Butalbital, Aspirin, Caffeine and Codeine Phosphate

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE- codeine phosphate, butalbital, caffeine and aspirin capsule
Jerome Stevens Pharmaceuticals

CIII Rx ONLY

DESCRIPTION

Each capsule for oral administration contains:

codeine phosphate, USP . . . . . . . . . . . . 30 mg (1/2 gr)

butalbital, USP . . . . . . . . . . . . . . . . . . . . . . . . . . 50 mg

caffeine, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 mg

aspirin, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 mg

Codeine phosphate occurs as fine, white, needle-shaped crystals, or white, crystalline powder. It is affected by light. Its chemical name is 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate. Its molecular weight is 406.37 and its molecular formula is C₁₈ H₂₁ NO₃ •H₃ PO₄ •½H₂ O.

Butalbital, 5-allyl-5-isobutyl-barbituric acid, a white odorless crystalline powder, is a short- to intermediate-acting barbiturate. Its molecular weight is 224.26 and its molecular formula is C₁₁ H₁₆ N₂ O₃ .

Caffeine, 1,3,7-trimethylxanthine, is a central nervous stimulant which occurs as a white powder or white glistening needles. Its molecular weight is (anhydrous) 194.19 and its molecular formula is C₈ H₁₀ N₄ O₂ .

Aspirin is benzoic acid, 2-(acetyloxy)-, with a molecular formula of C₉ H₈ O₄ and its molecular weight is 180.16.

Inactive Ingredients: D&C Yellow #10, D&C Yellow #10 Aluminum Lake, D&C Red #33, D&C Red #28, FD&C Blue #1, FD&C Blue #1 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Blue #10 Aluminum Lake, FD&C Red #40 Aluminum Lake, gelatin, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide, stearic acid, colloidal silicon dioxide.

CLINICAL PHARMACOLOGY

Butalbital, Aspirin, Caffeine and Codeine Phosphate Capsules is a combination drug product intended as a treatment for tension headache.

Pharmacokinetics

Bioavailability: The bioavailability of the components of the fixed combination of butalbital, aspirin, caffeine and codeine is identical to their bioavailability when butalbital, aspirin, caffeine and codeine is administered separately in equivalent molar doses.

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%-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 3.0 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 hepatcytes. 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 component of butalbital, aspirin, caffeine and codeine phosphate capsules is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.80 mcg/mL was obtained at 40 minutes after a 650 mg dose.

See OVERDOSAGE for toxicity information.

Codeine

Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. Codeine is not bound to plasma proteins and does not accumulate in body tissues.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide-conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

The bioavailability of the codeine component is equivalent to that of a solution. Peak concentrations of 198 ng/mL were obtained at 1 hour after a 60 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%-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 component of butalbital, aspirin, caffeine and codeine phosphate 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.

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-methyl-xanthine 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 component of butalbital, aspirin, caffeine and codeine phosphate 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.

INDICATIONS AND USAGE

Butalbital, Aspirin, Caffeine and Codeine Phosphate Capsules are indicated for the relief of the symptom complex of tension (or muscle contraction) headache.

Evidence supporting the efficacy of butalbital, aspirin, caffeine and codeine phosphate capsules is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: 1) butalbital, aspirin, caffeine and codeine; 2) codeine; 3) butalbital, aspirin and caffeine; 4) placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours. The combination product of butalbital, aspirin, caffeine and codeine proved statistically significantly superior to each of its components and to placebo on measures of pain relief.

Evidence supporting the efficacy and safety of butalbital, aspirin, caffeine and codeine in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable.