Hyoscyamine, atropine, scopolamine, and phenobarbital: Drug information

Dosing: Adult

Duodenal ulcer, irritable bowel syndrome, and acute enterocolitis

Duodenal ulcer, irritable bowel syndrome, and acute enterocolitis (adjunct treatment): Oral: 1 to 2 tablets or 5 to 10 mL of elixir 3 to 4 times/day.

Dosing: Older Adult

Avoid use (Ref).

Dosing: Pediatric

(For additional information see "Hyoscyamine, atropine, scopolamine, and phenobarbital: Pediatric drug information")

Duodenal ulcer, irritable bowel syndrome, and acute enterocolitis, adjunct treatment

Duodenal ulcer, irritable bowel syndrome, and acute enterocolitis, adjunct treatment:

Infants weighing ≥4.5 kg, Children, and Adolescents: Immediate release (Donnatal elixir):

4.5 to <9.1 kg: 0.5 mL every 4 hours or 0.75 mL every 6 hours

9.1 to <13.6 kg: 1 mL every 4 hours or 1.5 mL every 6 hours

13.6 to <22.7 kg: 1.5 mL every 4 hours or 2 mL every 6 hours

22.7 to <34 kg: 2.5 mL every 4 hours or 3.75 mL every 6 hours

34 to <45.4 kg: 3.75 mL every 4 hours or 5 mL every 6 hours

≥45.4 kg: 5 mL every 4 hours or 7.5 mL every 6 hours

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Liver Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.

Cardiovascular: Palpitations, tachycardia

Central nervous system: Dizziness, drowsiness, excitement, headache, insomnia, nervousness

Dermatologic: Hypohidrosis, urticaria

Gastrointestinal: Ageusia, bloating, constipation, nausea, vomiting, xerostomia

Genitourinary: Decreased lactation, impotence, urinary hesitancy, urinary retention

Hypersensitivity: Anaphylaxis, hypersensitivity reaction (may be severe)

Neuromuscular & skeletal: Musculoskeletal pain, weakness

Ophthalmic: Blurred vision, cycloplegia, increased intraocular pressure, mydriasis

Contraindications

Hypersensitivity to hyoscyamine, atropine, scopolamine, phenobarbital, or any component of the formulation; narrow-angle glaucoma; GI and GU obstruction; myasthenia gravis; paralytic ileus; intestinal atony; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis (especially complicated by toxic megacolon); hiatal hernia associated with reflux esophagitis; acute intermittent porphyria; restlessness and/or excitement caused by phenobarbital

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: May cause drowsiness and/or blurred vision, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Diarrhea: May be a sign of incomplete intestinal obstruction; use caution in patients with ileostomy or colostomy.

• Heat prostration: May occur in the presence of increased environmental temperature; use caution in hot weather and/or exercise.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with coronary artery disease, arrhythmias, tachycardia, heart failure, or hypertension.

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

• Gastric ulcer treatment: Use of anticholinergics in gastric ulcer treatment may cause a delay in gastric emptying due to antral stasis.

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

• Hyperthyroidism: Use with caution in patients with hyperthyroidism.

• Neuropathy: Use with caution in patients with autonomic neuropathy.

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

Concurrent drug therapy issues:

• Anticoagulants: Use with caution in patients on anticoagulant therapy.

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

Other warnings/precautions:

• Appropriate use: Use has not been shown to prevent or treat duodenal ulcers.

• Withdrawal: Should not be discontinued abruptly because of the possibility of increased seizure frequency (due to phenobarbital component); 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

Elixir may contain up to 23.8% (v/v) of alcohol. 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).

Dosage Forms Considerations

Elixir contains ethanol (up to 23.8%).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product.

Elixir, Oral:

Donnatal: Hyoscyamine sulfate 0.1037 mg, atropine sulfate 0.0194 mg, scopolamine hydrobromide 0.0065 mg, and phenobarbital 16.2 mg per 5 mL (120 mL, 480 mL) [contains ethanol <23.8%; grape flavor]

Donnatal: Hyoscyamine sulfate 0.1037 mg, atropine sulfate 0.0194 mg, scopolamine hydrobromide 0.0065 mg, and phenobarbital 16.2 mg per 5 mL (120 mL, 480 mL) [contains ethanol <23.8%, tartrazine; mint flavor]

Generic: Hyoscyamine sulfate 0.1037 mg, atropine sulfate 0.0194 mg, scopolamine hydrobromide 0.0065 mg, and phenobarbital 16.2 mg per 5 mL (120 mL, 480 mL)

Tablet, Oral:

Donnatal: Hyoscyamine sulfate 0.1037 mg, atropine sulfate 0.0194 mg, scopolamine hydrobromide 0.0065 mg, and phenobarbital 16.2 mg

Phenohytro: Hyoscyamine sulfate 0.1037 mg, atropine sulfate 0.0194 mg, scopolamine hydrobromide 0.0065 mg, and phenobarbital 16.2 mg

Generic: Hyoscyamine sulfate 0.1037 mg, atropine sulfate 0.0194 mg, scopolamine hydrobromide 0.0065 mg, and phenobarbital 16.2 mg

Generic Equivalent Available: US

Yes

Pricing: US

Elixir (Donnatal Oral)

16.2 mg/5 mL (per mL): $5.22

Elixir (PB-Hyoscy-Atropine-Scopolamine Oral)

16.2 mg/5 mL (per mL): $3.20

Elixir (Phenohytro Oral)

16.2 mg/5 mL (per mL): $0.87

Tablets (Donnatal Oral)

16.2 mg (per each): $16.69

Tablets (PB-Hyoscy-Atropine-Scopolamine Oral)

16.2 mg (per each): $9.33

Tablets (Phenohytro Oral)

16.2 mg (per each): $2.96

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.

Administration: Pediatric

Oral: Administer without regard to meals; do not crush or chew extended release tablets

Use: Labeled Indications

Adjunct in treatment of irritable bowel syndrome, acute enterocolitis, duodenal ulcer

Medication Safety Issues

Sound-alike/look-alike issues:

Donnatal may be confused with Donnagel

Older Adult: High-Risk Medication:

Beers Criteria: Atropine, hyoscyamine, and scopolamine are each identified separately in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older (independent of diagnosis or condition) due to their highly anticholinergic properties and uncertain effectiveness as antispasmodics (Beers Criteria [AGS 2023]).

Beers Criteria: Phenobarbital is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its high rate of physical dependence, tolerance to sleep benefits, and increased risk of overdose at low dosages (Beers Criteria [AGS 2023]).

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Abemaciclib. Risk X: Avoid

Abiraterone Acetate: CYP3A4 Inducers (Moderate) may decrease serum concentration of Abiraterone Acetate. Risk C: Monitor

Acalabrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Acalabrutinib. Risk C: Monitor

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

Acetylcholinesterase Inhibitors: May decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Acetylcholinesterase Inhibitors. Risk C: Monitor

Aclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Acoramidis: UGT1A1 Inducers may decrease serum concentration of Acoramidis. Risk X: Avoid

Acrivastine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Afatinib: PHENobarbital may decrease 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

Ajmaline: Phenobarbital-Primidone may decrease serum concentration of Ajmaline. Risk C: Monitor

Albendazole: PHENobarbital may decrease active metabolite exposure of Albendazole. Risk C: Monitor

Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor

Alfacalcidol: Phenobarbital-Primidone may decrease serum concentration of Alfacalcidol. Risk C: Monitor

ALfentanil: CYP3A4 Inducers (Moderate) may decrease serum concentration of ALfentanil. Management: If concomitant use of alfentanil and moderate 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Alpelisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Alpelisib. Risk C: Monitor

Alpha1-Agonists: Atropine (Systemic) may increase hypertensive effects of Alpha1-Agonists. Risk C: Monitor

ALPRAZolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of ALPRAZolam. Risk C: Monitor

Amantadine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Amezinium: Atropine (Systemic) may increase stimulatory effects of Amezinium. Risk C: Monitor

Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

AmLODIPine: CYP3A4 Inducers (Moderate) may decrease serum concentration of AmLODIPine. Risk C: Monitor

Antacids: May decrease serum concentration of Hyoscyamine. Management: Administer immediate release and sublingual oral hyoscyamine before meals, and antacids after meals, when these agents are given in combination. Risk D: Consider Therapy Modification

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

Apixaban: Phenobarbital-Primidone may decrease serum concentration of Apixaban. Risk C: Monitor

Apremilast: CYP3A4 Inducers (Moderate) may decrease serum concentration of Apremilast. Risk C: Monitor

Aprepitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Aprepitant. Risk C: Monitor

ARIPiprazole Lauroxil: CYP3A4 Inducers (Moderate) may decrease serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor

ARIPiprazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of ARIPiprazole. Risk C: Monitor

Artemether and Lumefantrine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Artemether and Lumefantrine. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. Risk C: Monitor

Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification

Atazanavir: May decrease serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of Atazanavir. Risk X: Avoid

Atogepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider Therapy Modification

Atorvastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atorvastatin. Risk C: Monitor

Atrasentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atrasentan. Risk X: Avoid

Avacopan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avacopan. Risk X: Avoid

Avanafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avanafil. Risk X: Avoid

Avapritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avapritinib. Risk X: Avoid

Axitinib: Phenobarbital-Primidone may decrease serum concentration of Axitinib. Management: Concurrent use of axitinib with phenobarbital or primidone, which is metabolized to phenobarbital, should be avoided when possible. If any such combination is necessary, monitor for reduced axitinib efficacy. Risk D: Consider Therapy Modification

Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Bazedoxifene: PHENobarbital may decrease 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

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bedaquiline. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Bedaquiline. Risk X: Avoid

Belumosudil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Belumosudil. Risk C: Monitor

Benperidol: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Benperidol. Risk C: Monitor

Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Benzhydrocodone: PHENobarbital may increase CNS depressant effects of Benzhydrocodone. PHENobarbital may decrease active metabolite exposure of Benzhydrocodone. Specifically, phenobarbital may decrease serum concentrations of hydrocodone. Management: Avoid use of benzhydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased benzhydrocodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor

Beta-Acetyldigoxin: Atropine (Systemic) may increase serum concentration of Beta-Acetyldigoxin. Risk C: Monitor

Bictegravir: PHENobarbital may decrease 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

Biperiden: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Biperiden. Risk C: Monitor

Blonanserin: CNS Depressants may increase CNS depressant effects 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 increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Bornaprine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Bornaprine. Risk C: Monitor

Bortezomib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bortezomib. Risk C: Monitor

Bosutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bosutinib. Risk C: Monitor

Botulinum Toxin-Containing Products: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor

Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Brexpiprazole. Risk C: Monitor

Brigatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Risk D: Consider Therapy Modification

Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Brivaracetam: PHENobarbital may decrease serum concentration of Brivaracetam. Risk C: Monitor

Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Buclizine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Buclizine. Risk C: Monitor

Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Buprenorphine: PHENobarbital may increase CNS depressant effects of Buprenorphine. PHENobarbital may decrease serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

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

BusPIRone: CYP3A4 Inducers (Moderate) may decrease serum concentration of BusPIRone. Risk C: Monitor

BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

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

Cabozantinib: Phenobarbital-Primidone may decrease serum concentration of Cabozantinib. Management: For cabozantinib tablets (Cabometyx), avoid combined use if possible. If combined, increase cabozantinib by 20 mg from previous dose, max 80 mg daily. For cabozantinib capsules (Cometriq), monitor for reduced cabozantinib efficacy if combined. Risk D: Consider Therapy Modification

Calcifediol: Phenobarbital-Primidone may decrease serum concentration of Calcifediol. Risk X: Avoid

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

Canagliflozin: PHENobarbital may decrease 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: Phenobarbital-Primidone may decrease serum concentration of Cannabidiol. Cannabidiol may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor

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

Capivasertib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Capivasertib. Risk X: Avoid

Capmatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Capmatinib. Risk X: Avoid

CarBAMazepine: CYP3A4 Inducers (Moderate) may decrease serum concentration of CarBAMazepine. Risk C: Monitor

Cariprazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cariprazine. Risk X: Avoid

Carmustine: PHENobarbital may decrease serum concentration of Carmustine. Management: Consider alternatives to phenobarbital when using carmustine. If combined, monitor for reduced carmustine efficacy. Risk D: Consider Therapy Modification

Cenobamate: May increase CNS depressant effects of Phenobarbital-Primidone. Cenobamate may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor

Ceritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ceritinib. Risk C: Monitor

Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification

Charcoal, Activated: May decrease serum concentration of PHENobarbital. Risk C: Monitor

Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification

Chloramphenicol (Systemic): PHENobarbital may decrease serum concentration of Chloramphenicol (Systemic). Chloramphenicol (Systemic) may increase serum concentration of PHENobarbital. Risk C: Monitor

Chlormethiazole: May increase CNS depressant effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

Chlorprothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Chlorprothixene. Risk C: Monitor

Cholestyramine Resin: May decrease serum concentration of PHENobarbital. Management: Administer phenobarbital at least 1 hour before or 4 to 6 hours after administration of cholestyramine in order to minimize the risk for any significant interaction. Risk D: Consider Therapy Modification

Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid

Clarithromycin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Clarithromycin. CYP3A4 Inducers (Moderate) may increase active metabolite exposure 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 impair its efficacy. Risk D: Consider Therapy Modification

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

CloBAZam: Phenobarbital-Primidone may increase CNS depressant effects of CloBAZam. Phenobarbital-Primidone may decrease serum concentration of CloBAZam. Risk C: Monitor

CloZAPine: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider Therapy Modification

Cobicistat: PHENobarbital may decrease serum concentration of Cobicistat. Risk X: Avoid

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cobimetinib. Risk X: Avoid

Codeine: PHENobarbital may increase CNS depressant effects of Codeine. PHENobarbital may decrease serum concentration of Codeine. Management: Avoid use of codeine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

Copanlisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Copanlisib. Risk C: Monitor

Crinecerfont: CYP3A4 Inducers (Moderate) may decrease serum concentration of Crinecerfont. Management: Double the evening dose of crinecerfont and continue the morning dose unchanged during coadministration with moderate CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider Therapy Modification

Crizotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Crizotinib. Risk C: Monitor

Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

CycloPHOSphamide: PHENobarbital may increase active metabolite exposure of CycloPHOSphamide. More specifically, phenobarbital may increase the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. PHENobarbital may decrease serum concentration of CycloPHOSphamide. Risk C: Monitor

CycloSPORINE (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of CycloSPORINE (Systemic). Risk C: Monitor

CYP2C19 Inducers (Moderate): May decrease serum concentration of PHENobarbital. Risk C: Monitor

CYP2C19 Inducers (Strong): May decrease serum concentration of PHENobarbital. Risk C: Monitor

CYP2C19 Inhibitors (Moderate): May increase serum concentration of PHENobarbital. Risk C: Monitor

CYP2C19 Inhibitors (Strong): May increase serum concentration of PHENobarbital. Risk C: Monitor

CYP2C9 Inhibitors (Moderate): May increase serum concentration of PHENobarbital. Risk C: Monitor

CYP2E1 Inhibitors (Moderate): May increase serum concentration of PHENobarbital. Risk C: Monitor

Dabigatran Etexilate: PHENobarbital may decrease serum concentration of Dabigatran Etexilate. Risk C: Monitor

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Risk D: Consider Therapy Modification

Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dapsone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Dapsone (Systemic). Risk C: Monitor

Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor

Daridorexant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Daridorexant. Risk X: Avoid

Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor

Darunavir: May decrease serum concentration of PHENobarbital. Risk C: Monitor

Dasabuvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dasabuvir. Risk X: Avoid

Dasatinib: CYP3A4 Inducers (Moderate) may increase serum concentration of Dasatinib. Risk C: Monitor

Deferasirox: UGT1A1 Inducers may decrease serum concentration of Deferasirox. Management: Avoid concomitant use of deferasirox and UGT1A1 inducers when possible. If combined, consider a 50% increase in the initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical response to guide further dosing. Risk D: Consider Therapy Modification

Deflazacort: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Deflazacort. Risk X: Avoid

Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor

DexAMETHasone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of DexAMETHasone (Systemic). Risk C: Monitor

DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification

Dexmethylphenidate: May increase serum concentration of PHENobarbital. Risk C: Monitor

DiazePAM: CYP3A4 Inducers (Moderate) may decrease serum concentration of DiazePAM. Risk C: Monitor

Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. Risk C: Monitor

Dienogest: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dienogest. Risk C: Monitor

Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor

DilTIAZem: CYP3A4 Inducers (Moderate) may decrease serum concentration of DilTIAZem. Risk C: Monitor

Dimethindene (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dimethindene (Systemic). Risk C: Monitor

Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Disopyramide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Disopyramide. Risk C: Monitor

Disulfiram: May increase adverse/toxic effects of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid

Dolutegravir: PHENobarbital may decrease serum concentration of Dolutegravir. Risk X: Avoid

Doravirine: Phenobarbital-Primidone may decrease serum concentration of Doravirine. Risk X: Avoid

Doxercalciferol: Phenobarbital-Primidone may increase active metabolite exposure of Doxercalciferol. Risk C: Monitor

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

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

Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor

DroNABinol: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of DroNABinol. Risk X: Avoid

Dronedarone: Phenobarbital-Primidone may decrease serum concentration of Dronedarone. Risk C: Monitor

DroPERidol: May increase CNS depressant effects 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 (Moderate) may decrease serum concentration of Duvelisib. Management: Avoid if possible. If used, on day 12 of combination increase duvelisib from 25 mg twice daily to 40 mg twice daily or from 15 mg twice daily to 25 mg twice daily. Resume prior duvelisib dose 14 days after stopping moderate CYP3A4 inducer. Risk D: Consider Therapy Modification

Dydrogesterone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dydrogesterone. Risk C: Monitor

Efavirenz: CYP3A4 Inducers (Moderate) may decrease serum concentration of Efavirenz. Risk C: Monitor

Elacestrant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elacestrant. Risk X: Avoid

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

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk C: Monitor

Elexacaftor, Tezacaftor, and Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk C: Monitor

Eliglustat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Eliglustat. Risk C: Monitor

Eluxadoline: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Eluxadoline. Risk X: Avoid

Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor

Encorafenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Encorafenib. Risk C: Monitor

Ensartinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ensartinib. Risk X: Avoid

Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Entrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Entrectinib. Risk X: Avoid

Enzalutamide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Enzalutamide. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Enzalutamide. Risk C: Monitor

EPHEDrine (Systemic): Atropine (Systemic) may increase therapeutic effects of EPHEDrine (Systemic). Risk C: Monitor

Erdafitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Erdafitinib. Management: If a moderate CYP3A4 inducer must be used at the start of erdafitinib, administer erdafitinib at a dose of 9 mg daily. If a moderate CYP3A4 inducer is discontinued, continue erdafitinib at the same dose unless there is evidence of drug toxicity. Risk D: Consider Therapy Modification

Erlotinib: CYP3A4 Inducers (Moderate) may decrease 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

Esketamine (Injection): Phenobarbital-Primidone may decrease serum concentration of Esketamine (Injection). Risk C: Monitor

Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Eslicarbazepine: PHENobarbital may decrease serum concentration of Eslicarbazepine. Risk C: Monitor

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

Ethosuximide: Phenobarbital-Primidone may decrease serum concentration of Ethosuximide. Risk C: Monitor

Etoposide Phosphate: CYP3A4 Inducers (Moderate) may decrease serum concentration of Etoposide Phosphate. Risk C: Monitor

Etoposide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Etoposide. Risk C: Monitor

Etravirine: Phenobarbital-Primidone may decrease serum concentration of Etravirine. Risk X: Avoid

Everolimus: CYP3A4 Inducers (Moderate) may decrease serum concentration of Everolimus. Risk C: Monitor

Exemestane: CYP3A4 Inducers (Moderate) may decrease serum concentration of Exemestane. Risk C: Monitor

Fedratinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fedratinib. Risk X: Avoid

Felbamate: PHENobarbital may decrease serum concentration of Felbamate. Felbamate may increase serum concentration of PHENobarbital. 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 phenobarbital dose by 20%. Risk D: Consider Therapy Modification

Felodipine: Phenobarbital-Primidone may decrease serum concentration of Felodipine. Risk C: Monitor

Fenoprofen: PHENobarbital may decrease serum concentration of Fenoprofen. Risk C: Monitor

FentaNYL: PHENobarbital may increase CNS depressant effects of FentaNYL. PHENobarbital may decrease serum concentration of FentaNYL. Management: Avoid use of fentanyl and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. Risk C: Monitor

Fexinidazole: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Fexinidazole. Risk X: Avoid

Finerenone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Finerenone. Risk X: Avoid

Flibanserin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Flibanserin. Risk X: Avoid

Fludrocortisone: Phenobarbital-Primidone may decrease serum concentration of Fludrocortisone. Risk C: Monitor

Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid

Flunitrazepam: CNS Depressants may increase CNS depressant effects 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

FluPHENAZine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Folic Acid: May decrease serum concentration of PHENobarbital. Risk C: Monitor

Fosamprenavir: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fosamprenavir. Risk C: Monitor

Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Risk C: Monitor

Fosnetupitant: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fosnetupitant. Risk C: Monitor

Fosphenytoin-Phenytoin: May increase CNS depressant effects of Phenobarbital-Primidone. Phenobarbital-Primidone may decrease serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor

Fostamatinib: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fostamatinib. Risk C: Monitor

Fruquintinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fruquintinib. Management: Avoid this combination when possible. If combined, continue the same fruquintinib dose, but monitor for reduced fruquintinib efficacy. Risk D: Consider Therapy Modification

Ganaxolone: May increase CNS depressant effects of Phenobarbital-Primidone. Phenobarbital-Primidone may decrease serum concentration of Ganaxolone. Management: Avoid this combination if possible. In patients stabilized on ganaxolone who initiate or dose escalate phenobarbital or primidone the ganaxolone dose may need to be increased, but should not exceed the maximum recommended daily dose. Risk D: Consider Therapy Modification

Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor

Gefitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gefitinib. Risk C: Monitor

Gemigliptin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gemigliptin. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Gemigliptin. Risk C: Monitor

Gepirone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gepirone. Risk C: Monitor

Gepotidacin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gepotidacin. Risk C: Monitor

Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Gestrinone: PHENobarbital may decrease serum concentration of Gestrinone. Risk C: Monitor

Glasdegib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Risk D: Consider Therapy Modification

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

Glucagon: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor

Glycopyrrolate (Oral Inhalation): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Oral Inhalation). Risk X: Avoid

Glycopyrrolate (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Systemic). Risk C: Monitor

Glycopyrronium (Topical): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

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

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease 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: Phenobarbital-Primidone may decrease serum concentration of Haloperidol. Risk C: Monitor

Hemin: Barbiturates may decrease therapeutic effects of Hemin. Risk X: Avoid

Hormonal Contraceptives: CYP3A4 Inducers (Moderate) may decrease 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 moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider Therapy Modification

HYDROcodone: PHENobarbital may increase CNS depressant effects of HYDROcodone. PHENobarbital may decrease serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

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

HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification

Ibrexafungerp: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ibrexafungerp. Risk X: Avoid

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ibrutinib. Risk C: Monitor

Idelalisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Idelalisib. Risk C: Monitor

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Ifosfamide. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Ifosfamide. Risk C: Monitor

Imatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Imatinib. Risk C: Monitor

Indinavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and moderate 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

Ipratropium (Nasal): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Ipratropium (Oral Inhalation): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Irinotecan Products: Phenobarbital-Primidone may decrease serum concentration of Irinotecan Products. Management: Avoid administration of phenobarbital or primidone during irinotecan treatment, and substitute non-CYP3A4 inducing agents at least 2 weeks prior to irinotecan initiation, whenever possible. If combined, monitor closely for reduced irinotecan efficacy. Risk D: Consider Therapy Modification

Isavuconazonium Sulfate: Phenobarbital-Primidone may decrease active metabolite exposure of Isavuconazonium Sulfate. Specifically, isavuconazole serum concentrations may be reduced. Risk X: Avoid

Isradipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Isradipine. Risk C: Monitor

Istradefylline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Istradefylline. Risk C: Monitor

Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor

Itraconazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Itraconazole. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Itraconazole. Risk C: Monitor

Ivabradine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ivabradine. Risk X: Avoid

Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Ivacaftor. Risk C: Monitor

Ixabepilone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ixabepilone. Risk C: Monitor

Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ixazomib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ixazomib. Risk C: Monitor

Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ketamine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ketamine. Risk C: Monitor

Ketoconazole (Systemic): Hyoscyamine may decrease serum concentration of Ketoconazole (Systemic). Management: Take hyoscyamine at least 2 hours after ingestion of ketoconazole. Monitor for decreased therapeutic effects of ketoconazole if used together with hyoscyamine. Risk D: Consider Therapy Modification

Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Lacosamide: May increase CNS depressant effects of PHENobarbital. PHENobarbital may decrease serum concentration of Lacosamide. Risk C: Monitor

LamoTRIgine: May increase adverse/toxic effects of Phenobarbital-Primidone. Specifically, the risk for hematologic toxicities may be increased. Phenobarbital-Primidone may decrease serum concentration of LamoTRIgine. Management: For patients taking primidone or phenobarbital 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 (Moderate) may decrease serum concentration of Lapatinib. Risk C: Monitor

Larotrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Larotrectinib. Management: Double the larotrectinib dose if used together with a moderate CYP3A4 inducer. Following discontinuation of the moderate CYP3A4 inducer, resume the previous dose of larotrectinib after a period of 3 to 5 times the inducer's half-life. Risk D: Consider Therapy Modification

Lazertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lazertinib. Risk X: Avoid

Ledipasvir: PHENobarbital may decrease serum concentration of Ledipasvir. Risk X: Avoid

Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification

Lefamulin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification

Lemborexant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lemborexant. Risk X: Avoid

Lenacapavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lenacapavir. Risk X: Avoid

Leniolisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Leniolisib. Risk X: Avoid

Lercanidipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lercanidipine. Risk C: Monitor

Letermovir: UGT1A1 Inducers may decrease serum concentration of Letermovir. Risk X: Avoid

Leucovorin Calcium-Levoleucovorin: May decrease serum concentration of PHENobarbital. Risk C: Monitor

Levamlodipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Levamlodipine. Risk C: Monitor

LevETIRAcetam: May increase CNS depressant effects of PHENobarbital. PHENobarbital may decrease serum concentration of LevETIRAcetam. Risk C: Monitor

Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Levoketoconazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Levoketoconazole. Risk C: Monitor

Levomethadone: PHENobarbital may increase CNS depressant effects of Levomethadone. PHENobarbital may decrease serum concentration of Levomethadone. Management: Avoid concomitant use of levomethadone and phenobarbital 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): Phenobarbital-Primidone may decrease therapeutic effects of Levonorgestrel (IUD). Phenobarbital-Primidone may decrease serum concentration of Levonorgestrel (IUD). Risk C: Monitor

Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid

Lidocaine (Systemic): Phenobarbital-Primidone may decrease serum concentration of Lidocaine (Systemic). Risk C: Monitor

LinaGLIPtin: CYP3A4 Inducers (Moderate) may decrease serum concentration of LinaGLIPtin. Risk C: Monitor

Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor

Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Lonafarnib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lonafarnib. Risk X: Avoid

Lopinavir: PHENobarbital may decrease serum concentration of Lopinavir. Management: Increased doses of lopinavir may be necessary when using these agents in combination. Do not use a once daily lopinavir/ritonavir regimen together with phenobarbital. Increase monitoring of therapeutic response in all patients using this combination. Risk D: Consider Therapy Modification

Lorlatinib: CYP3A4 Inducers (Moderate) may increase hepatotoxic effects of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, increase lorlatinib to 125 mg daily. Monitor for reduced lorlatinib efficacy and consider closer monitoring of AST, ALT, and bilirubin. Risk D: Consider Therapy Modification

Lovastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lovastatin. Risk C: Monitor

Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification

Lumacaftor and Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Lumacaftor and Ivacaftor. Risk C: Monitor

Lumateperone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lumateperone. Risk X: Avoid

Lurasidone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lurasidone. Management: After chronic treatment (7 days or more) with a moderate CYP3A4 inducer, lurasidone dose increases may be needed. Monitor closely for decreased lurasidone effects and increase the lurasidone dose as needed. Risk D: Consider Therapy Modification

Macimorelin: Coadministration of Atropine (Systemic) and Macimorelin may alter diagnostic results. Risk X: Avoid

Macitentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Macitentan. Risk C: Monitor

Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Maprotiline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Maprotiline. Risk C: Monitor

Maraviroc: CYP3A4 Inducers (Moderate) may decrease 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: PHENobarbital may decrease serum concentration of Maribavir. Management: Increase the dose of maribavir to 1,200 mg twice daily with concomitant use of phenobarbital. Risk D: Consider Therapy Modification

Mavacamten: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mavacamten. Risk X: Avoid

Mavorixafor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mavorixafor. Risk C: Monitor

Mefloquine: May decrease therapeutic effects of PHENobarbital. PHENobarbital may decrease serum concentration of Mefloquine. Mefloquine may decrease serum concentration of PHENobarbital. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If phenobarbital is being used for another indication, monitor for decreased concentrations and efficacy of both phenobarbital and mefloquine. Risk D: Consider Therapy Modification

Melperone: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Meperidine: PHENobarbital may increase CNS depressant effects of Meperidine. PHENobarbital may increase active metabolite exposure of Meperidine. Management: Avoid concomitant use of meperidine and phenobarbital 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

Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Methadone: PHENobarbital may increase CNS depressant effects of Methadone. PHENobarbital may decrease serum concentration of Methadone. Management: Avoid concomitant use of methadone and phenobarbital 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: May increase CNS depressant effects of Products Containing Ethanol. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid

Methoxyflurane: Barbiturates may increase nephrotoxic effects of Methoxyflurane. Barbiturates may increase metabolism of Methoxyflurane. Risk X: Avoid

Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor

Methylphenidate: May increase serum concentration of PHENobarbital. Risk C: Monitor

MethylPREDNISolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of MethylPREDNISolone. Risk C: Monitor

Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

MetroNIDAZOLE (Systemic): May increase adverse/toxic effects of PHENobarbital. A disulfiram-like reaction may occur if combined with phenobarbital dosage forms that contain propylene glycol or alcohol. PHENobarbital may decrease serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor

MetroNIDAZOLE (Topical): May increase adverse/toxic effects of Products Containing Ethanol. A disulfiram-like reaction may occur. Risk C: Monitor

MetyraPONE: Coadministration of Antiseizure Agents and MetyraPONE may alter diagnostic results. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider Therapy Modification

MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor

Mianserin: May increase CNS depressant effects of Barbiturates. Mianserin may decrease therapeutic effects of Barbiturates. Barbiturates may decrease serum concentration of Mianserin. Risk X: Avoid

Midazolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of Midazolam. Risk C: Monitor

Midostaurin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Midostaurin. Risk C: Monitor

MiFEPRIStone: CYP3A4 Inducers (Moderate) may decrease serum concentration of MiFEPRIStone. Management: Avoid combined use in patients treated for Cushing's disease. When used for pregnancy termination, mifepristone efficacy may be reduced and an alternative pregnancy termination procedure may be warranted. Ensure a follow-up assessment after combined use. Risk D: Consider Therapy Modification

Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Mirabegron: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Mirabegron. Risk C: Monitor

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mirodenafil. Risk C: Monitor

Mitapivat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mitapivat. Management: Consider alternatives to this combination when possible. If combined, monitor hemoglobin and titrate mitapivat beyond 50 mg twice daily, if needed, but do not exceed doses of 100 mg twice daily. Risk D: Consider Therapy Modification

Mobocertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mobocertinib. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Mobocertinib. Risk X: Avoid

Montelukast: Phenobarbital-Primidone may decrease serum concentration of Montelukast. Risk C: Monitor

Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

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

Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Naldemedine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Naldemedine. Risk C: Monitor

Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Naloxegol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Naloxegol. Risk C: Monitor

Nelfinavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nelfinavir. Risk C: Monitor

Neratinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Neratinib. Risk X: Avoid

Netupitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Netupitant. Risk C: Monitor

Nevirapine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nevirapine. Risk C: Monitor

NIFEdipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of NIFEdipine. Risk C: Monitor

Nilotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nilotinib. Risk C: Monitor

Nilvadipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nilvadipine. Risk C: Monitor

NiMODipine: Phenobarbital-Primidone may decrease serum concentration of NiMODipine. Risk X: Avoid

Nirmatrelvir and Ritonavir: May decrease serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of Nirmatrelvir and Ritonavir. Risk X: Avoid

Nirogacestat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nirogacestat. Risk X: Avoid

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nisoldipine. Risk X: Avoid

Nitric Oxide: May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor

Nitroglycerin: Agents with Clinically Relevant Anticholinergic Effects may decrease absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor

Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid

OLANZapine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OLANZapine. Risk C: Monitor

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

Olaparib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olaparib. Risk X: Avoid

Olmutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olmutinib. Risk C: Monitor

Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Olutasidenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olutasidenib. Risk X: Avoid

Omaveloxolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Omaveloxolone. Risk X: Avoid

Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Opioid Agonists: CNS Depressants may increase CNS depressant effects 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

Opipramol: Antiseizure Agents may decrease serum concentration of Opipramol. Risk C: Monitor

Opipramol: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

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

Ornidazole: PHENobarbital may decrease serum concentration of Ornidazole. Risk C: Monitor

Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid

Osimertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Osimertinib. Risk C: Monitor

Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

OXcarbazepine: Phenobarbital-Primidone may decrease serum concentration of OXcarbazepine. Risk C: Monitor

Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Oxybate Salt Products: Barbiturates may increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid

OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor

OxyCODONE: PHENobarbital may increase CNS depressant effects of OxyCODONE. PHENobarbital may decrease serum concentration of OxyCODONE. Management: Avoid use of oxycodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

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

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

Pacritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pacritinib. Risk C: Monitor

Palbociclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Palbociclib. Risk C: Monitor

Paliperidone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Paliperidone. Risk C: Monitor

Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Palovarotene: CYP3A4 Inducers (Moderate) may decrease serum concentration of Palovarotene. Risk X: Avoid

Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid

PAZOPanib: CYP3A4 Inducers (Moderate) may decrease serum concentration of PAZOPanib. Risk C: Monitor

Pemigatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pemigatinib. Risk X: Avoid

Perampanel: CYP3A4 Inducers (Moderate) may decrease serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with moderate 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

Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Perphenazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Perphenazine. Risk C: Monitor

Pimavanserin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pimavanserin. Risk X: Avoid

Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

Piperaquine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Piperaquine. Risk C: Monitor

Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor

Pirtobrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pirtobrutinib. Management: Avoid concomitant use if possible. If combined, if the current pirtobrutinib dose is 200 mg once daily, increase to 300 mg once daily. If current pirtobrutinib dose is 50 mg or 100 mg once daily, increase the dose by 50 mg. Risk D: Consider Therapy Modification

Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

PONATinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of PONATinib. Risk C: Monitor

Potassium Chloride: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid

Potassium Citrate: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid

Pralsetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pralsetinib. Management: If this combo cannot be avoided, increase pralsetinib dose from 400 mg daily to 600 mg daily; from 300 mg daily to 500 mg daily; and from 200 mg daily to 300 mg daily. Risk D: Consider Therapy Modification

Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor

Pramlintide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. These effects are specific to the GI tract. Risk X: Avoid

Praziquantel: CYP3A4 Inducers (Moderate) may decrease serum concentration of Praziquantel. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for reduced praziquantel efficacy. If possible, stop the moderate CYP3A4 inducer 2 to 4 weeks before praziquantel initiation. Risk D: Consider Therapy Modification

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

PredniSONE: CYP3A4 Inducers (Moderate) may decrease serum concentration of PredniSONE. Risk C: Monitor

Pretomanid: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pretomanid. Risk X: Avoid

Prilocaine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor

Primaquine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Primaquine. Specifically, the risk for methemoglobinemia may be increased. Management: Avoid concomitant use of primaquine and other drugs that are associated with methemoglobinemia when possible. If combined, monitor methemoglobin levels closely. Risk D: Consider Therapy Modification

Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Promethazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Promethazine. Risk C: Monitor

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

Propantheline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Propantheline. Risk C: Monitor

Propiverine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Pyridoxine: May decrease serum concentration of PHENobarbital. Risk C: Monitor

Pyrimethamine: Phenobarbital-Primidone may decrease serum concentration of Pyrimethamine. Risk C: Monitor

QUEtiapine: CYP3A4 Inducers (Moderate) may decrease serum concentration of QUEtiapine. Risk C: Monitor

QuiNIDine: CYP3A4 Inducers (Moderate) may decrease serum concentration of QuiNIDine. Risk C: Monitor

QuiNIDine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

QuiNINE: May increase serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of QuiNINE. Management: Consider alternatives to this combination when possible. If coadministration of phenobarbital and quinine cannot be avoided, monitor for reduced quinine efficacy and for increased phenobarbital serum concentrations and toxicities. Risk D: Consider Therapy Modification

Quizartinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Quizartinib. Risk X: Avoid

Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor

Ranolazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ranolazine. Risk X: Avoid

Reboxetine: Phenobarbital-Primidone may decrease serum concentration of Reboxetine. Risk C: Monitor

Regorafenib: Phenobarbital-Primidone may decrease serum concentration of Regorafenib. Phenobarbital-Primidone may increase active metabolite exposure of Regorafenib. Risk C: Monitor

Repaglinide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Repaglinide. Risk C: Monitor

Repotrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Repotrectinib. Risk X: Avoid

Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid

Revumenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Revumenib. Risk X: Avoid

Ribociclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ribociclib. Risk C: Monitor

Rifapentine: May decrease serum concentration of PHENobarbital. Risk C: Monitor

Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Rilpivirine: PHENobarbital may decrease serum concentration of Rilpivirine. Risk X: Avoid

Rimegepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Rimegepant. Risk X: Avoid

Ripretinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ripretinib. Management: Avoid this combination if possible. If concomitant use is required, increase ripretinib to 150 mg twice daily. Decrease ripretinib to 150 mg once daily 14 days after stopping a moderate CYP3A4 inducer. Monitor patients for ripretinib response and toxicity Risk D: Consider Therapy Modification

RisperiDONE: CYP3A4 Inducers (Moderate) may decrease serum concentration of RisperiDONE. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of RisperiDONE. Risk C: Monitor

Ritlecitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ritlecitinib. Risk C: Monitor

Ritodrine: Atropine (Systemic) may increase adverse/toxic effects of Ritodrine. Risk C: Monitor

Ritonavir: May decrease serum concentration of PHENobarbital. PHENobarbital may decrease 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: Phenobarbital-Primidone may decrease serum concentration of Rivaroxaban. Risk C: Monitor

Rivastigmine: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Rivastigmine. Rivastigmine may decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider Therapy Modification

Roflumilast (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Roflumilast (Systemic). CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Roflumilast (Systemic). Risk C: Monitor

Roflumilast (Systemic): Phenobarbital-Primidone may decrease serum concentration of Roflumilast (Systemic). Risk C: Monitor

Rolapitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Rolapitant. Risk C: Monitor

Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects 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 increase sedative effects of ROPINIRole. Risk C: Monitor

Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor

Rufinamide: May increase serum concentration of PHENobarbital. PHENobarbital may decrease serum concentration of Rufinamide. Risk C: Monitor

Sacituzumab Govitecan: UGT1A1 Inducers may decrease active metabolite exposure of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be decreased. Risk X: Avoid

Samidorphan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Samidorphan. Risk C: Monitor

Sapropterin: PHENobarbital may decrease serum concentration of Sapropterin. Specifically, phenobarbital may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor

Saquinavir: PHENobarbital may decrease serum concentration of Saquinavir. Risk X: Avoid

Secnidazole: Products Containing Ethanol may increase adverse/toxic effects of Secnidazole. Risk X: Avoid

Secretin: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider Therapy Modification

Selpercatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Selpercatinib. Risk X: Avoid

Selumetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Selumetinib. Risk X: Avoid

Sertraline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sertraline. Risk C: Monitor

Sildenafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sildenafil. Risk C: Monitor

Simeprevir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Simeprevir. Risk X: Avoid

Simvastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Simvastatin. Risk C: Monitor

Sincalide: Drugs that Affect Gallbladder Function may decrease therapeutic effects of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider Therapy Modification

Sirolimus (Conventional): CYP3A4 Inducers (Moderate) may decrease serum concentration of Sirolimus (Conventional). Risk C: Monitor

Sirolimus (Protein Bound): CYP3A4 Inducers (Moderate) may decrease serum concentration of Sirolimus (Protein Bound). Risk C: Monitor

Sodium Nitrite: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor

Sofosbuvir: PHENobarbital may decrease serum concentration of Sofosbuvir. Risk X: Avoid

Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid

Sonidegib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sonidegib. Risk X: Avoid

SORAfenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of SORAfenib. Risk C: Monitor

Sotorasib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sotorasib. Risk C: Monitor

Sparsentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sparsentan. Risk C: Monitor

Stiripentol: Phenobarbital-Primidone may decrease serum concentration of Stiripentol. Stiripentol may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor

SUFentanil: PHENobarbital may increase CNS depressant effects of SUFentanil. PHENobarbital may decrease serum concentration of SUFentanil. Management: Avoid use of sufentanil and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased sufentanil efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

Sulthiame: May increase adverse/toxic effects of PHENobarbital. Risk C: Monitor

SUNItinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of SUNItinib. Risk C: Monitor

Suvorexant: CNS Depressants may increase CNS depressant effects 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

Suzetrigine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Suzetrigine. Risk X: Avoid

Tacrolimus (Systemic): Phenobarbital-Primidone may decrease serum concentration of Tacrolimus (Systemic). Risk C: Monitor

Tadalafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tadalafil. Risk C: Monitor

Tamoxifen: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tamoxifen. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Tamoxifen. Risk C: Monitor

Tasimelteon: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tasimelteon. Risk C: Monitor

Tazemetostat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tazemetostat. Risk X: Avoid

Temsirolimus: CYP3A4 Inducers (Moderate) may decrease serum concentration of Temsirolimus. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Temsirolimus. Specifically, sirolimus concentrations may be decreased. Risk C: Monitor

Teniposide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Teniposide. Risk C: Monitor

Tenofovir Alafenamide: PHENobarbital may decrease serum concentration of Tenofovir Alafenamide. Risk X: Avoid

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor

Tetrahydrocannabinol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tetrahydrocannabinol. Risk C: Monitor

Tezacaftor and Ivacaftor: Phenobarbital-Primidone may decrease serum concentration of Tezacaftor and Ivacaftor. Risk C: Monitor

Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid

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

Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor

Thiotepa: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Thiotepa. CYP3A4 Inducers (Moderate) may decrease serum concentration of Thiotepa. Risk C: Monitor

Thiothixene: PHENobarbital may decrease serum concentration of Thiothixene. Risk C: Monitor

Thyroid Products: PHENobarbital may decrease serum concentration of Thyroid Products. Risk C: Monitor

TiaGABine: Phenobarbital-Primidone may decrease serum concentration of TiaGABine. Risk C: Monitor

Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor

Ticagrelor: Phenobarbital-Primidone may decrease serum concentration of Ticagrelor. Risk C: Monitor

Timolol (Systemic): PHENobarbital may increase hypotensive effects of Timolol (Systemic). PHENobarbital may decrease serum concentration of Timolol (Systemic). Risk C: Monitor

Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid

Tipranavir: PHENobarbital may decrease serum concentration of Tipranavir. Tipranavir may decrease serum concentration of PHENobarbital. Risk C: Monitor

Tivozanib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tivozanib. Risk C: Monitor

Tofacitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tofacitinib. Risk C: Monitor

Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor

Tolvaptan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tolvaptan. Risk C: Monitor

Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. Risk C: Monitor

Toremifene: Phenobarbital-Primidone may decrease serum concentration of Toremifene. Risk C: Monitor

Trabectedin: Phenobarbital-Primidone may decrease serum concentration of Trabectedin. Risk C: Monitor

TraMADol: PHENobarbital may increase CNS depressant effects of TraMADol. PHENobarbital may decrease serum concentration of TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

TraZODone: CYP3A4 Inducers (Moderate) may decrease serum concentration of TraZODone. Risk C: Monitor

Tretinoin (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Tretinoin (Systemic). Risk C: Monitor

Triazolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of Triazolam. Risk C: Monitor

Tricyclic Antidepressants: Barbiturates may increase 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Trimethobenzamide: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trimethobenzamide. Risk C: Monitor

Tropisetron: Phenobarbital-Primidone may decrease serum concentration of Tropisetron. Risk C: Monitor

Trospium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trospium. Risk C: Monitor

Tucatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tucatinib. Risk C: Monitor

Ubrogepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Risk D: Consider Therapy Modification

Ulipristal: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ulipristal. Risk X: Avoid

Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Upadacitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Upadacitinib. Risk C: Monitor

Valbenazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Valbenazine. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Valbenazine. Risk C: Monitor

Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Valproic Acid and Derivatives: May increase CNS depressant effects of Barbiturates. Valproic Acid and Derivatives may increase serum concentration of Barbiturates. Barbiturates may decrease serum concentration of Valproic Acid and Derivatives. Risk C: Monitor

Vandetanib: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Vandetanib. CYP3A4 Inducers (Moderate) may decrease serum concentration of Vandetanib. Risk C: Monitor

Vanzacaftor, Tezacaftor, and Deutivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Risk X: Avoid

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Velpatasvir. Risk X: Avoid

Vemurafenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vemurafenib. Risk C: Monitor

Venetoclax: CYP3A4 Inducers (Moderate) may decrease serum concentration of Venetoclax. Risk X: Avoid

Verapamil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Verapamil. Risk C: Monitor

Vilazodone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vilazodone. Risk C: Monitor

VinCRIStine: CYP3A4 Inducers (Moderate) may decrease serum concentration of VinCRIStine. Risk C: Monitor

Vitamin K Antagonists: Barbiturates may increase 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 (Moderate) may decrease serum concentration of Voclosporin. Risk X: Avoid

Vonoprazan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vonoprazan. Risk X: Avoid

Vorapaxar: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vorapaxar. Risk X: Avoid

Voriconazole: PHENobarbital may decrease serum concentration of Voriconazole. Risk X: Avoid

Vortioxetine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vortioxetine. Risk C: Monitor

Voxelotor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,000 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 (Moderate) may decrease serum concentration of Voxilaprevir. Risk X: Avoid

Zaleplon: Phenobarbital-Primidone may decrease serum concentration of Zaleplon. Risk C: Monitor

Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zanubrutinib. Management: Avoid this combination if possible. If coadministration of zanubrutinib and a moderate CYP3A4 inducer is required, increase the zanubrutinib dose to 320 mg twice daily. Risk D: Consider Therapy Modification

Zolpidem: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects of PHENobarbital. PHENobarbital may decrease serum concentration of Zonisamide. Risk C: Monitor

Zopiclone: PHENobarbital may increase CNS depressant effects of Zopiclone. PHENobarbital may decrease serum concentration of Zopiclone. Risk C: Monitor

Zuclopenthixol: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor

Zuranolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zuranolone. Risk X: Avoid

Pregnancy Considerations

Reproduction studies with this combination have not been done; refer to individual monographs.

Breastfeeding Considerations

The manufacturer recommends that caution be exercised when administering this combination to breastfeeding women. Also see individual agents.

Mechanism of Action

Anticholinergic agents (hyoscyamine, atropine, and scopolamine) inhibit the muscarinic actions of acetylcholine at the postganglionic parasympathetic neuroeffector sites including smooth muscle, secretory glands, and CNS sites; specific anticholinergic responses are dose-related.

Pharmacokinetics (Adult Data Unless Noted)

Absorption: Well absorbed from the GI tract

خرید پکیج

Hyoscyamine, atropine, scopolamine, and phenobarbital: Drug information