Version July 2025
Note : Because barbiturates have been associated with medication-overuse headache, reserve use for patients without alternative treatment options (Ref). If used, 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).
Tension-type headache: Oral: 1 to 2 capsules every 4 hours as needed; maximum: 6 capsules per day.
Discontinuation of therapy: 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, at high doses, or if a patient has developed chronic migraines, discontinue the butalbital-containing product and replace with a gradual (eg, over ~9 to 28 days) phenobarbital taper 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 headaches (Ref).
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; use with caution in severe renal impairment.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution with severe hepatic impairment.
Avoid use (Ref).
The following adverse drug reactions are derived from product labeling unless otherwise specified. Also see Aspirin and Caffeine monographs.
Frequency not defined:
Gastrointestinal: Flatulence, nausea, vomiting
Nervous system: Dizziness, drowsiness
Postmarketing:
Dermatologic: Erythema multiforme, toxic epidermal necrolysis
Hematologic and oncologic: Bone marrow depression
Hypersensitivity to aspirin, caffeine, butalbital, or any component of the formulation; hemorrhagic diathesis (eg, hemophilia, hypoprothrombinemia, von Willebrand disease, thrombocytopenias, thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe vitamin K deficiency, severe liver damage); syndrome of nasal polyps, angioedema, and bronchospastic reactivity to aspirin or other nonsteroidal anti-inflammatory drugs; peptic ulcer or other serious GI lesions; porphyria.
Canadian labeling: Additional contraindications (not in US labeling): History of abuse or overdose due to alcohol, hypnotics, analgesics, or psychotropic drugs; during third trimester of pregnancy.
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 or driving).
• 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.
• Salicylate sensitivity: Patients with sensitivity to tartrazine dyes, nasal polyps, and asthma may have an increased risk of salicylate sensitivity; therapeutic doses of aspirin may cause anaphylactic shock and other severe allergic reactions.
Disease-related concerns:
• Addison disease: Use with caution in patients with Addison disease.
• Bleeding disorders: Use with caution in patients with platelet and bleeding disorders.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance and psychological and physical dependence may occur with prolonged use.
• Gastrointestinal disease: Use with caution in patients with acute abdominal conditions, erosive gastritis, or other GI lesions, and extreme caution in patients with peptic ulcer disease.
• 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 severe hepatic impairment.
• Prostatic hypertrophy/urinary stricture: Use with caution in patients with prostatic hypertrophy and/or urinary stricture.
• Renal impairment: Use with caution in patients with severe renal impairment.
• Respiratory disease: Use with caution in patients with preexisting respiratory compromise (hypoxia and/or hypercapnia), chronic obstructive pulmonary disease (COPD) or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder that may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Special populations:
• Pediatric: 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 health care provider if these occur.
• Older adults: Use with caution in older adults.
• 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.
Other warnings/precautions:
• 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: Contains caffeine; limit the use of other caffeine-containing beverages or foods. May cause CNS and cardiovascular stimulation. Avoid in patients with symptomatic cardiac arrhythmias.
• Discontinuation of therapy: When discontinuing chronic or high-dose treatment with butalbital, or if a patient has developed chronic migraines 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).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: Butalbital 50 mg, aspirin 325 mg, and caffeine 40 mg
Yes
Capsules (Butalbital-Aspirin-Caffeine Oral)
50-325-40 mg (per each): $0.93 - $1.37
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Fiorinal: 50-330-40 MG [contains corn starch]
Generic: 330-50-40 MG
Tablet, Oral:
Trianal: Butalbital 50 mg, aspirin 325 mg, and caffeine 40 mg
Generic: 50-330-40 MG
C-III
Tension-type headache: Relief of the symptoms of tension-type headache.
Butalbital, aspirin, and caffeine may be confused with butalbital, acetaminophen, and caffeine; butalbital, aspirin, caffeine, and codeine; butalbital, acetaminophen, caffeine, and codeine.
Fiorinal may be confused with Fioricet, Florical, Florinef.
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: 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
Ajmaline: Salicylates may increase adverse/toxic effects of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor
Alcohol (Ethyl): May increase adverse/toxic effects of Aspirin. Specifically, alcohol may increase the bleeding risk of aspirin. Alcohol (Ethyl) may decrease therapeutic effects of Aspirin. Specifically, alcohol may interfere with the controlled release mechanism of extended release aspirin. 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
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
Ammonium Chloride: May increase serum concentration of Salicylates. 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
Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Atomoxetine: May increase hypertensive effects of Sympathomimetics. Atomoxetine may increase tachycardic effects of Sympathomimetics. Risk C: Monitor
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
Benzbromarone: Salicylates may decrease therapeutic effects of Benzbromarone. Risk C: Monitor
Blonanserin: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Blonanserin. Specifically, the risk of seizures may be increased. Risk C: Monitor
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
Broccoli: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor
Bromperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Bromperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Bromperidol: Caffeine and Caffeine Containing Products may decrease absorption of Bromperidol. Risk C: Monitor
BuPROPion: May increase neuroexcitatory and/or seizure-potentiating effects of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor
Calcium Channel Blockers (Nondihydropyridine): May increase antiplatelet effects of Aspirin. 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
ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor
Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CloZAPine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of CloZAPine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CloZAPine: CYP1A2 Inhibitors (Weak) may increase serum concentration of CloZAPine. 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
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
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
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
Diazoxide Choline: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk X: Avoid
Dihydralazine: Sympathomimetics may decrease therapeutic effects of Dihydralazine. 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
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: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of DroPERidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
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 hypertensive effects of CNS Stimulants. Risk C: Monitor
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase serum concentration of Fezolinetant. Risk X: Avoid
Flupentixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor
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
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
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
Haloperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Haloperidol. Specifically, the risk of seizures may be increased. 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
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
Iloperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iloperidone. Specifically, the risk of seizures may be increased. 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
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
Kratom: May increase adverse/toxic effects of Sympathomimetics. 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
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
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
Lipid Emulsion (Fish Oil Based): May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Lithium: Caffeine and Caffeine Containing Products may decrease serum concentration of Lithium. 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: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Macimorelin: Coadministration of Aspirin and Macimorelin may alter diagnostic results. Risk X: Avoid
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: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Methotrimeprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Methoxyflurane: Barbiturates may increase nephrotoxic effects of Methoxyflurane. Barbiturates may increase metabolism of Methoxyflurane. Risk X: Avoid
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
Miscellaneous Antiplatelets: May increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. 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
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
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
OLANZapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
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
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
Oxybate Salt Products: Barbiturates may increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
Paliperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. 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
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
Pimozide: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor
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
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
Primaquine: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor
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
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. 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
QUEtiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of QUEtiapine. Specifically, the risk of seizures may be increased. 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
RisperiDONE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor
Salicylates: May increase anticoagulant effects of Salicylates. Risk C: Monitor
Selective Serotonin Reuptake Inhibitor: May increase antiplatelet effects of Aspirin. Risk C: Monitor
Selumetinib: May increase antiplatelet effects of Therapeutic Antiplatelets. 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
Spironolactone: Aspirin may decrease therapeutic effects of Spironolactone. 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
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
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
Thiopental: Aspirin may decrease protein binding of Thiopental. Risk C: Monitor
Thioridazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. 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
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
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Valproic Acid and Derivatives: May increase CNS depressant effects of Barbiturates. Valproic Acid and Derivatives may increase serum concentration of Barbiturates. Barbiturates may decrease serum concentration of Valproic Acid and Derivatives. Risk C: Monitor
Valproic Acid and Derivatives: Salicylates may increase serum concentration of Valproic Acid and Derivatives. 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
Ziprasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Butalbital, aspirin, and caffeine cross the placenta.
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.
Maternal use of nonsteroidal anti-inflammatory drugs (including this combination) beginning ~20 weeks' gestation increases the risk for oligohydramnios. Use beginning ~30 weeks' gestation increases the risk of premature closure of the fetal ductus arteriosus.
The use of combination products containing butalbital 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 for congenital malformations (ACOG 2022).
Refer to the Aspirin and Caffeine monographs for additional information.
Barbiturates, aspirin, and caffeine 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 breastfeeding infants, the manufacturer recommends a decision be made whether to discontinue breastfeeding or the drug, considering the importance of treatment to the mother. The use of combination products containing butalbital is 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. In addition, the dose of aspirin in this combination product is not recommended in lactating patients (ACOG 2022).
Refer to the Aspirin and Caffeine monographs for additional information.
Serial hepatic and/or renal function tests (in patients with hepatic and/or renal impairment)
Aspirin: Inhibits prostaglandin synthesis in the CNS and peripherally blocks pain impulse generation.
Butalbital: Short- to intermediate-acting barbiturate; depresses the sensory cortex, decreases motor activity, alters cerebellar function, and produces drowsiness, sedation, hypnosis, and dose-dependent respiratory depression.
Caffeine: Increases levels of 3'5' cyclic AMP by inhibiting phosphodiesterase; CNS stimulant that increases medullary respiratory center sensitivity to carbon dioxide, stimulates central inspiratory drive, and improves skeletal muscle contraction (diaphragmatic contractility); prevention of apnea may occur by competitive inhibition of adenosine.
See individual agents.
