Butalbital, Aspirin, And Caffeine

INDICATIONS 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.

DOSAGE AND ADMINISTRATION One or 2 capsules every 4 hours. Total daily dose should not exceed 6 capsules. Extended and repeated use of this product is not recommended because of the potential for physical dependence.

ADVERSE REACTIONS The most frequent adverse reactions are drowsiness and dizziness. Less frequent adverse reactions are lightheadedness and gastrointestinal disturbances including nausea, vomiting, and flatulence. A single incidence of bone marrow suppression has been reported with the use of butalbital, aspirin, and caffeine capsules. Several cases of dermatological reactions including toxic epidermal necrolysis and erythema multiforme have been reported. Butalbital, aspirin, and caffeine capsules may also cause exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and fixed drug eruption (FDE) ( see WARNINGS ).

Pharmacokinetics The behavior of the individual components is described below. 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. 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 as lower 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 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 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. 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. 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 . Caffeine 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 1,660 ng/mL was obtained in less than an hour for an 80 mg dose. See OVERDOSAGE for toxicity information .