Butalbital/aspirin/caffeine

— THERAPEUTIC CATEGORIES —
  • 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/aspirin/caffeine Generic Name & Formulations

    Legal Class

    CIII

    General Description

    Butalbital 50mg, aspirin 325mg, caffeine 40mg; caps.

    Pharmacological Class

    Barbiturate + salicylate + methylxanthine.

    How Supplied

    Contact supplier

    Manufacturer

    Various generic manufacturers

    Butalbital/aspirin/caffeine Indications

    Indications

    Tension (or muscle contraction) headache.

    Indications

    Butalbital, aspirin, and caffeine capsules are indicated for the relief of the symptom complex of tension (or muscle contraction) headache. The efficacy and safety data supporting butalbital, aspirin, and caffeine capsules in the treatment of multiple recurrent headaches is unavailable. Butalbital should be used with caution because it is habit-forming and potentially abusable.

    Butalbital/aspirin/caffeine Dosage and Administration

    Adult

    Use lowest effective dose for shortest duration. Not recommended for extended or repeated use. 1–2 caps every 4hrs, as needed; max 6 caps/day. 

    Children

    Not established.

    Butalbital/aspirin/caffeine Contraindications

    Contraindications

    Hemorrhagic diathesis (eg, hemophilia, hypoprothrombinemia, von Willebrand's disease, the 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.

    Butalbital/aspirin/caffeine Boxed Warnings

    Not Applicable

    Butalbital/aspirin/caffeine Warnings/Precautions

    Warnings/Precautions

    Abuse potential. Bleeding disorders. Coagulation disorders. Head injuries. Elevated intracranial pressure. Acute abdominal conditions. Hypothyroidism. Urethral stricture. Addison's disease. Prostatic hypertrophy. Underlying hemostatic defects. Reye's syndrome. Children/teenagers with chicken pox or flu. Asthma. Aspirin allergy. Severe renal or hepatic impairment. Elderly. Debilitated. Embryo-fetal toxicity. Pregnancy (avoid during ≥30 weeks gestation): increased risk of premature closure of the fetal ductus arteriosus; (20–30 weeks gestation): may cause fetal renal dysfunction/oligohydramnios; if treatment needed, limit dose and duration of use. Risk of neonatal opioid withdrawal syndrome during prolonged use. Labor & delivery, nursing mothers: not recommended.

    Warnings/Precautions

    General

    • May cause anaphylactic shock and other severe allergic reactions. Confirm if the patient is allergic to aspirin, although a specific history of allergy may be lacking.

    • Significant bleeding may occur in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders. May prolong the bleeding time if aspirin is administered preoperatively. Butalbital is habit-forming and potentially abusable. The extended use of Butalbital, Aspirin, and Caffeine Capsules, USP are not recommended. 

    • Epidemiologic studies have indicated an associated between aspirin and Reye’s Syndrome. Use caution in children, including teenagers, with chicken pox or flu.

    • Use caution for certain special-risk patients such as the elderly or debilitated, and those with severe renal or hepatic impairment, coagulation disorders, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, or prostatic hypertrophy.

    • Use caution in patients on anticoagulant therapy and in patients with underlying hemostatic defects, and extreme caution in the presence of peptic ulcer.

    • Use precaution when administering salicylates to persons with known allergies. Increased likelihood of hypersensitivity to aspirin in patients with nasal polyps, and relatively common in those with asthma.

    Fetal Toxicity

    • Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women at about 30 weeks gestation and later. Increased risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

    • Oligohydramnios/Neonatal Renal Impairment: May cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment if used at about 20 weeks gestation or later in pregnancy. 

      • Oligohydramnios is often, but not always, reversible with treatment discontinuation. Prolonged oligohydramnios may lead to complications including limb contractures and delayed lung maturation. 

      • If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit use to the lowest effective dose and shortest duration possible. If Butalbital, Aspirin, and Caffeine Capsules, USP treatment extends beyond 48 hours, consider ultrasound monitoring of amniotic fluid. Discontinue if oligohydramnios occurs and follow up according to clinical practice.

    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

    • DRESS has been reported with some of these events being fatal or life-threatening. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. 

    • It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. 

    • Discontinue use and evaluate the patient immediately if early manifestations of hypersensitivity, such as fever or lymphadenopathy, are present.

    Laboratory Tests

    • Monitor with serial liver and/or renal function tests in patients with severe hepatic or renal disease.

    Pregnancy Considerations

    Embryo-Fetal Toxicity 

    • Avoid use of aspirin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment is unavoidable for a pregnant woman between about 20 to 30 weeks gestation, monitor for oligohydramnios if treatment continues for longer than 48 hours.

    Risk Summary

    • May cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Limit dose and duration of use between about 20 and 30 weeks of gestation, and avoid use at about 30 weeks of gestation and later in pregnancy.

    Clinical Considerations

    • Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women at about 30 weeks gestation and later. Increased risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

    • Oligohydramnios/Neonatal Renal Impairment: If treatment is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If treatment extends beyond 48 hours, consider ultrasound monitoring of amniotic fluid.  Discontinue treatment if oligohydramnios occurs.

    Nursing Mother Considerations

    While the significance of aspirin, caffeine, and barbiturates on nursing infants are not known, they are excreted in breast milk in small amounts. 

    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 have not been established.

    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 

    • Adequate long-term studies have been conducted in mice and rats with aspirin, alone or in combination with other drugs, in which no evidence of carcinogenesis was seen. No adequate studies have been conducted in animals to determine whether aspirin has a potential for mutagenesis or impairment of fertility. No adequate studies have been conducted in animals to determine whether butalbital has a potential for carcinogenesis, mutagenesis, or impairment of fertility.

    Labor and Delivery

    • Ingestion of aspirin prior to delivery may prolong delivery or lead to bleeding in the mother or neonate.

    Butalbital/aspirin/caffeine Pharmacokinetics

    Absorption

    Aspirin: The systemic availability of aspirin after an oral dose is highly dependent on the dosage form, the presence of food, the gastric emptying time, gastric pH, antacids, buffering agents, and particle size. These factors affect not necessarily the extent of absorption of total salicylates but more the stability of aspirin prior to absorption. 

    The bioavailability of the aspirin component of butalbital, aspirin, and caffeine capsules is equivalent to that of a solution except for as lower rate of absorption. A peak concentration of 8.8 mcg/mL was obtained at 40 minutes after a 650 mg dose. 

    Butalbital: Butalbital is well absorbed from the gastrointestinal tract. The bioavailability of the butalbital component of butalbital, aspirin, 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, aspirin, 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

    Aspirin: During the absorption process and after absorption, aspirin is mainly hydrolyzed to salicylic acid and distributed to all body tissues and fluids, including fetal tissues, breast milk, and the central nervous system (CNS). Highest concentrations are found in plasma, liver, renal cortex, heart, and lung. In plasma, about 50% to 80% of the salicylic acid and its metabolites are loosely bound to plasma proteins.

    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

    Aspirin: The biotransformation of aspirin occurs primarily in the hepatocytes. The major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides of salicylate (15%), and gentisic and gentisuric acid (1%). 

    Caffeine:  Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid.

     

    Elimination

    Aspirin: The clearance of total salicylates is subject to saturable kinetics; however, first-order elimination kinetics are still a good approximation for doses up to 650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic acid and/or total salicylates is about 3 hours. The elimination of therapeutic doses is through the kidneys either as salicylic acid or other biotransformation products. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate.

    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/aspirin/caffeine Interactions

    Interactions

    Additive effects of CNS depression with alcohol and other CNS depressants (eg, narcotic analgesics, general anesthetics, tranquilizers, chlordiazepoxide, sedative-hypnotics); avoid. Concomitant MAOIs may enhance CNS effects. Increased risk of bleeding with concomitant NSAIDs (avoid), oral anticoagulants. Increased hypoglycemia with oral antidiabetic agents, insulin. Withdrawal of corticosteroids may result in salicylism in those receiving concomitant corticosteroids and chronic use of aspirin. May potentiate 6-mercaptopurine, methotrexate. Antagonizes uricosuric agents (eg, probenecid, sulfinpyrazone). May interfere with lab tests in blood or urine (eg, serum amylase, fasting blood glucose, cholesterol, protein, SGOT, uric acid, prothrombin time, bleeding time, glucose, 5- hydroxyindoleacetic acid, Gerhardt ketone, VMA, uric acid, diacetic acid, and spectrophotometric detection of barbiturates).

    Butalbital/aspirin/caffeine Adverse Reactions

    Adverse Reactions

    Drowsiness, dizziness, lightheadedness, nausea, vomiting, flatulence; hypersensitivity reactions, DRESS (discontinue if occurs), erythema multiforme, TEN.

    Butalbital/aspirin/caffeine Clinical Trials

    See Literature

    Butalbital/aspirin/caffeine Note

    Notes

    Formerly known under the brand name Fiorinal.

    Butalbital/aspirin/caffeine Patient Counseling

    Patient Counseling

    Patients should be informed that butalbital, aspirin, and caffeine capsules contain aspirin and should not be taken by patients with an aspirin allergy. 

    Serious Skin Reactions, including DRESS 

    • Patient should stop taking butalbital, aspirin, and caffeine capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible.

    • Butalbital, aspirin, and caffeine capsules may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking butalbital, aspirin, and caffeine capsules.

    • Alcohol and other CNS depressants may produce an additive CNS depression when taken with butalbital, aspirin, and caffeine capsules and should be avoided. 

    • 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.

    Pregnancy

    • Embryo-Fetal Toxicity: Inform pregnant women to avoid use of aspirin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with butalbital, aspirin, and caffeine capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours.

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