels 2004)

Distribution: Vd: 0.6 to 0.75 L/kg (Bourgeois 2000; Neels 2004)

Protein binding: <20% (Bourgeois 2000; Neels 2004)

Metabolism: Hepatic to phenobarbital (active) by oxidation and to phenylethylmalonamide (PEMA; active) by ring cleavage at the second carbon position (El-Masri 1998)

Bioavailability: >90% (Bourgeois 2000)

Half-life elimination (age dependent): Primidone: 5 to16 hours (variable); PEMA: 16 to 50 hours (variable); Phenobarbital: 50 to 150 hours (Bourgeois 2000; Neels 2004)

Time to peak, serum: 0.5 to 9 hours (variable) (Neels 2004)

Excretion: Urine (15% to 65% as unchanged drug; the remainder is unconjugated PEMA, phenobarbital and its metabolites) (Neels 2004)

Pricing: US

Tablets (Mysoline Oral)

50 mg (per each): $20.75

250 mg (per each): $71.40

Tablets (Primidone Oral)

50 mg (per each): $0.24 - $0.50

250 mg (per each): $0.45 - $1.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Hexamidin (RU);
  • Liskantin (BG, CZ, DE, EE, LU);
  • Majsolin (HR);
  • Mizodin (PL);
  • Mutigan (VE);
  • Mylepsinum (DE);
  • Mysoline (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BR, CH, CI, CL, CY, DK, EE, ES, ET, FI, FR, GH, GM, GN, GR, HK, IE, IN, IQ, IR, IT, JO, KE, LB, LR, LU, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, OM, PT, RU, SA, SC, SD, SE, SG, SK, SL, SN, SY, TN, TR, TW, TZ, UG, UY, YE, ZA, ZM, ZW);
  • Pridona (CR, DO, GT, HN, NI, PA, SV);
  • Primid (BR);
  • Primidon (HR);
  • Prysoline (IL);
  • Sertan (HU)


For country abbreviations used in Lexicomp (show table)

REFERENCES

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