Butalbital, Acetaminophen and Caffeine with Codeine Phosphate

BUTALBITAL, ACETAMINOPHEN AND CAFFEINE WITH CODEINE PHOSPHATE- acetaminophen, butalbital, caffeine and codeine phosphate capsule
West-Ward Pharmaceutical Corp

WARNING: HEPATOTOXICITY AND DEATH RELATED TO ULTRA-RAPID METABOLISMOF CODEINE TO MORPHINE

  • 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.
  • Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to CYP2D6 polymorphism.

DESCRIPTION:

Butalbital, acetaminophen, and caffeine with codeine phosphate is supplied in capsule form for oral administration. Each capsule contains the following active ingredients:

Butalbital, USP……………………………………………………….50 mg
Acetaminophen, USP…………………………………………………325 mg
Caffeine, USP………………………………………………………..40 mgCodeine Phosphate, USP…………………………………………….30 mg

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

The structural formula for Butalbital.
(click image for full-size original)

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

The structural formula for Acetaminophen.
(click image for full-size original)

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

The structural formula for Caffeine.
(click image for full-size original)

Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt)hemihydrate) is a narcotic analgesic and antitussive. It has the following structural formula:

The structural formula for Codeine phosphate.
(click image for full-size original)

In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, and sodium starch glycolate.

Capsule shell contains: FD&C Blue #2, FD&C Red #3, Gelatin, Red Iron Oxide, Titanium Dioxide, and Yellow Iron Oxide. The imprinting ink contains Titanium Dioxide.

CLINICAL PHARMACOLOGY:

Butalbital, acetaminophen, and caffeine with codeine phosphate is a combination drug product intended as a treatment for tension headache.

Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules, consist of a fixed combination of butalbital 50 mg, acetaminophen 325 mg and caffeine 40 mg. 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 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 OVERDOSAGEfor 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.

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. The plasma concentration does not correlate with brain concentration or relief of pain; however, 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 (about 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.

See OVERDOSAGE for toxicity information.

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