BUTALBITAL, ASPIRIN, AND CAFFEINE- butalbital, aspirin and caffeine capsule
MUTUAL PHARMACEUTICAL COMPANY, INC.
Each butalbital, aspirin, and caffeine capsule for oral administration contains: butalbital, USP, 50 mg; aspirin, USP, 325 mg; caffeine, USP, 40 mg.
Butalbital, 5-allyl-5-isobutyl-barbituric acid, has a molecular formula of C11 H16 N2 O3 and a molecular weight of 224.26.
Aspirin, benzoic acid, 2-(acetyloxy)-, has a molecular formula of C9 H8 O4 and a molecular weight of 180.16.
Caffeine, 1, 3, 7-trimethylxanthine, has a molecular formula of C8 H10 N4 O2 and a molecular weight of 194.19.
Active Ingredients: aspirin, USP, butalbital, USP, and caffeine, USP.
Inactive Ingredients: alginic acid, corn starch, pregelatinized starch, sodium lauryl sulfate, and talc. The capsule contains: FD&C Blue #2, FDA/E172 yellow iron oxide, gelatin and titanium dioxide. The imprinting ink contains: D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, and propylene glycol.
Pharmacologically, butalbital, aspirin, and caffeine capsules combines the analgesic properties of aspirin with the anxiolytic and muscle relaxant properties of butalbital.
The clinical effectiveness of butalbital, aspirin and caffeine capsules in tension headache has been established in double-blind, placebo-controlled, multi-clinic trials. A factorial design study compared butalbital, aspirin and caffeine capsules with each of its major components. This study demonstrated that each component contributes to the efficacy of butalbital, aspirin, and caffeine capsules in the treatment of the target symptoms of tension headache (headache pain, psychic tension, and muscle contraction in the head, neck, and shoulder region). For each symptom and the symptom complex as a whole, butalbital, aspirin, and caffeine capsules were shown to have significantly superior clinical effects to either component alone.
The behavior of the individual components is described below.
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. The factors affect not necessarily the extent of absorption of total salicylates but more the stability of aspirin prior to absorption.
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.
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.
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%). The bioavailability of the aspirin component of butalbital, aspirin, and caffeine capsules is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.8 mcg/mL was obtained at 40 minutes after a 650 mg dose.
See OVERDOSAGE for toxicity information.
Butalbital is well absorbed from the gastrointestinal tract and 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.
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-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with 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.
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 2020 ng/mL is obtained at about 1.5 hours after a 100 mg dose.
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.
See OVERDOSAGE for toxicity information.
Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.
Caffeine is cleared rapidly through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid. Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug.
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 1660 ng/mL was obtained in less than an hour for an 80 mg dose.
See OVERDOSAGE for toxicity information.
BUTALBITAL, ASPIRIN, AND CAFFEINE Indications and Usage
Butalbital aspirin, and caffeine capsules are indicated for the relief of the symptom complex of tension (or muscle contraction) headache. Evidence supporting the efficacy and safety of butalbital, aspirin, and caffeine capsules in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because butalbital is habit-forming and potentially abusable.
Butalbital, aspirin, and caffeine capsules are contraindicated under the following conditions:
- Hypersensitivity or intolerance to aspirin, caffeine, or butalbital.
- Patients with hemorrhagic diathesis (e.g., hemophilia, hypoprothrombinemia, von Willebrand’s disease, the thrombocytopenias, thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe vitamin K deficiency and severe liver damage).
- Patients with the syndrome of nasal polyps, angioedema and bronchospastic reactivity to aspirin or other nonsteroidal anti-inflammatory drugs. Anaphylactoid reactions have occurred in such patients.
- Peptic ulcer or other serious gastrointestinal lesions.
- Patients with porphyria.
Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking.
Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders. Aspirin administered preoperatively may prolong the bleeding time. Butalbital is habit-forming and potentially abusable. Consequently, the extended use of butalbital, aspirin, and caffeine capsules is not recommended. Results from epidemiologic studies indicate an association between aspirin and Reye’s Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu.
Butalbital, aspirin, and caffeine capsules should be prescribed with caution for certain special-risk patients such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, coagulation disorders, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, or prostatic hypertrophy.
Aspirin should be used with caution in patients on anticoagulant therapy and in patients with underlying hemostatic defects, and extreme caution in the presence of peptic ulcer.
Precautions should be taken when administering salicylates to persons with known allergies. Hypersensitivity to aspirin is particularly likely in patients with nasal polyps, and relatively common in those with asthma.
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