Version July 2025
Note: Safety and efficacy for the use of cough and cold products in infants and young children is limited; the AAP warns against the use of these products for respiratory illnesses in infants and young children; the FDA does not recommend OTC use in infants and children <2 years of age due to the risk of serious and life-threatening adverse effects (including death) and recommends to use with caution in pediatric patients ≥2 years of age (Ref).
Cold and flu symptoms:
Note: When calculating the maximum daily dose, consider all sources of acetaminophen (prescription and OTC) and all routes of administration. Do not exceed the maximum recommended daily dose. Multiple formulations of tablet strengths and oral liquid concentrations exist; pay close attention to the concentration/strength when ordering or administering.
Caplet:
Acetaminophen 325 mg/diphenhydramine 12.5 mg/phenylephrine 5 mg per caplet (eg, Theraflu ExpressMax Nighttime Severe Cold and Cough): Children ≥12 years and Adolescents: Oral: 2 caplets every 4 hours as needed; maximum daily dose: 10 caplets per 24 hours.
Acetaminophen 650 mg/diphenhydramine 25 mg/phenylephrine 10 mg per caplet (eg, One Tab Cold & Flu):
Children 6 to <12 years: Oral: 1/2 caplet every 4 hours as needed; maximum daily dose: 5 doses (2.5 caplets) per 24 hours.
Children ≥12 years and Adolescents: Oral: 1 caplet every 4 hours as needed; maximum daily dose: 6 doses (6 caplets) per 24 hours.
Liquid:
Acetaminophen 325 mg/diphenhydramine 12.5 mg/phenylephrine 5 mg per 10 mL (eg, Delsym Cough Plus Cold Night Time, Children's Mucinex Night Time Multi-Symptom Cold, Mucinex Sinus-Max Night Time Congestion & Cough):
Children 6 to <12 years: Oral: 10 mL every 4 hours as needed; maximum daily dose: 5 doses (50 mL) per 24 hours.
Children ≥12 years and Adolescents: Oral: 20 mL every 4 hours as needed; maximum daily dose: 6 doses (120 mL) per 24 hours.
Acetaminophen 650 mg/diphenhydramine 25 mg/phenylephrine 10 mg per 30 mL (eg, Theraflu ExpressMax Flu Cough and Sore Throat): Children ≥12 years and Adolescents: Oral: 30 mL every 4 hours as needed; maximum dose: 5 doses (150 mL) per 24 hours.
Powder for oral solution:
Acetaminophen 500 mg/diphenhydramine 25 mg/phenylephrine 10 mg per packet (eg, Theraflu Nighttime Multi-Symptom Severe Cold Powder): Children ≥12 years and Adolescents: Oral: 1 packet diluted in water every 4 hours as needed; maximum daily dose: 6 packets per 24 hours.
Acetaminophen 650 mg/diphenhydramine 25 mg/phenylephrine 10 mg per pod (eg, Theraflu PowerPods Severe Cold): Children ≥12 years and Adolescents: Oral: 1 pod every 4 hours as needed; maximum daily dose: 5 pods per 24 hours.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Limited, low-dose therapy is usually well tolerated in hepatic disease/cirrhosis; however, cases of hepatotoxicity at recommended daily acetaminophen dosages have been reported. Avoid chronic use in hepatic impairment. Also see Acetaminophen monograph.
(For additional information see "Acetaminophen (paracetamol), diphenhydramine, and phenylephrine: Drug information")
Cold and flu symptoms: Oral: General dosing guidelines; refer to specific product labeling:
Caplet: Acetaminophen 650 mg/diphenhydramine 25 mg/phenylephrine 10 mg every 4 hours as needed; Maximum: Acetaminophen 3,250 mg/diphenhydramine 125 mg/phenylephrine 50 mg per 24 hours.
Powder for solution: Acetaminophen 500 mg/diphenhydramine 25 mg/phenylephrine 10 mg every 4 hours as needed; Maximum: Acetaminophen 3,000 mg/diphenhydramine 150 mg/phenylephrine 60 mg per 24 hours.
Liquid, syrup: Acetaminophen 650 mg/diphenhydramine 25 mg/phenylephrine 10 mg every 4 hours as needed; Maximum: Acetaminophen 3,250 to 3,900 mg/diphenhydramine 125 to 150 mg/phenylephrine 50 to 60 mg per 24 hours.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
See individual agents.
OTC labeling: When used for self-medication, do not use if allergic to acetaminophen; concurrently with other products containing acetaminophen or diphenhydramine (including topical); concurrently with or within 14 days of monoamine oxidase inhibitor therapy; to sedate a child; or in children <12 years of age.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hepatotoxicity: Acetaminophen has been associated with acute liver failure, at times resulting in liver transplant and death. Hepatotoxicity is usually associated with excessive acetaminophen intake and often involves >1 product that contains acetaminophen. Do not exceed the maximum recommended daily dose (>4 g daily in adults). In addition, long-term daily dosing may also result in liver damage in some patients.
• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur.
• Skin reactions: Rarely, acetaminophen may cause serious and potentially fatal skin reactions such as acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Discontinue treatment if severe skin reactions develop.
Disease-related concerns:
• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage. Avoid ethanol or limit to <3 drinks/day.
• Hepatic impairment: Use caution in patients with hepatic impairment; acetaminophen may cause severe hepatic toxicity with acute overdose.
Special populations:
• Pediatric: Use with caution in children; may cause excitability. Do not exceed pediatric dosing recommendations. If no recommendations exist on OTC labeling for patient's age, the product should not be administered without the guidance of a physician.
Dosage forms specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggest that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Other warnings/precautions:
• Dosage limit: Limit acetaminophen dose to <4 g/day (adults) or <2.6 g/day (children <12 years of age).
• Self-medication (OTC use): When used for self-medication, patients should contact health care provider if they have liver disease, hypertension, thyroid disease, diabetes mellitus, glaucoma, cardiovascular disease, breathing problems (eg, emphysema, chronic bronchitis), persistent or chronic cough (associated with smoking, asthma, chronic bronchitis, or emphysema), productive cough (eg, copious amounts of phlegm), trouble urinating due to an enlarged prostate, and/or currently taking a blood thinner, sedatives, or tranquilizers. Discontinue use and notify health care provider if pain, nasal congestion, or cough worsens or lasts >7 days in adults (or >5 days in children); fever worsens or lasts >3 days; sore throat is severe, persists, lasts >2 days, or is accompanied by fever, headache, rash, nausea, or vomiting; if any new symptoms or nervousness, dizziness, or sleeplessness occur; if redness or swelling is present; or if cough returns or occurs with fever, rash, or persistent headache.
Hepatoxicity has been reported in patients using acetaminophen. In pediatric patients, this is most commonly associated with supratherapeutic dosing, more frequent administration than recommended, and use of multiple acetaminophen-containing products; however, hepatotoxicity has been rarely reported with recommended dosages (AAP [Sullivan 2011]; Heard 2014). All sources of acetaminophen (eg, prescription, OTC, combination) should be considered when evaluating a patient's maximum daily dose. To lower the risk for hepatotoxicity, the maximum daily acetaminophen dose should be limited to ≤75 mg/kg/day (maximum of 5 daily doses), not to exceed 4,000 mg/day (AAP [Sullivan 2011]; Heard 2014; Krenzelok 2012; Lavonas 2010). Acetaminophen avoidance or a lower total daily dose (2,000 to 3,000 mg/day) has been suggested for adults with increased risk for acetaminophen hepatotoxicity (eg, malnutrition, certain liver diseases, use of drugs that interact with acetaminophen metabolism); similar data are unavailable in pediatric patients (Hayward 2016; Larson 2007; Worriax 2007).
Safety and efficacy for the use of cough and cold products in pediatric patients <4 years of age is limited; the AAP warns against the use of these products for respiratory illnesses in young children. Serious adverse effects including death have been reported. Many of these products contain multiple active ingredients, increasing the risk of accidental overdose when used with other products. The FDA does not recommend OTC uses for these products in pediatric patients <2 years of age and recommends to use with caution in pediatric patients ≥2 years of age. Health care providers are reminded to ask caregivers about the use of OTC cough and cold products in order to avoid exposure to multiple medications containing the same ingredient (AAP 2018; CDC 2007; FDA 2017; FDA 2018). Multiple formulations of tablet strengths and oral liquid concentrations exist; pay close attention to the strength/concentration when ordering or administering.
Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Caplet, oral:
Benadryl Allergy and Cold [DSC], Benadryl Allergy and Sinus Headache [DSC], Sudafed PE Severe Cold [DSC]: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg
Benadryl Maximum Strength Severe Allergy and Sinus Headache [DSC]: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg
Cold Control PE: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg
GoodSense Severe Allergy Relief Plus Sinus Headache: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg
One Tab Allergy & Sinus: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg [dye free]
One Tab Cold and Flu: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg [dye free]
Sudafed PE Nighttime Cold: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg [DSC]
Theraflu ExpressMax Nighttime Severe Cold & Cough: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg
Tylenol Allergy Multi-Symptom Nighttime: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg [Cool Burst flavor]
Liquid, oral:
Delsym Children's Cough+Cold Night Time: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 10 mL (180 mL) [contains edetate disodium, propylene glycol, sodium 6 mg/10 mL, sodium benzoate; berry flavor]
Delsym Cough+Cold Night Time: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per 20 mL (180 mL [DSC]) [contains edetate disodium, propylene glycol, sodium 12 mg/20 mL, sodium benzoate; mixed berry flavor]
Dimetapp Children's Multi-Symptom Cold & Flu: Acetaminophen 160 mg, diphenhydramine hydrochloride 6.25 mg, and phenylephrine hydrochloride 2.5 mg per 5 mL (118 mL) [alcohol free; contains edetate disodium, menthol, polyethylene glycol, propylene glycol, sodium benzoate, sodium 3.5 mg/5 mL; red grape flavor]
Mucinex Sinus-Max Night Time: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 10 mL (180 mL [DSC]) [contains edetate disodium, propylene glycol, sodium benzoate]
Theraflu ExpressMax Flu Cough & Sore Throat: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains edetate disodium, ethanol 10%, potassium 12.5 mg/15 mL, propylene glycol, sodium 8 mg/15 mL, sodium benzoate; berry flavor]
Robitussin Peak Cold Nighttime Multi-Symptom Cold: Acetaminophen 160 mg, diphenhydramine hydrochloride 6.25 mg, and phenylephrine hydrochloride 2.5 mg per 5 mL (118 mL [DSC], 237 mL[DSC]) [contains menthol, propylene glycol, sodium 4 mg/5 mL, sodium benzoate]
Robitussin Severe Multi-Symptom Cough Cold + Flu Nighttime: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per 20 mL (118 mL, 237 mL) [contains edetate disodium, fd&c red #40, polyethylene glycol, propylene glycol, sodium 12 mg/20 mL, sodium benzoate, sorbitol]
Powder for solution, oral:
GoodSense Nighttime Flu & Severe Cold & Cough: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [contains phenylalanine 13 mg/packet, potassium 10 mg/packet, sodium 25 mg/packet; honey lemon flavor]
Mucinex Fast-Max Night Time Cold & Flu: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (4s [DSC]) [contains phenylalanine 41 mg/packet, sodium 130 mg/packet; honey lemon flavor]
Theraflu Nighttime Severe Cold: Acetaminophen 500 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [contains phenylalanine 13 mg, potassium 10 mg, and sodium 23 mg per packet; green tea and citrus flavor]
Theraflu Nighttime Severe Cold & Cough: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [contains phenylalanine 13 mg, potassium 10 mg, and sodium 23 mg per packet; honey lemon flavor]
Theraflu Sugar-Free Nighttime Severe Cold & Cough: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [sugar free; contains phenylalanine 13 mg, potassium 10 mg, and sodium 23 mg per packet; honey lemon flavor]
Syrup, oral:
Theraflu Warming Relief Flu & Sore Throat: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains ethanol, potassium 5 mg/15 mL, propylene glycol, sodium 5 mg/15 mL, sodium benzoate; cherry flavor]
Theraflu ExpressMax Nighttime Severe Cold & Cough: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains ethanol, potassium 12.5 mg/15 mL, propylene glycol, sodium 8 mg/15 mL, sodium benzoate; cherry flavor]
No
Liquid (Delsym Cgh/Cld Nighttime Child Oral)
12.5-5-325 mg/10 mL (per mL): $0.09
Liquid (Mucinex Childrens Night Time Oral)
12.5-5-325 mg/10 mL (per mL): $0.09
Liquid (Robitussin Severe Nighttime Oral)
12.5-5-325 mg/10 mL (per mL): $0.10
Liquid (Theraflu ExpressMax Sev Cld/Cg Oral)
12.5-5-325 mg/15 mL (per mL): $0.05
Misc (Theraflu PowerPods Severe Cold Oral)
25-10-650 mg (per each): $1.42
Pack (Theraflu Severe Cold/Cgh Night Oral)
25-10-650 mg (per each): $1.87
Tablets (Theraflu ExpressMax Sev Cld/Cg Oral)
12.5-5-325 mg (per each): $0.31
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.
Oral: Administer without regard to meals; if GI distress, may administer with food.
Liquid: Only use enclosed dosing cup; do not use other devices.
Powder for solution: Children ≥12 years and Adolescents:
Powder packet: Dissolve contents of 1 packet into 8 ounces of hot water; sip while hot and consume within 10 to 15 minutes. If using microwave, add contents of packet to 8 ounces of cool water, stir briskly before and after heating.
Pod: Brew in a minimum of 8 ounces of water in a compatible brewer.
Oral: Administer without regard to meals.
Liquid, syrup: Only use enclosed dosing cup; do not use other devices.
Powder for solution: Dissolve contents of 1 packet into 8 ounces of hot water and stir until dissolved; sip while hot and consume within 10 to 15 minutes. If using microwave, add contents of packet to 8 ounces of cool water, stir briskly after heating.
Store at room temperature. Protect from moisture.
Temporary relief of flu and common cold symptoms including sinus/nasal congestion, headache, sneezing, runny nose, itchy/watery eyes, sore throat, fever, cough, and minor aches and pains (OTC product: FDA approved in ages ≥6 years and adults). Note: Approved ages and indications may vary by product; consult product-specific labeling.
Beers Criteria: Diphenhydramine (oral), a first-generation antihistamine, 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 potent anticholinergic properties resulting in increased risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity; use should also be avoided due to reduced clearance with advanced age and tolerance associated with use as a hypnotic. Exposure to concurrent anticholinergic drugs also increases risk of falls, delirium, and dementia; consider total anticholinergic burden when conducting medication reviews. However, use of diphenhydramine may be appropriate in certain situations such as acute treatment of severe allergic reaction (Beers Criteria [AGS 2023]).
Duplicate therapy issues: This product contains acetaminophen, which may be a component of combination products. Do not exceed the maximum recommended daily dose of acetaminophen.
Benadryl brand name for acetaminophen, diphenhydramine, and phenylephrine [U.S.], but also the brand name for cetirizine [Great Britain, Phillipines] and acrivastine and pseudoephedrine [Great Britain]
Refer to individual components.
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.
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
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
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
Alcohol (Ethyl): May increase hepatotoxic effects of Acetaminophen. Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alpha1-Blockers: May decrease vasoconstricting effects of Phenylephrine (Systemic). Risk C: Monitor
Amantadine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Amezinium: Antihistamines may increase stimulatory effects of Amezinium. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. 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 increase serum concentration of UGT1A1 Substrates. Management: Do not use UGT1A1 substrates for which small increases in exposure can cause serious adverse effects together with atazanavir, and use caution with any UGT1A1 substrate, even when small changes in exposure are less likely to cause serious adverse effects. Risk D: Consider Therapy Modification
Atomoxetine: May increase hypertensive effects of Sympathomimetics. Atomoxetine may increase tachycardic effects of Sympathomimetics. Risk C: Monitor
Atropine (Systemic): May increase hypertensive effects of Alpha1-Agonists. Risk C: Monitor
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Belumosudil: May increase serum concentration of UGT1A1 Substrates. Management: Avoid coadministration of belumosudil with substrates of UGT1A1 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the UGT1A1 substrate may be required. Risk D: Consider Therapy Modification
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
Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor
Benzylpenicilloyl Polylysine: Coadministration of Alpha1-Agonists and Benzylpenicilloyl Polylysine may alter diagnostic results. Management: Consider delaying skin testing until alpha1-agonists are no longer required, or use of a histamine skin test as a positive control to assess a patient's ability to mount a wheal and flare response. Risk D: Consider Therapy Modification
Benzylpenicilloyl Polylysine: Coadministration of Antihistamines and Benzylpenicilloyl Polylysine may alter diagnostic results. Management: Suspend systemic H1 antagonists for benzylpenicilloyl-polylysine skin testing and delay testing until systemic antihistaminic effects have dissipated. A histamine skin test may be used to assess persistent antihistaminic effects. Risk D: Consider Therapy Modification
Betahistine: Antihistamines may decrease therapeutic effects of Betahistine. Betahistine may decrease therapeutic effects of Antihistamines. Risk C: Monitor
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
Bornaprine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Bornaprine. Risk C: Monitor
Bornaprine: Sympathomimetics may increase anticholinergic effects of Bornaprine. 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
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromocriptine: May increase hypertensive effects of Alpha1-Agonists. Management: Consider alternatives to this combination when possible. If combined, monitor for hypertension and tachycardia, and do not coadminister these agents for more than 10 days. Risk D: Consider Therapy Modification
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: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Busulfan: Acetaminophen may increase serum concentration of Busulfan. Risk C: Monitor
Cannabinoid-Containing Products: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of Cannabinoid-Containing Products. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cannabinoid-Containing Products: May increase tachycardic effects of Sympathomimetics. Risk C: Monitor
CarBAMazepine: May increase metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor
Certoparin: Antihistamines may increase therapeutic effects of Certoparin. 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
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
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
Chloroprocaine (Systemic): May increase hypotensive effects of Phenylephrine (Systemic). Risk C: Monitor
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
Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid
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
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cocaine (Topical): May increase hypertensive effects of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider Therapy Modification
Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor
Dasatinib: Acetaminophen may increase hepatotoxic effects of Dasatinib. Dasatinib may increase serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and dasatinib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider Therapy Modification
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
Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. 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
Dihydralazine: Sympathomimetics may decrease therapeutic effects of Dihydralazine. 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
Disulfiram: May increase adverse/toxic effects of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxofylline: Sympathomimetics may increase adverse/toxic effects of Doxofylline. 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
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
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
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): May increase vasoconstricting effects of Alpha1-Agonists. Risk X: Avoid
Esketamine (Injection): May increase adverse/toxic effects of Sympathomimetics. Specifically, the risk for elevated heart rate, hypertension, and arrhythmias may be increased. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. Risk C: Monitor
Flucloxacillin: May increase adverse/toxic effects of Acetaminophen. Specifically, the risk for high anion gap metabolic acidosis may be increased. 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
Fosphenytoin-Phenytoin: May decrease serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor
Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. 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
Guanethidine: May increase hypertensive effects of Sympathomimetics. Guanethidine may increase arrhythmogenic effects of Sympathomimetics. Risk C: Monitor
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects of Haloperidol. Risk C: Monitor
Hyaluronidase: May increase vasoconstricting effects of Phenylephrine (Systemic). Management: Do not use hyaluronidase to enhance the dispersion or absorption of phenylephrine. Use of hyaluronidase for other purposes in patients receiving phenylephrine may be considered as clinically indicated. Risk D: Consider Therapy Modification
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
Imatinib: Acetaminophen may increase hepatotoxic effects of Imatinib. Risk C: Monitor
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Acetaminophen may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Iobenguane Radiopharmaceutical Products: Alpha1-Agonists may decrease therapeutic effects of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid
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
Isoniazid: May increase hepatotoxic effects of Acetaminophen. Isoniazid may increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Isoproterenol: DiphenhydrAMINE (Systemic) may increase therapeutic effects of Isoproterenol. Risk C: Monitor
Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase adverse/toxic effects of Sympathomimetics. Risk X: Avoid
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
LamoTRIgine: Acetaminophen may decrease serum concentration of LamoTRIgine. Risk C: Monitor
Landiolol: Sympathomimetics may decrease therapeutic effects of Landiolol. Risk C: Monitor
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid
Levothyroxine: May increase therapeutic effects of Sympathomimetics. Sympathomimetics may increase therapeutic effects of Levothyroxine. Levothyroxine may increase adverse/toxic effects of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Risk C: Monitor
Linezolid: May increase hypertensive effects of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider Therapy Modification
Lisuride: May increase hypertensive effects of Alpha1-Agonists. Risk X: Avoid
Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lorlatinib: May decrease serum concentration of Acetaminophen. 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
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
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melperone: May decrease therapeutic effects of Phenylephrine (Systemic). Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase adverse/toxic effects of Alpha1-Agonists. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: May increase CNS depressant effects of Products Containing Ethanol. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetroNIDAZOLE (Systemic): May increase adverse/toxic effects of Products Containing Ethanol. A disulfiram-like reaction may occur. Risk X: Avoid
MetroNIDAZOLE (Topical): May increase adverse/toxic effects of Products Containing Ethanol. A disulfiram-like reaction may occur. Risk C: Monitor
MetyraPONE: May increase serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk X: Avoid
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
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
Mitapivat: May decrease serum concentration of UGT1A1 Substrates. Risk C: Monitor
Monoamine Oxidase Inhibitors: May increase hypertensive effects of Alpha1-Agonists. While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Risk X: Avoid
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
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
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. 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: 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
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone 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
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Pergolide: May increase hypertensive effects of Alpha1-Agonists. 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
PHENobarbital: May increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pitolisant: Antihistamines may decrease therapeutic effects of Pitolisant. Risk X: Avoid
Pizotifen: May increase CNS depressant effects of CNS Depressants. 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
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
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
Primidone: May increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Probenecid: May increase serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Management: Consider limiting acetaminophen use in combination with probenecid. Probenecid may reduce clearance of acetaminophen to one of its non-toxic metabolities, increasing the risk for acetaminophen toxicity, even a lower doses. 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: May increase serum concentration of Phenylephrine (Systemic). Management: Monitor patients closely for increased side effects of phenylephrine if propacetamol is used concomitantly. Patients with underlying blood pressure issues or arrhythmias may need closer monitoring and may warrant consideration of alternative therapies. 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
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QuiNIDine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor
Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid
RifAMPin: May increase hepatotoxic effects of Acetaminophen. RifAMPin may decrease serum concentration of Acetaminophen. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. 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
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
Scopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Scopolamine. Risk C: Monitor
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
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
Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid
Solriamfetol: Sympathomimetics may increase hypertensive effects of Solriamfetol. Sympathomimetics may increase tachycardic effects of Solriamfetol. Risk C: Monitor
SORAfenib: Acetaminophen may increase hepatotoxic effects of SORAfenib. SORAfenib may increase serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and sorafenib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider Therapy Modification
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
Sympathomimetics: May increase adverse/toxic effects of Sympathomimetics. Risk C: Monitor
Tedizolid: May increase adverse/toxic effects of Sympathomimetics. Specifically, the risk for increased blood pressure and heart rate may be increased. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor
Thioridazine: CYP2D6 Inhibitors (Weak) may increase serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider Therapy Modification
Thiothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Thiothixene. Risk C: Monitor
Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor
Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid
Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor
Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. Risk C: Monitor
Tranylcypromine: May increase anticholinergic effects of Antihistamines, First Generation. Risk X: Avoid
Tricyclic Antidepressants: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tricyclic Antidepressants. Risk C: Monitor
Tricyclic Antidepressants: May increase therapeutic effects of Alpha1-Agonists. Tricyclic Antidepressants may decrease therapeutic effects of Alpha1-Agonists. Risk C: Monitor
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
Trospium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trospium. Risk C: Monitor
Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Vaccines: Acetaminophen may decrease therapeutic effects of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider Therapy Modification
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Vitamin K Antagonists: Acetaminophen may increase anticoagulant effects of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Risk C: Monitor
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
Zuclopenthixol: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Some products may contain phenylalanine, potassium, and/or sodium.
Refer to individual monographs.
Acetaminophen: Although not fully elucidated, the analgesic effects are believed to be due to activation of descending serotonergic inhibitory pathways in the CNS. Interactions with other nociceptive systems may be involved as well (Smith 2009). Antipyresis is produced from inhibition of the hypothalamic heat-regulating center.
Diphenhydramine: An H1-receptor antagonist.
Phenylephrine: Causes vasoconstriction of the arterioles of the nasal mucosa.
See individual agents.
