BUTALBITAL, ACETAMINOPHEN AND CAFFEINE (butalbital 50 mg acetaminophen 500 mg caffeine 40 mg) Dailymed

Rx only

Description Section

DESCRIPTION
Butalbital, Acetaminophen and Caffeine Tablets, USP are supplied in tablet form for oral administration.

Butalbital (5-allyl-5-isobutylbarbituric acid), a slightly bitter, white, odorless, crystalline powder, is a short to intermediate-acting barbiturate. It has the following structural formula:

     BUTALBITAL STRUCTURE IMAGE

Acetaminophen (4'-hydroxyacetanilide), a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

     ACETAMINOPHEN STRUCTURE IMAGE

Caffeine (1,3,7-trimethylxanthine), a bitter, white powder or white-gulening needles, is a central nervous system stimulant. It has the following structural formula:

     CAFFEINE STRUCTURE IMAGE

Each Butalbital, Acetaminophen and Caffeine Tablet contains:
 Butalbital ...................................................................................... 50 mg Acetaminophen .......................................................................... 500 mg Caffeine ........................................................................................ 40 mg
In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and stearic acid.

Clinical Pharmacology Section

CLINICAL PHARMACOLOGY
This combination drug product is intended as a treatment for tension headache.

It consists of a fixed combination of butalbital, acetaminophen and caffeine. The role each component plays in the relief of the complex of symptoms known as tension headache is incompletely understood.

PHARMACOKINETICS SECTION

The behavior of the individual components is described below.
Butalbital
Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most 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 include 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% is conjugated.

The in vitro  plasma 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.
Acetaminophen
Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. 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.

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 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 is recovered in the urine, only 3% is unchanged drug.

See OVERDOSAGE   for toxicity information.

Indications & Usage Section

INDICATIONS AND USAGE
Butalbital, Acetaminophen and Caffeine Tablets are indicated for the relief of the symptom complex of tension (or muscle contraction) headache.

Evidence supporting the efficacy and safety of this combination product in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because butalbital is habit-forming and potentially abusable.

Contraindications Section

This product is contraindicated under the following conditions:
–Hypersensitivity or intolerance to any component of this product–Patients with porphyria.

Warnings And Precautions Section

WARNINGS
Butalbital is habit-forming and potentially abusable. Consequently, the extended use of this product is not recommended.
PRECAUTIONS General
Butalbital, Acetaminophen and Caffeine Tablets should be prescribed with 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.

INFORMATION FOR PATIENTS SECTION

Information for Patients
This product 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.

Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, 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.

MECHANISM OF ACTION SECTION

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

DRUG INTERACTIONS SECTION

Drug Interactions
The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.

Butalbital, Acetaminophen and Caffeine Tablets may enhance the effects of: other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression

DRUG & OR LABORATORY TEST INTERACTIONS SECTION

Drug/Laboratory Test Interactions
Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION

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.

PREGNANCY SECTION

Pregnancy 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 Mothers
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 USE SECTION

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

GERIATRIC USE SECTION

Geriatric Use
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 renal 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.

Adverse Reactions Section

ADVERSE REACTIONS
Frequently Observed

The most frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling.

Infrequently Observed

All adverse events tabulated below are classified as infrequent.

Central Nervous System:   headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells, numbness, sluggishness, seizure. Mental confusion, exclient, or depression can also occur due to intolerance, particularly in elderly or debilitated patients, or due to overdosage of butalbital.

Autonomic Nervous System:   dry mouth, hyperhidrosis.

Gastrointestinal:   difficulty swallowing, heartburn, flatulence, constipation.

Cardiovascular:   tachycardia.

Musculoskeletal:   leg pain, muscle fatigue.

Genitourinary:   diuresis.

Miscellaneous:   pruritus, fever, earache, nasal congestion, tinnitus, euphoria, allergic reactions.

Several cases of dermatological reactions, including toxic epidermal necrolysis and erythema multiforme, have been reported.

The following adverse drug events may be borne in mind as potential effects of the components of this product. Potential effects of high dosage are uled in the OVERDOSAGE   section.

Acetaminophen:   allergic reactions, rash, thrombocytopenia, agranulocytosis.

Caffeine:   cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia