Butalbital, Acetaminophen and Caffeine

BUTALBITAL, ACETAMINOPHEN AND CAFFEINE- butalbital, acetaminophen and caffeine tablet
West-Ward Pharmaceutical Corp

Hepatotoxicity
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product.

DESCRIPTION:

Each tablet, for oral administration contains:

Butalbital, USP………………………….50 mg
Acetaminophen, USP…………………..325 mgCaffeine, USP …………………………..40 mg

In addition, each tablet contains the following inactive ingredients: Colloidal Silicon Dioxide, Croscarmellose Sodium, FD&C Blue No. 1 Aluminum Lake, Magnesium Stearate, Microcrystalline Cellulose, Polyvinylpyrrolidone, Pregelatinized Starch, Sodium Starch Glycolate,and Stearic Acid.

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

Structural Formula
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Acetaminophen (4′-hydroxyacetanilide), is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

Structural Formula
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Caffeine (1,3,7-trimethylxanthine), is a central nervous system stimulant. It has the following structural formula:

Structural Formula
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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

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 protein binding of butalbital is 45% over the concentration range of 0.5-20 mcg/mL. This falls within the range of plasma protein binding (20%-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 OVERDOSAGEfor 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 AND USAGE

Butalbital, Acetaminophen, and Caffeine Tablets, USP 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

This product is contraindicated under the following conditions:

  • Hypersensitivity or intolerance to any component of this product
  • Patients with porphyria.

WARNINGS

Butalbital is habit-forming and potentially abusable. Consequently, the extended use of this product is not recommended.

Hepatotoxicity
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

Serious skin reactions
Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity/anaphylaxis
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Butalbital, Acetaminophen and Caffeine tablets immediately and seek medical care if they experience these symptoms. Do not prescribe Butalbital, Acetaminophen and Caffeine tablets for patients with acetaminophen allergy.

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