Version July 2025
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 mg/day, and often involve more than 1 acetaminophen-containing product.
Note: Butalbital, acetaminophen, and caffeine oral solutions have been discontinued in the United States for >1 year.
Tension-type headache:
Note: Because barbiturates have been associated with medication overuse headache, transformation from episodic to chronic headache, and risk of dependence and abuse, reserve use for patients without alternative treatment options (Ref). If used, limit to ≤3 days per month to avoid medication overuse headache (Ref); studies have found increased risk with use of ≥5 days per month (Ref).
Solution (butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg per 15 mL): Oral: 15 to 30 mL every 4 hours, as needed; not to exceed 90 mL (butalbital 300 mg; acetaminophen 1,950 mg; and caffeine 240 mg) per day.
Tablets/Capsules: Oral: 1 to 2 tablets or capsules every 4 hours as needed; not to exceed 6 tablets or 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 or at high doses or if a patient has developed chronic migraines, 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, and 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.
No dosage adjustment provided in the manufacturer’s labeling; use with caution, especially with severe impairment.
No dosage adjustment provided in the manufacturer’s labeling; use with caution, especially with severe impairment.
Avoid use (Ref).
(For additional information see "Butalbital, acetaminophen (paracetamol), and caffeine: Pediatric drug information")
Note: Based on experience in adult patients, limit use to ≤3 days per month to avoid medication overuse headache (MOH); an adult study found increased risk of developing MOH at 1 year with use of ≥5 days per month (Ref). Some formulations may contain more acetaminophen; consult product-specific labeling. All sources of acetaminophen (eg, prescription, OTC, combination products) should be considered when evaluating a patient's maximum daily dose. To lower the risk for hepatotoxicity, limit daily dose to ≤75 mg/kg/day (maximum of 5 daily doses), not to exceed 4,000 mg/day; while recommended doses are generally considered safe, hepatotoxicity has been reported (rarely) even with doses below recommendations (Ref).
Headache, tension or muscle contraction: Note: Dosing based on products containing: Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg per tablet/capsule or per 15 mL (Vtol LQ).
Children ≥12 years and Adolescents:
Capsules, tablets: Oral: 1 to 2 tablets or capsules every 4 hours as needed; maximum daily dose: 6 tablets or capsules/day.
Solution (Vtol LQ): Oral: 15 to 30 mL every 4 hours as needed; maximum daily dose: 90 mL/day.
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, especially with severe impairment.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution, especially with severe impairment.
The following adverse drug reactions are derived from product labeling unless otherwise specified. Also see individual agents.
Frequency not defined:
Cardiovascular: Syncope, tachycardia
Dermatologic: Hyperhidrosis, pruritus
Endocrine & metabolic: Hot flash
Gastrointestinal: Abdominal pain, constipation, dysphagia, flatulence, heartburn, nausea, vomiting, xerostomia
Genitourinary: Diuresis
Hepatic: Acute hepatic failure
Hypersensitivity: Hypersensitivity reaction
Nervous system: Agitation, confusion, depression, dizziness, drowsiness, euphoria, excitement, fatigue, headache, increased energy, intoxicated feeling, lethargy, numbness, sedated state, seizure, shakiness, tingling sensation
Neuromuscular & skeletal: Lower extremity pain, muscle fatigue
Ophthalmic: Heavy eyelids
Otic: Otalgia, tinnitus
Respiratory: Dyspnea, nasal congestion
Miscellaneous: Fever
Postmarketing: Dermatologic: Erythema multiforme, toxic epidermal necrolysis
Hypersensitivity or intolerance to any component of the formulation; porphyria
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) (Yeakel 2013; manufacturer's labeling).
• Hepatotoxicity: Acetaminophen may cause severe hepatotoxicity, usually associated with excessive intake; risk is increased with alcohol use, preexisting liver disease, and intake of more than one source of acetaminophen-containing medication.
• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions (eg, swelling of face, mouth, and throat; respiratory distress; urticaria; rash; pruritus; vomiting) occur.
• Respiratory depression: Barbiturates may cause respiratory depression, particularly at increased doses (Bryczkowski 2012; Hocker 2018).
• Skin reactions: Rarely, acetaminophen may cause serious and potentially fatal skin reactions such as acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Discontinue treatment if skin reactions develop.
Disease-related concerns:
• Abdominal conditions: Use with caution in patients with acute abdominal conditions.
• Dependence: Tolerance, psychological dependence, and physical dependence may occur, particularly with prolonged use.
• G6PD deficiency: Use with caution in patients with known G6PD deficiency.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Renal impairment: Use with caution in patients with severe renal impairment.
Dosage form specific:
• Oral solution: Contains alcohol (7.368%).
Other warnings/precautions:
• Appropriate use: Because barbiturates have been associated with medication overuse headache, transformation from episodic to chronic headache, and risk of dependence and abuse, reserve use for patients without alternative treatment options (Bigal 2008; CHS [Worthington 2013]; EFNS [Bendtsen 2010]; EHF [Steiner 2019]; Loder 2013). If used, 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. Use with caution in patients with a history of peptic ulcer or gastroesophageal reflux disease; avoid in patients with symptomatic cardiac arrhythmias.
• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day.
• Withdrawal symptoms: Withdrawal symptoms (eg, worsened headache, nausea/vomiting, restlessness, anxiety, delirium, diaphoresis, disturbed sleep, seizures) may occur when discontinuing chronic or high-dose treatment with butalbital or if a patient has developed chronic migraines on butalbital. Tapering and discontinuation of therapy or replacement with a gradual phenobarbital taper is advised to minimize symptoms (Boes 2006; Garza 2025; manufacturer's labeling).
Hepatoxicity has been reported in patients using acetaminophen. In pediatric patients, this is most commonly associated with supratherapeutic dosing, more frequent administration than recommended, and use of multiple acetaminophen-containing products; however, hepatotoxicity has been rarely reported with recommended dosages (AAP [Sullivan 2011]; Heard 2014). All sources of acetaminophen (eg, prescription, OTC, combination) should be considered when evaluating a patient's maximum daily dose. To lower the risk for hepatotoxicity, the maximum daily acetaminophen dose should be limited to ≤75 mg/kg/day (maximum of 5 daily doses), not to exceed 4,000 mg/day (AAP [Sullivan 2011]; Heard 2014; Krenzelok 2012; Lavonas 2010). Acetaminophen avoidance or a lower total daily dose (2,000 to 3,000 mg/day) has been suggested for adults with increased risk for acetaminophen hepatotoxicity (eg, malnutrition, certain liver diseases, use of drugs that interact with acetaminophen metabolism); similar data are unavailable in pediatric patients (Hayward 2016; Larson 2007; Worriax 2007).
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Butalbital, acetaminophen, and caffeine oral solutions have been discontinued in the United States for >1 year.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Esgic: Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg [DSC]
Fioricet: Butalbital 50 mg, acetaminophen 300 mg, and caffeine 40 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
Zebutal: Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg [DSC]
Generic: Butalbital 50 mg, acetaminophen 300 mg, and caffeine 40 mg, Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg
Solution, Oral:
Vtol LQ: Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg per 15 mL (473 mL [DSC]) [contains alcohol, usp, fd&c yellow #6 (sunset yellow), methylparaben, propylene glycol, propylparaben, saccharin sodium]
Tablet, Oral:
BAC (Butalbital-Acetamin-Caff): Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg [scored; contains corn starch]
Esgic: Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg [DSC] [scored]
Generic: Butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg
May be product dependent
Capsules (Butalbital-APAP-Caffeine Oral)
50-300-40 mg (per each): $1.08 - $5.20
50-325-40 mg (per each): $4.81
Capsules (Fioricet Oral)
50-300-40 mg (per each): $10.10
Tablets (BAC (Butalbital-Acetamin-Caff) Oral)
50-325-40 mg (per each): $0.59
Tablets (Butalbital-APAP-Caffeine Oral)
50-325-40 mg (per each): $1.69 - $6.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
C-III or nonscheduled (DEA exemption status dependent)
Oral: Administer oral solution with a calibrated measuring device; do not use a household teaspoon or tablespoon to measure dose.
Oral: May take without regard to food; if GI upset occurs, may take with food.
Oral solution: Administer with a calibrated measuring device; do not use a household teaspoon or tablespoon to measure dose.
Tension-type headache: Relief of tension-type headache symptoms.
Limitations of use: Because barbiturates have been associated with medication overuse headache, transformation from episodic to chronic headache, and risk of dependence and abuse, reserve use for patients without alternative treatment options (Bigal 2008; CHS [Worthington 2013]; EFNS [Bendtsen 2010]; EHF [Steiner 2019]; Loder 2013). If used, limit 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). Safety and efficacy for the treatment of multiple recurrent headaches have not been established.
Butalbital, acetaminophen, and caffeine may be confused with butalbital, aspirin, and caffeine; butalbital and acetaminophen; butalbital, acetaminophen, caffeine, and codeine; butalbital, aspirin, caffeine, and codeine.
Fioricet may be confused with Fiorinal, Florinef, Lorcet, Percocet.
Repan may be confused with Riopan.
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]).
Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.
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.
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
Alcohol (Ethyl): May increase hepatotoxic effects of Acetaminophen. 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
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
Atazanavir: May increase serum concentration of UGT1A1 Substrates. Management: Do not use UGT1A1 substrates for which small increases in exposure can cause serious adverse effects together with atazanavir, and use caution with any UGT1A1 substrate, even when small changes in exposure are less likely to cause serious adverse effects. Risk D: Consider Therapy Modification
Atomoxetine: May increase hypertensive effects of Sympathomimetics. Atomoxetine may increase tachycardic effects of Sympathomimetics. Risk C: Monitor
Belumosudil: May increase serum concentration of UGT1A1 Substrates. Management: Avoid coadministration of belumosudil with substrates of UGT1A1 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the UGT1A1 substrate may be required. Risk D: Consider Therapy Modification
Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. 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
Busulfan: Acetaminophen may increase serum concentration of Busulfan. 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
CarBAMazepine: May increase metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor
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
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
Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor
Dasatinib: Acetaminophen may increase hepatotoxic effects of Dasatinib. Dasatinib may increase serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and dasatinib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider Therapy Modification
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
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
Flucloxacillin: May increase adverse/toxic effects of Acetaminophen. Specifically, the risk for high anion gap metabolic acidosis may be increased. Risk C: Monitor
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
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
Fosphenytoin-Phenytoin: May decrease serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor
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
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
Imatinib: Acetaminophen may increase hepatotoxic effects of Imatinib. Risk C: Monitor
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Acetaminophen may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
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
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
Isoniazid: May increase hepatotoxic effects of Acetaminophen. Isoniazid may increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Kratom: May increase adverse/toxic effects of Sympathomimetics. Risk X: Avoid
LamoTRIgine: Acetaminophen may decrease serum concentration of LamoTRIgine. Risk C: Monitor
Landiolol: Sympathomimetics may decrease therapeutic effects of Landiolol. Risk C: Monitor
Levothyroxine: May increase therapeutic effects of Sympathomimetics. Sympathomimetics may increase therapeutic effects of Levothyroxine. Levothyroxine may increase adverse/toxic effects of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Risk C: Monitor
Linezolid: May increase hypertensive effects of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider Therapy Modification
Lithium: Caffeine and Caffeine Containing Products may decrease serum concentration of Lithium. Risk C: Monitor
Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor
Lorlatinib: May decrease serum concentration of Acetaminophen. 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
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
MetyraPONE: May increase serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk X: Avoid
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
Mitapivat: May decrease serum concentration of UGT1A1 Substrates. 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/Minerals (with ADEK, Folate, Iron): May decrease serum concentration of Barbiturates. Risk C: Monitor
Nitric Oxide: May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Norfloxacin: May increase serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
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
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
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
PHENobarbital: May increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Phenylephrine (Systemic): Acetaminophen may increase serum concentration of Phenylephrine (Systemic). 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
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
Prilocaine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor
Primaquine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Primaquine. Specifically, the risk for methemoglobinemia may be increased. Management: Avoid concomitant use of primaquine and other drugs that are associated with methemoglobinemia when possible. If combined, monitor methemoglobin levels closely. Risk D: Consider Therapy Modification
Primidone: May increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Probenecid: May increase serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Management: Consider limiting acetaminophen use in combination with probenecid. Probenecid may reduce clearance of acetaminophen to one of its non-toxic metabolities, increasing the risk for acetaminophen toxicity, even a lower doses. Risk D: Consider Therapy Modification
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
RifAMPin: May increase hepatotoxic effects of Acetaminophen. RifAMPin may decrease serum concentration of Acetaminophen. Risk C: Monitor
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
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
Sodium Nitrite: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
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
SORAfenib: Acetaminophen may increase hepatotoxic effects of SORAfenib. SORAfenib may increase serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and sorafenib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider Therapy Modification
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
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
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
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
Vaccines: Acetaminophen may decrease therapeutic effects of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider Therapy Modification
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
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
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 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.
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).
Also refer to individual monographs for information specific to acetaminophen or caffeine.
Barbiturates, caffeine, and acetaminophen are present in breast milk.
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 (ACOG 2022).
Also refer to individual monographs for information specific to acetaminophen or caffeine.
Butalbital: Short- to intermediate-acting barbiturate; causes CNS depression via activation of inhibitory GABA receptors and inhibition of excitatory α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (Silberstein 2001; manufacturer's labeling).
Acetaminophen: Although not fully elucidated, the analgesic effects are believed to be due to activation of descending serotonergic inhibitory pathways in the CNS. Interactions with other nociceptive systems may be involved as well (Smith 2009). Antipyresis is produced from inhibition of the hypothalamic heat-regulating center.
Caffeine: Increases levels of 3'5' cyclic AMP by inhibiting phosphodiesterase; CNS stimulant which increases medullary respiratory center sensitivity to carbon dioxide, stimulates central inspiratory drive, and improves skeletal muscle contraction (diaphragmatic contractility).
Also see individual monographs for Acetaminophen and Caffeine.
Absorption: Butalbital: Well absorbed
Protein binding: Butalbital: 45%
Half-life elimination: Butalbital: 35 hours
Excretion: Butalbital: Urine (59% to 88% as unchanged drug and metabolites)
