Butalbital/acetaminophen/caffeine

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  • Migraine and headache
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Butalbital/acetaminophen/caffeine Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Butalbital 50mg, acetaminophen 325mg, caffeine 40mg; tabs; caps.

    Pharmacological Class

    Barbiturate + analgesic + methylxanthine.

    How Supplied

    Contact supplier

    Manufacturer

    Various generic manufacturers

    Butalbital/acetaminophen/caffeine Indications

    Indications

    Tension (or muscle contraction) headache.

    Butalbital/acetaminophen/caffeine Dosage and Administration

    Adult

    1–2 tabs or caps every 4hrs as needed; max 6 daily. Not recommended for extended or repeated use.

    Children

    <12yrs: not established.

    Butalbital/acetaminophen/caffeine Contraindications

    Contraindications

    Porphyria.

    Butalbital/acetaminophen/caffeine Boxed Warnings

    Boxed Warning

    Hepatotoxicity.

    Boxed Warning

    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 4000 mg/day, and often involve more than one acetaminophen-containing product.

    Butalbital/acetaminophen/caffeine Warnings/Precautions

    Warnings/Precautions

    Increased risk of acute liver failure esp. in those with underlying liver disease and concomitant alcohol. Discontinue at the 1st sign of skin rash or any other hypersensitivity. Drug abusers. Severe hepatic or renal impairment (monitor). Acute abdominal conditions.  Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended.

    Warnings/Precautions

    General

    • Use caution in certain special-risk patients, such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, or acute abdominal conditions.

    • Butalbital is habit-forming and potentially abusable. The extended use of this product is not recommended.

    Hepatotoxicity

    • 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 4000 milligrams per day. 

    • The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

    • Increased risk of acute liver failure in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

    • Instruct patients not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately if they ingest more than 4000 milligrams of acetaminophen per day, even if they feel well. 

    Serious skin reactions

    • May cause rare, serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. 

    • Inform patients about the signs of serious skin reactions, and discontinue treatment at the first appearance of skin rash or any other sign of hypersensitivity.

    Hypersensitivity/anaphylaxis

    • There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. 

    • Discontinue treatment immediately and seek medical care if patients experience symptoms of hypersensitivity and anaphylaxis. Do not initiate treatment in patients with acetaminophen allergy. 

    Laboratory Tests

    • In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.  

    Pregnancy Considerations

    Teratogenic Effects 

    • Pregnancy Category C: Animal reproduction studies have not been conducted with this combination product. It is also not known whether butalbital, acetaminophen and caffeine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. This product should be given to a pregnant woman only when clearly needed.

    Nonteratogenic Effects

    • Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital-containing drug during the last two months of pregnancy. Butalbital was found in the infant's serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms. 

    Nursing Mother Considerations

    Caffeine, barbiturates and acetaminophen are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of potential for serious adverse reactions in nursing infants from butalbital, acetaminophen and caffeine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 

    Pediatric Considerations

    Safety and effectiveness in pediatric patients below the age of 12 have not been established.

    Geriatric Considerations

    Clinical studies of butalbital, acetaminophen and caffeine tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

    Renal Impairment Considerations

    In patients with severe renal disease, effects of therapy should be monitored with serial renal function tests.

    Hepatic Impairment Considerations

    In patients with severe hepatic disease, effects of therapy should be monitored with serial liver function tests.

    Other Considerations for Specific Populations

    Carcinogenesis, Mutagenesis, Impairment of Fertility 

    • No adequate studies have been conducted in animals to determine whether acetaminophen or butalbital have a potential for carcinogenesis, mutagenesis or impairment of fertility.

    Butalbital/acetaminophen/caffeine Pharmacokinetics

    Absorption

    Acetaminophen:  Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues.

    Butalbital: Butalbital is well absorbed from the gastrointestinal tract. The bioavailability of the butalbital component of butalbital, acetaminophen, and caffeine capsules is equivalent to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2,020 ng/mL is obtained at about 1.5 hours after a 100 mg dose.

    Caffeine: Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk. The bioavailability of the caffeine component for butalbital, acetaminophen, and caffeine capsules is equivalent to that of a solution except for a slightly longer time to peak. A peak concentration of 1,660 ng/mL was obtained in less than an hour for an 80 mg dose.

    Distribution

    Acetaminophen: Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues.

    Butalbital: Butalbital is expected to distribute to most of the tissues in the body. Barbiturates, in general, may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.

    The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL.This falls within the range of plasma protein binding (20% to 45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells.

    Caffeine: Caffeine is distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk. 

    Metabolism

    Acetaminophen: Acetaminophen is principally by liver metabolism (conjugation).

    Caffeine:  Caffeine is mainly metabolized by CYP1A2. Other enzymes, including CYP2E1, CYP3A4, CYP2C8 and CYP2C9 may play a minor role in its metabolism. Hepatic biotransformation prior to excretion results in about equal amounts of 1methylxanthine and 1-methyluric acid.

    Elimination

    Acetaminophen: The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. 

    Butalbital: Elimination of butalbital is primarily via the kidney (59% to 88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2, 3- dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% was conjugated. 

    Caffeine: Caffeine is cleared rapidly through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug.

    Butalbital/acetaminophen/caffeine Interactions

    Interactions

    May potentiate effects of alcohol, general anesthetics, tranquilizers, sedative-hypnotics, or other CNS depressants or narcotic analgesics; avoid. MAOIs may enhance CNS effects of butalbital. May cause false (+) urine test for 5-hydroxyindoleacetic acid.

    Butalbital/acetaminophen/caffeine Adverse Reactions

    Adverse Reactions

    Drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, intoxicated feeling; hepatotoxicity (APAP doses >4g/day); rare: serious skin reactions (eg, acute generalized exanthematous pustulosis [AGEP], Stevens-Johnson Syndrome [SJS], toxic epidermal necrolysis [TEN]), hypersensitivity.

    Butalbital/acetaminophen/caffeine Clinical Trials

    See Literature

    Butalbital/acetaminophen/caffeine Note

    Notes

    Formerly known under the brand name Esgic or Fioricet.

    Butalbital/acetaminophen/caffeine Patient Counseling

    Patient Counseling

    • Do not take Butalbital, Acetaminophen and Caffeine Tablets, USP if you are allergic to any of its ingredients. 

    • Discontinue treatment immediately and contact your healthcare provider if you develop signs of allergy such as a rash or difficulty breathing. 

    • Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.

    • May impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking this product. 

    • Avoid concomitant use with alcohol and other CNS depressants, which may produce an additive CNS depression.

    • Butalbital may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

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