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 per day, and often involve more than one acetaminophen-containing product.
Note: Based on experience in adult patients, limit use to ≤3 days per month to avoid medication overuse headache (Ref). Multiple product formulations available; use precaution with product selection. 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: Children ≥12 years and Adolescents:
Butalbital 25 mg/acetaminophen 325 mg: Oral: 2 tablets every 4 hours as needed; maximum daily dose: 12 tablets/24 hours (total: butalbital 300 mg/acetaminophen 3,900 mg per 24 hours).
Butalbital 50 mg/acetaminophen 300 or 325 mg: Oral: 1 or 2 tablets every 4 hours as needed; maximum daily dose: 6 tablets/24 hours (butalbital 300 mg/acetaminophen ≤1,950 mg per 24 hours).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment; see individual agents.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment; see individual agents.
(For additional information see "Butalbital and acetaminophen (paracetamol): Drug information")
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:
Butalbital 25 mg/acetaminophen 325 mg: 2 tablets every 4 hours as needed (maximum: 12 tablets [butalbital 300 mg/acetaminophen 3,900 mg] per 24 hours).
Butalbital 50 mg/acetaminophen 300 to 325 mg: 1 or 2 tablets every 4 hours as needed (maximum: 6 tablets [butalbital 300 mg/acetaminophen 1,950 mg] per 24 hours).
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 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.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment.
The following adverse drug reactions are derived from product labeling unless otherwise specified. Also see acetaminophen.
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: 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 leg pain, muscle fatigue
Ophthalmic: Heavy eyelids
Otic: Otalgia, tinnitus
Respiratory: Dyspnea, nasal congestion
Miscellaneous: Fever
Postmarketing: Dermatologic: Erythema multiforme, toxic epidermal necrolysis
Hypersensitivity to butalbital, acetaminophen, or 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 that require mental alertness (eg, operating machinery, driving).
• Hepatotoxicity: Risk is increased with alcohol use, preexisting liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients.
• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur.
• Skin reactions: Rarely, acetaminophen may cause serious and potentially fatal skin reactions such as acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Discontinue treatment if severe skin reactions develop.
Disease-related concerns:
• Abdominal conditions: Use with caution in patients with acute abdominal conditions.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological, and physical dependence may occur with prolonged use.
• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks per day may increase the risk of liver damage.
• 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.
• Respiratory disease: Use with caution in patients with preexisting respiratory compromise (hypoxia and/or hypercapnia), chronic obstructive pulmonary disease, or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.
Special populations:
• Older adult: Use with caution in older adults.
Other warnings/precautions:
• Appropriate use: Because barbiturates have been associated with medication-overuse headache, reserve use for patients without alternative treatment options (EFNS [Bendtsen 2010]; Kaniecki 2012). 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).
• 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).
• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day.
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).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Generic: Butalbital 50 mg and acetaminophen 300 mg
Tablet, Oral:
Allzital: Butalbital 25 mg and acetaminophen 325 mg
Bupap: Butalbital 50 mg and acetaminophen 300 mg [DSC] [contains fd&c red #40(allura red ac)aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Generic: Butalbital 50 mg and acetaminophen 300 mg, Butalbital 50 mg and acetaminophen 325 mg
Yes
Capsules (Butalbital-Acetaminophen Oral)
50-300 mg (per each): $14.55
Tablets (Allzital Oral)
25-325 mg (per each): $4.70
Tablets (Butalbital-Acetaminophen Oral)
50-300 mg (per each): $1.13 - $14.55
50-325 mg (per each): $1.55 - $1.56
Tablets (Tencon Oral)
50-325 mg (per each): $0.80
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: May take without regard to food; if GI upset occurs, may take with food.
Store at 20ºC to 25ºC (68ºF to 77ºF). Protect from light and moisture.
Treatment of tension or muscle contraction headache (FDA approved in ages ≥12 years and adults)
Butalbital and acetaminophen may be confused with butalbital, acetaminophen, and caffeine; and butalbital, acetaminophen, caffeine, and codeine.
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.
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
Alcohol (Ethyl): May increase hepatotoxic effects of Acetaminophen. 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
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
Blood Pressure Lowering Agents: Barbiturates may increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Busulfan: Acetaminophen may increase serum concentration of Busulfan. 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
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
Doxycycline: Barbiturates may decrease serum concentration of Doxycycline. Risk C: Monitor
Flucloxacillin: May increase adverse/toxic effects of Acetaminophen. Specifically, the risk for high anion gap metabolic acidosis may be increased. Risk C: Monitor
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
Hemin: Barbiturates may decrease therapeutic effects of Hemin. Risk X: Avoid
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
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
LamoTRIgine: Acetaminophen may decrease serum concentration of LamoTRIgine. 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
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
Mitapivat: May decrease serum concentration of UGT1A1 Substrates. 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
Oxybate Salt Products: Barbiturates may increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
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
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
RifAMPin: May increase hepatotoxic effects of Acetaminophen. RifAMPin may decrease serum concentration of Acetaminophen. 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
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
Theophylline Derivatives: Barbiturates may decrease serum concentration of Theophylline Derivatives. 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
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
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).
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 acetaminophen monograph for information specific to acetaminophen.
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.
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.
Also see Acetaminophen monograph.
Absorption: Butalbital: Well absorbed
Protein binding: Butalbital: 45%
Half-life elimination: Butalbital: ~35 hours
Excretion: Butalbital: Urine (59% to 88% as unchanged drug or metabolites)
