Version July 2025
Because the use of butalbital/aspirin/caffeine/codeine exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions.
Health care providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.
Serious, life-threatening, or fatal respiratory depression may occur with use of butalbital/aspirin/caffeine/codeine, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of butalbital/aspirin/caffeine/codeine are essential.
Accidental ingestion of even one dose of butalbital/aspirin/caffeine/codeine, especially by children, can result in a fatal overdose of butalbital/aspirin/caffeine/codeine.
If opioid use if required for an extended period of time in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome (NOWS), which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.
Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital/aspirin/caffeine/codeine is contraindicated in pediatric patients <12 years of age and pediatric patients <18 years of age following tonsillectomy and or adenoidectomy. Avoid the use of butalbital/aspirin/caffeine/codeine in pediatric patients 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with butalbital/aspirin/caffeine/codeine requires careful consideration of the effects on codeine, and the active metabolite, morphine.
Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of butalbital/aspirin/caffeine/codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Dosage guidance:
Safety: Consider prescribing naloxone or nalmefene for patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, patients with sleep-disordered breathing, higher opioid dosages (≥50 morphine milligram equivalents/day orally [equivalent to ≥333.3 mg oral codeine/day]), and/or concomitant benzodiazepine use (Ref). Limit butalbital use to ≤3 days per month to avoid medication overuse headache (Ref); studies have found increased risk with use of ≥5 days per month (Ref).
Dosing: Dosing provided is based on typical doses; some patients may require higher or lower doses. Individualize dosing based on patient-specific factors (eg, severity of pain, comorbidities, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time.
Clinical considerations: Opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for managing severe pain. Maximize nonopioid analgesia (when appropriate) prior to initiation of opioid analgesia (Ref).
Tension or muscle contraction headache: Oral: 1 to 2 capsules (butalbital 50 mg/aspirin 325 mg/caffeine 40 mg/codeine 30 mg) every 4 hours as needed; maximum: 6 capsules (butalbital 300 mg/aspirin 1,950 mg/caffeine 240 mg/codeine 180 mg) per day.
Discontinuation of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid’s pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone or nalmefene. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (Ref). For low butalbital doses or less frequent use, consider abrupt discontinuation of therapy or a gradual taper over 2 to 4 weeks. If use is frequent or at high doses or if a patient has developed chronic migraine, discontinuing the butalbital-containing product and replacing with a gradual (eg, over ~9 to 28 days) phenobarbital taper is advised to avoid withdrawal symptoms (ie, worsened headache, nausea/vomiting, restlessness, anxiety, diaphoresis, disturbed sleep, seizures). Consider providing bridge therapy with a medication to treat acute headaches and optimizing a preventative regimen to avoid rebound headache (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
GFR ≥10 mL/minute: There are no specific dosage adjustments provided in the manufacturer's labeling; initiate with a low dose or with longer dosing intervals and titrate slowly; use with caution and monitor carefully.
GFR <10 mL/minute: Avoid use.
There are no specific dosage adjustments provided in the manufacturer's labeling; initiate with a low dose or with longer dosing intervals and titrate slowly; use with caution and monitor carefully.
Avoid use (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see Aspirin, Caffeine, and Codeine monographs.
1% to 10%:
Gastrointestinal: Abdominal pain (≤4%), nausea (≤4%)
Nervous system: Dizziness (3%), drowsiness (2%), intoxicated feeling (1%)
<1%:
Cardiovascular: Syncope, tachycardia
Dermatologic: Hyperhidrosis, pruritus
Gastrointestinal: Dysphagia, heartburn, vomiting, xerostomia
Genitourinary: Diuresis
Nervous system: Agitation, fatigue, feeling hot, headache, increased energy, lethargy, numbness, shakiness, tingling sensation
Neuromuscular & skeletal: Lower extremity pain, muscle fatigue
Ophthalmic: Heavy eyelids
Otic: Otalgia, tinnitus
Respiratory: Nasal congestion
Miscellaneous: Fever
Frequency not defined:
Respiratory: Respiratory depression
Nervous system: Neonatal withdrawal
Postmarketing:
Cardiovascular: Chest pain, edema, flushing, hypotension, palpitations
Dermatologic: Erythema multiforme, erythema of skin, exfoliative dermatitis, fixed drug eruption, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Decreased libido, increased libido
Gastrointestinal: Anorexia, burning sensation of mouth, constipation, diarrhea, esophagitis, gastric ulcer (pyloric ulcer), gastroenteritis, gastrointestinal spasm, hiccups, increased appetite, salivation
Genitourinary: Hypogonadism (Brennan 2013; Debono 2011), urinary hesitancy
Hematologic & oncologic: Adenocarcinoma (cholangiocarcinoma)
Hypersensitivity: Hypersensitivity reaction (including anaphylactic shock, anaphylaxis)
Nervous system: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023), anxiety, depression, disorientation, drug abuse, hallucination, hyperactive behavior, insomnia, loss of consciousness, nervousness, neuropathy, opioid dependence, psychosis, sedated state, slurred speech, twitching, vertigo
Ophthalmic: Miosis
Renal: Kidney impairment
Respiratory: Epistaxis
Hypersensitivity or intolerance to butalbital, codeine, aspirin, caffeine, NSAIDs, or any component of the formulation; pediatric patients <12 years of age; postoperative pain management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; hemophilia; Reye syndrome; syndrome of nasal polyps, asthma, and rhinitis; GI obstruction, including paralytic ileus (known or suspected); concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in US labeling): Suspected surgical abdomen (eg, acute appendicitis, pancreatitis); mild pain that can be managed with other analgesics; acute alcoholism or delirium tremens; convulsive disorders; severe CNS depression; acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale, chronic obstructive airway, increased cerebrospinal or intracranial pressure; head trauma; pregnancy or during labor and delivery; breastfeeding; hemorrhagic diathesis (eg, hypoprothrombinemia, von Willebrand’s disease, thrombocytopenia, thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe vitamin K deficiency, severe liver damage); peptic ulcer or other serious GI lesions; porphyria; history of alcohol, hypnotic, analgesic or psychotropic abuse or overdose; pneumonia; coma; known CYP2D6 ultra-rapid metabolizers.
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 which require mental alertness (eg, operating machinery or driving).
• Constipation: May cause or aggravate constipation.
• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.
• Gastrointestinal events: Aspirin may cause serious GI adverse reactions, including inflammation, bleeding ulceration and perforation. Other adverse reactions include stomach pain, heartburn, nausea, and vomiting. Monitor patients for signs of ulceration and bleeding. Discontinue therapy if active and significant bleeding occurs. Use aspirin with caution in patients with erosive gastritis; avoid use in patients with active peptic ulcer disease.
• Hyperalgesia: Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).
• Respiratory depression: Fatal respiratory depression may occur. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.
• Salicylate sensitivity: Patients with sensitivity to tartrazine dyes, nasal polyps, and asthma may have an increased risk of salicylate sensitivity.
• Skin reactions: NSAIDs, including aspirin, may cause serious skin adverse events (sometimes fatal), including exfoliative dermatitis, fixed drug eruption (including generalized bullous fixed drug eruption), Stevens-Johnson syndrome, and toxic epidermal necrolysis; may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• Bleeding disorders: Use with caution in patients with platelet and bleeding disorders.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Ethanol use: Heavy ethanol use (>3 drinks/day) can increase bleeding risks.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, posttraumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Avoid use in patients with severe renal failure (GFR <10 mL/minute).
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and central nervous system depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Special populations:
• Cachectic or debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• CYP2D6 "poor metabolizers": Poor metabolizers have decreased metabolism of codeine to its active metabolite, which may diminish analgesia; avoid the use of codeine and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]).
• CYP2D6 "ultrarapid metabolizers": Ultrarapid metabolizers have increased metabolism of codeine to its active metabolite, which may increase the risk of serious adverse effects; avoid the use of codeine and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]). The prevalence of this phenotype is estimated to be 1% to 10% for White (European and North American) patients; 3% to 4% for Black patients; 1% to 2% for Chinese, Japanese, and Korean patients; and >10% in certain ethnic groups such as Oceanian, Northern African, Middle Eastern, Ashkenazi Jew, and Puerto Rican patients.
• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.
• Neonates: Neonatal withdrawal syndrome: Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
• Pediatric:
Respiratory depression: Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. Deaths have also occurred in breastfeeding infants after being exposed to high concentrations of morphine because the mothers were ultra-rapid metabolizers.
Children and teenagers who have or are recovering from chickenpox or flu-like symptoms should not use this product. Changes in behavior (along with nausea and vomiting) may be an early sign of Reye syndrome; patients should be instructed to contact their healthcare provider if these occur.
• Surgical patients: Aspirin should be avoided (if possible) in surgical patients for 1 to 2 weeks prior to surgery, to reduce the risk of excessive bleeding (except in patients with cardiac stents that have not completed their full course of dual antiplatelet therapy [aspirin, clopidogrel]; patient specific situations need to be discussed with cardiologist; AHA/ACC/SCAI/ACS/ADA Science Advisory provides recommendations).
Other warnings/precautions:
• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances; provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.
• Abuse/misuse/diversion: Use with caution in patients with a history of substance abuse disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other central nervous system depressants. Consider offering naloxone or nalmefene prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).
• Appropriate use: Limit butalbital use to ≤3 days per month to avoid medication overuse headache (Garza 2006); studies have found increased risk with use of ≥5 days per month (Da Silva 2014).
• Caffeine: May cause CNS and cardiovascular stimulation, as well as GI irritation in high doses.
• Discontinuation of therapy: When discontinuing chronic or high-dose treatment with butalbital, or if a patient has developed chronic migraine on butalbital, discontinuing butalbital and replacing with a gradual phenobarbital taper is advised to avoid barbiturate withdrawal symptoms (ie, anxiety, diaphoresis, disturbed sleep, nausea/vomiting, restlessness, seizures, worsened headache). These patients will likely require bridge therapy with a medication to treat acute headaches and may benefit from an optimized preventative regimen (Boes 2006; Garza 2025).
• Naloxone/Nalmefene access: Discuss the availability of naloxone or nalmefene with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone or nalmefene to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone or nalmefene (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone or nalmefene, and getting emergency help.
• REMS program: Additional information is available at http://www.opioidanalgesicrems.com or at 1-800-503-0784.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Ascomp-Codeine: Butalbital 50 mg, aspirin 325 mg, caffeine 40 mg, and codeine phosphate 30 mg
Generic: Butalbital 50 mg, aspirin 325 mg, caffeine 40 mg, and codeine phosphate 30 mg
Yes
Capsules (Ascomp-Codeine Oral)
50-325-40-30 mg (per each): $2.74
Capsules (Butalbital-ASA-Caff-Codeine Oral)
50-325-40-30 mg (per each): $2.74
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Fiorinal-C 1/2: Butalbital 50 mg, aspirin 330 mg, caffeine 40 mg, and codeine 30 mg [contains fd&c blue #1 (brilliant blue)]
Fiorinal-C 1/4: Butalbital 50 mg, aspirin 330 mg, caffeine 40 mg, and codeine 15 mg [contains fd&c blue #1 (brilliant blue)]
Trianal C1/4: Butalbital 50 mg, aspirin 330 mg, caffeine 40 mg, and codeine 15 mg [DSC]
Trianal C 1/2: Butalbital 50 mg, aspirin 330 mg, caffeine 40 mg, and codeine 30 mg [DSC]
Generic: Butalbital 50 mg, aspirin 330 mg, caffeine 40 mg, and codeine 15 mg, Butalbital 50 mg, aspirin 330 mg, caffeine 40 mg, and codeine 30 mg
C-III
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Butalbital, Aspirin, Caffeine, and Codeine: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019429s043lbl.pdf#page=39
Tension or muscle contraction headache: Management of the symptom complex of tension (muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate.
Limitations of use: Because of the risks of substance use disorder, abuse, and misuse with opioids, which may occur at any dosage or duration, reserve butalbital/aspirin/caffeine/codeine for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) have not been tolerated or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia. Not intended to be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.
Fiorinal may be confused with Fioricet, Florical, Florinef
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (opioids, all formulations and routes of administration) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Beers Criteria: Butalbital 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]).
Beers Criteria: Aspirin, when used chronically at doses more than 325 mg/day, is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (unless alternative agents ineffective and patient can receive concomitant gastroprotective agent) due to increased risk of GI bleeding and peptic ulcer disease in older adults in high-risk category (eg, older than 75 years of age or receiving concomitant oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents). In addition, avoid for short-term scheduled use in combination with oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents unless alternatives are ineffective and patient can receive concomitant gastroprotective agent (Beers Criteria [AGS 2023]).
KIDs List: Codeine, when used in pediatric patients <18 years of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be avoided due to risk of respiratory depression and death unless pharmacogenetic testing completed (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).
KIDs List: Salicylates, when used in pediatric patients <18 years of age with suspicion of viral illness (influenza, chickenpox), are identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be used with caution due to risk of Reye syndrome (weak recommendation; very low quality of evidence) (PPA [Meyers 2020]).
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.
Abrocitinib: Aspirin may increase antiplatelet effects of Abrocitinib. Management: Do not use aspirin at doses greater than 81 mg/day with abrocitinib during the first 3 months of abrocitinib therapy. The abrocitinib prescribing information lists this combination as contraindicated. Risk D: Consider Therapy Modification
Acalabrutinib: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Acebrophylline: May increase stimulatory effects of CNS Stimulants. Risk X: Avoid
Adenosine: Caffeine and Caffeine Containing Products may decrease therapeutic effects of Adenosine. Management: Monitor for decreased effect of adenosine if patient is receiving caffeine; significantly higher adenosine doses or alternative agents may be required. Discontinue caffeine 24 hours in advance of scheduled diagnostic use of adenosine if possible. Risk D: Consider Therapy Modification
Aducanumab: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Agents with Blood Glucose Lowering Effects: Salicylates may increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Agents with Clinically Relevant Anticholinergic Effects: May increase adverse/toxic effects of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor
Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Ajmaline: Salicylates may increase adverse/toxic effects of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor
Alendronate: Aspirin may increase adverse/toxic effects of Alendronate. Specifically, the incidence of upper gastrointestinal adverse events may be increased Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alvimopan: Opioid Agonists may increase adverse/toxic effects of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider Therapy Modification
Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ammonium Chloride: May increase serum concentration of Salicylates. Risk C: Monitor
Amphetamines: May increase analgesic effects of Opioid Agonists. Risk C: Monitor
Anagrelide: May increase antiplatelet effects of Aspirin. Risk C: Monitor
Angiotensin-Converting Enzyme Inhibitors: Salicylates may decrease therapeutic effects of Angiotensin-Converting Enzyme Inhibitors. Salicylates may increase nephrotoxic effects of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor
Anticoagulants (Miscellaneous Agents): Aspirin may increase anticoagulant effects of Anticoagulants (Miscellaneous Agents). Risk C: Monitor
Antiplatelet Agents (P2Y12 Inhibitors): Therapeutic Antiplatelets may increase antiplatelet effects of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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
Atomoxetine: May increase hypertensive effects of Sympathomimetics. Atomoxetine may increase tachycardic effects of Sympathomimetics. Risk C: Monitor
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benzbromarone: Salicylates may decrease therapeutic effects of Benzbromarone. 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: Sympathomimetics may increase anticholinergic effects of Bornaprine. Risk C: Monitor
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Broccoli: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). 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: 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
Buprenorphine: May decrease therapeutic effects of Opioid Agonists. Management: Seek alternatives to buprenorphine in patients receiving pure opioid agonists. If combined in certain pain management situations (eg, surgery), monitor for symptoms of therapeutic failure/high dose requirements or opioid withdrawal symptoms. Risk D: Consider Therapy Modification
BuPROPion: May increase neuroexcitatory and/or seizure-potentiating effects of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Calcium Channel Blockers (Nondihydropyridine): May increase antiplatelet effects of Aspirin. 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
Cannabis: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor
Caplacizumab: May increase antiplatelet effects of Therapeutic Antiplatelets. Management: Avoid this combination if possible. If coadministration is required, monitor closely for bleeding. Interrupt caplacizumab if clinically significant bleeding occurs and administer von Willebrand factor concentrate to rapidly correct hemostasis, if needed. Risk D: Consider Therapy Modification
Carbonic Anhydrase Inhibitors: Salicylates may increase adverse/toxic effects of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Management: Avoid these combinations when possible.Dichlorphenamide use with high-dose aspirin as contraindicated. If another combination is used, monitor patients closely for adverse effects. Tachypnea, anorexia, lethargy, and coma have been reported. Risk D: Consider Therapy Modification
Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. 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
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
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
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
Collagenase (Systemic): Aspirin may increase adverse/toxic effects of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor
Corticosteroids (Systemic): Salicylates may increase adverse/toxic effects of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor
CYP1A2 Inducers (Moderate): May decrease serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
CYP1A2 Inhibitors (Moderate): May increase serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
CYP1A2 Inhibitors (Strong): May increase serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
CYP2D6 Inhibitors (Moderate): May decrease therapeutic effects of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor
CYP2D6 Inhibitors (Strong): May decrease therapeutic effects of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease active metabolite exposure of Codeine. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease active metabolite exposure of Codeine. Risk C: Monitor
CYP3A4 Inhibitors (Moderate): May increase active metabolite exposure of Codeine. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase active metabolite exposure of Codeine. 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
Dasatinib: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Deoxycholic Acid: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Desirudin: Therapeutic Antiplatelets may increase anticoagulant effects of Desirudin. Risk C: Monitor
Desmopressin: Opioid Agonists may increase hyponatremic effects of Desmopressin. Risk C: Monitor
Dexibuprofen: Aspirin may increase adverse/toxic effects of Dexibuprofen. Dexibuprofen may decrease cardioprotective effects of Aspirin. Risk X: Avoid
Dexketoprofen: Salicylates may increase adverse/toxic effects of Dexketoprofen. Dexketoprofen may decrease therapeutic effects of Salicylates. Salicylates may decrease serum concentration of Dexketoprofen. Management: The use of high-dose salicylates (3 g/day or more in adults) together with dexketoprofen is inadvisable. Consider administering dexketoprofen 30-120 min after or at least 8 hrs before cardioprotective doses of aspirin to minimize any possible interaction. Risk X: Avoid
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
Diazoxide Choline: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk X: Avoid
Difelikefalin: 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 (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dipyrone: May decrease antiplatelet effects of Aspirin. Management: Use caution and consider avoiding use of dipyrone in patients treated with aspirin for the treatment or prevention of cardiovascular events or stroke. Risk D: Consider Therapy Modification
Direct Oral Anticoagulants (DOACs): Aspirin may increase anticoagulant effects of Direct Oral Anticoagulants (DOACs). Risk C: Monitor
Diuretics: Opioid Agonists may increase adverse/toxic effects of Diuretics. Opioid Agonists may decrease therapeutic effects of Diuretics. Risk C: Monitor
Donanemab: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Doxofylline: Caffeine and Caffeine Containing Products may increase adverse/toxic effects of Doxofylline. Risk X: Avoid
Doxycycline: Barbiturates may decrease serum concentration of Doxycycline. 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
Eluxadoline: Opioid Agonists 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
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase serum concentration of Fezolinetant. Risk X: Avoid
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
Fondaparinux: Aspirin may increase anticoagulant effects of Fondaparinux. Management: Discontinue aspirin prior to fondaparinux therapy, if possible. If co-administration is required use caution and monitor for bleeding. Risk D: Consider Therapy Modification
Formoterol: Caffeine and Caffeine Containing Products may increase adverse/toxic effects of Formoterol. Caffeine and Caffeine Containing Products may increase hypokalemic effects of Formoterol. Risk C: Monitor
Gastrointestinal Agents (Prokinetic): Opioid Agonists may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Ginkgo Biloba: May increase anticoagulant effects of Salicylates. Management: Consider alternatives to this combination of agents. Monitor for signs and symptoms of bleeding (especially intracranial bleeding) if salicylates are used in combination with ginkgo biloba. Risk D: Consider Therapy Modification
Glycoprotein IIb/IIIa Inhibitors: Therapeutic Antiplatelets may increase anticoagulant effects of Glycoprotein IIb/IIIa Inhibitors. Risk C: Monitor
Grapefruit Juice: May increase serum concentration of Codeine. Risk C: Monitor
Griseofulvin: Barbiturates may decrease serum concentration of Griseofulvin. Risk C: Monitor
Guanethidine: May increase hypertensive effects of Sympathomimetics. Guanethidine may increase arrhythmogenic effects of Sympathomimetics. Risk C: Monitor
Hemin: Barbiturates may decrease therapeutic effects of Hemin. Risk X: Avoid
Heparin: Aspirin may increase anticoagulant effects of Heparin. Risk C: Monitor
Heparins (Low Molecular Weight): Aspirin may increase anticoagulant effects of Heparins (Low Molecular Weight). Risk C: Monitor
Herbal Products with Anticoagulant/Antiplatelet Effects: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Hyaluronidase: Salicylates may decrease therapeutic effects of Hyaluronidase. 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
Ibritumomab Tiuxetan: Therapeutic Antiplatelets may increase antiplatelet effects of Ibritumomab Tiuxetan. Risk C: Monitor
Ibrutinib: Therapeutic Antiplatelets may increase adverse/toxic effects of Ibrutinib. Specifically, the risks of bleeding and hemorrhage may be increased. Risk C: Monitor
Icosapent Ethyl: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): May decrease therapeutic effects of Opioid Agonists. Opioid Agonists may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Indacaterol: Caffeine and Caffeine Containing Products may increase adverse/toxic effects of Indacaterol. Caffeine and Caffeine Containing Products may increase hypokalemic effects of Indacaterol. Risk C: Monitor
Influenza Virus Vaccine (Live/Attenuated): May increase adverse/toxic effects of Salicylates. Specifically, Reye's syndrome may develop. Risk X: Avoid
Inotersen: Therapeutic Antiplatelets may increase adverse/toxic effects of Inotersen. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
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
Ketorolac (Nasal): May increase adverse/toxic effects of Aspirin. An increased risk of bleeding may be associated with use of this combination. Ketorolac (Nasal) may decrease cardioprotective effects of Aspirin. Management: Concurrent use of nasal ketorolac with analgesic doses of aspirin is generally not recommended. If using low-dose, cardioprotective aspirin with nasal ketorolac, monitor the patient closely for evidence of adverse GI effects. Risk D: Consider Therapy Modification
Ketorolac (Systemic): May increase adverse/toxic effects of Aspirin. An increased risk of bleeding may be associated with use of this combination. Ketorolac (Systemic) may decrease cardioprotective effects of Aspirin. Risk X: Avoid
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
Landiolol: Sympathomimetics may decrease therapeutic effects of Landiolol. Risk C: Monitor
Lecanemab: May increase antiplatelet effects of Therapeutic Antiplatelets. 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
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
Limaprost: May increase adverse/toxic effects of Therapeutic Antiplatelets. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Lipid Emulsion (Fish Oil Based): May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lithium: Caffeine and Caffeine Containing Products may decrease serum concentration of Lithium. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loop Diuretics: Salicylates may decrease therapeutic effects of Loop Diuretics. Loop Diuretics may increase serum concentration of Salicylates. 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
Macimorelin: Coadministration of Aspirin and Macimorelin may alter diagnostic results. Risk X: Avoid
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrexate: Salicylates may increase serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Management: Consider avoiding coadministration of methotrexate and salicylates. If coadministration cannot be avoided, monitor for increased toxic effects of methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider Therapy Modification
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: Barbiturates may increase nephrotoxic effects of Methoxyflurane. Barbiturates may increase metabolism of Methoxyflurane. Risk X: Avoid
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
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
MigALAstat: Caffeine and Caffeine Containing Products may decrease serum concentration of MigALAstat. Risk X: Avoid
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Miscellaneous Antiplatelets: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Monoamine Oxidase Inhibitors: May increase adverse/toxic effects of Codeine. Risk X: Avoid
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Multivitamins/Fluoride (with ADE): May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease serum concentration of Barbiturates. Risk C: Monitor
Multivitamins/Minerals (with ADEK, Folate, Iron): May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Multivitamins/Minerals (with AE, No Iron): May increase antiplatelet effects of Therapeutic Antiplatelets. 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
Nalfurafine: Opioid Agonists may increase adverse/toxic effects of Nalfurafine. Opioid Agonists may decrease therapeutic effects of Nalfurafine. Risk C: Monitor
Nalmefene: May decrease therapeutic effects of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider Therapy Modification
Naltrexone: May decrease therapeutic effects of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid
Nefazodone: Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for increased opioid effects, including fatal respiratory depression, when these agents are combined and consider opioid dose reductions until stable drug effects are achieved. Additionally, monitor for serotonin syndrome/serotonin toxicity. Risk C: Monitor
Nicorandil: Aspirin may increase adverse/toxic effects of Nicorandil. Specifically, the risk of gastrointestinal ulceration and hemorrhage may be increased. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Aspirin may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Specifically, the risk of gastrointestinal adverse effects may be increased. Management: Concurrent use of aspirin at doses beyond cardioprotective levels is not recommended. While concurrent use of low-dose aspirin with a COX-2 inhibitor is permissible, patients should be monitored closely for signs/symptoms of GI ulceration/bleeding. Risk D: Consider Therapy Modification
Nonsteroidal Anti-Inflammatory Agents (Nonselective): May decrease therapeutic effects of Aspirin. Aspirin may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Specifically, the risk for bleeding may be increased. Aspirin may decrease serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Management: In general, avoid regular, frequent use of NSAIDs with aspirin whenever possible. If combined, monitor for increased bleeding and a reduced cardioprotective effect of aspirin. Risk D: Consider Therapy Modification
Nonsteroidal Anti-Inflammatory Agents (Topical): May increase adverse/toxic effects of Salicylates. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of salicylates and topical NSAIDs is not recommended. If salicylates and topical NSAIDs are coadministered, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider Therapy Modification
Norfloxacin: May increase serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Obinutuzumab: Therapeutic Antiplatelets may increase adverse/toxic effects of Obinutuzumab. Specifically, the risk of bleeding may be increased. Management: Consider avoiding coadministration of obinutuzumab and therapeutic antiplatelets, especially during the first cycle of obinutuzumab therapy. Risk D: Consider Therapy Modification
Olodaterol: Caffeine and Caffeine Containing Products may increase adverse/toxic effects of Olodaterol. Caffeine and Caffeine Containing Products may increase hypokalemic effects of Olodaterol. Risk C: Monitor
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Omacetaxine: Aspirin may increase adverse/toxic effects of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of aspirin with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid
Omega-3 Fatty Acids: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
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
Opioids (Mixed Agonist / Antagonist): May decrease analgesic effects of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid
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
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
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
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Pegvisomant: Opioid Agonists may decrease therapeutic effects of Pegvisomant. Risk C: Monitor
Pentosan Polysulfate Sodium: Therapeutic Antiplatelets may increase adverse/toxic effects of Pentosan Polysulfate Sodium. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor
Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
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
Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid
Pipemidic Acid: May increase serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pirtobrutinib: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor
Potassium Phosphate: May increase serum concentration of Salicylates. Risk C: Monitor
PRALAtrexate: Salicylates may increase serum concentration of PRALAtrexate. Salicylate doses used for prophylaxis of cardiovascular events are unlikely to be of concern. Management: Consider avoiding concomitant use of salicylates and pralatrexate. If coadministered, monitor for increased pralatrexate adverse effects. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider Therapy Modification
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Primaquine: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor
Primidone: May increase CNS depressant effects of Codeine. Primidone may decrease serum concentration of Codeine. Management: Avoid use of codeine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Probenecid: Salicylates may decrease therapeutic effects of Probenecid. Salicylates may increase serum concentration of Probenecid. Probenecid may increase serum concentration of Salicylates. Risk X: Avoid
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Ramosetron: Opioid Agonists may increase constipating effects of Ramosetron. Risk C: Monitor
Regadenoson: Caffeine and Caffeine Containing Products may decrease vasodilatory effects of Regadenoson. Management: Avoid use of caffeine and caffeine-containing products for at least 12 hours prior to regadenoson administration. Risk D: Consider Therapy Modification
Rilmenidine: May increase CNS depressant effects of CNS Depressants. 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
Salicylates: May increase anticoagulant effects of Salicylates. Risk C: Monitor
Samidorphan: May decrease therapeutic effects of Opioid Agonists. Risk X: Avoid
Selective Serotonin Reuptake Inhibitor: May increase antiplatelet effects of Aspirin. Risk C: Monitor
Selumetinib: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Serotonin/Norepinephrine Reuptake Inhibitor: May increase antiplatelet effects of Aspirin. Risk C: Monitor
Sertindole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sertindole. Specifically, the risk of seizures may be increased. 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
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor
Solriamfetol: CNS Stimulants may increase hypertensive effects of Solriamfetol. CNS Stimulants may increase tachycardic effects of Solriamfetol. Risk C: Monitor
Solriamfetol: Sympathomimetics may increase hypertensive effects of Solriamfetol. Sympathomimetics may increase tachycardic effects of Solriamfetol. Risk C: Monitor
Somatostatin Analogs: May decrease active metabolite exposure of Codeine. Specifically, the concentrations of the active metabolite morphine may be reduced. Risk C: Monitor
Spironolactone: Aspirin may decrease therapeutic effects of Spironolactone. Risk C: Monitor
Succinylcholine: May increase bradycardic effects of Opioid Agonists. Risk C: Monitor
Sucroferric Oxyhydroxide: May decrease serum concentration of Aspirin. Management: Administer aspirin at least 1 hour before administration of sucroferric oxyhydroxide. Risk D: Consider Therapy Modification
Sulfinpyrazone: Salicylates may decrease serum concentration of Sulfinpyrazone. Risk X: Avoid
Sulpiride: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sulpiride. Specifically, the risk of seizures may be increased. 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
Sympathomimetics: May increase adverse/toxic effects of Sympathomimetics. Risk C: Monitor
Talniflumate: Aspirin may increase adverse/toxic effects of Talniflumate. Management: When possible, consider alternatives to this combination. Concurrent use is generally not recommended. Risk D: Consider Therapy Modification
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
Theophylline Derivatives: Barbiturates may decrease serum concentration of Theophylline Derivatives. Risk C: Monitor
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase serum concentration of Theophylline Derivatives. Risk C: Monitor
Thrombolytic Agents: Therapeutic Antiplatelets may increase adverse/toxic effects of Thrombolytic Agents. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Ticagrelor: Aspirin may increase antiplatelet effects of Ticagrelor. Aspirin may decrease therapeutic effects of Ticagrelor. More specifically, the benefits of ticagrelor relative to clopidogrel may be diminished in adult patients receiving daily aspirin doses greater than 100-150 mg daily. Management: Avoid maintenance aspirin doses greater than 150 mg/day in patients receiving ticagrelor. After any initial dose, only low-dose aspirin (75 to 100 mg/day) is recommended. Risk D: Consider Therapy Modification
Tilidine: May increase therapeutic effects of Opioid Agonists. Risk X: Avoid
Tipranavir: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
TiZANidine: CYP1A2 Inhibitors (Weak) may increase serum concentration of TiZANidine. Management: Avoid the use of tizanidine with weak CYP1A2 inhibitors when possible. If combined, monitor closely for increased tizanidine toxicities (eg, hypotension, bradycardia, drowsiness). Tizanidine dose reduction or discontinuation may be necessary. Risk D: Consider Therapy Modification
Tobacco (Smoked): May decrease serum concentration of Caffeine and Caffeine Containing Products. 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
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Varicella Virus-Containing Vaccines: Salicylates may increase adverse/toxic effects of Varicella Virus-Containing Vaccines. Specifically, the risk for Reye's syndrome may increase. Risk X: Avoid
Vitamin E (Systemic): May increase antiplatelet effects of Therapeutic Antiplatelets. 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
Volanesorsen: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Zanubrutinib: May increase antiplatelet effects of Therapeutic Antiplatelets. 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
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
Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction and infertility (Brennan 2013).
Butalbital crosses the placenta (Ostrea 1982).
Outcome data following maternal use of butalbital during pregnancy are limited (Browne 2014; Heinonen 1977). Withdrawal seizures were reported in an infant 2 days after birth following maternal use of a butalbital product during the last 2 months of pregnancy; butalbital was detected in the newborn’s serum (Ostrea 1982).
Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period during pregnancy, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate will be available.
The use of combination products containing butalbital or codeine are not recommended for the treatment of headache during pregnancy due to the increased risk of overuse headache, lack of supplemental analgesia, and increased risk of addiction and potential adverse fetal/neonatal effects (ACOG 2022).
Also refer to individual monographs for information specific to aspirin, caffeine, and codeine.
Barbiturates, aspirin, caffeine, and codeine are present in breast milk.
Emesis, lethargy, and poor feeding were reported in a 7-day-old, breastfed infant following maternal use of a product containing butalbital 50 mg every 6 hours for 24 hours (Vohra 2019).
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer. The use of combination products containing butalbital or codeine are not recommended for the treatment of headache in lactating patients due to the increased risk of overuse headache, lack of supplemental analgesia, and increased risk of addiction and potential adverse effects in the breastfeeding infant. In addition, the dose of aspirin in this combination product is not recommended in lactating patients (ACOG 2022).
Also refer to individual monographs for information specific to aspirin, caffeine, and codeine.
Relief of symptoms; respiratory and mental status, blood pressure, heart rate; bowel function; signs/symptoms of misuse, abuse, and substance use disorder; hepatic and renal function tests (in patients with impairment); signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013).
Aspirin: Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors, acts on the hypothalamic heat-regulating center to reduce fever, blocks thromboxane synthetase action which prevents formation of the platelet-aggregating substance thromboxane A2.
Butalbital: A short- to intermediate-acting barbiturate. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, hypnosis, and dose-dependent respiratory depression.
Caffeine: A cranial vasoconstrictor to enhance the vasoconstrictor effect; also used as a central stimulant for relief of headache.
Codeine: Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.
See individual agents.
