Butalbital
CATEGORIES, DRUG CLASSES & BRAND NAMES
CATEGORIES:
Headache, tension;
DEA Class CIII;
FDA Approved 1984 Nov
Drug Classes:
Analgesics, non-narcotic;
Barbiturates;
Xanthine derivatives
BRAND NAMES: Americet; Anolor 300; Anoquan; Endolor; Esgic; Esgic-Plus; Ezol; Femcet; Fioricet; Fiorpap; Geone; Isocet; Medigesic; Minotal; Pacaps; Pharmagesic; Repan; Tencet; Triad
DESCRIPTION
Each Tablet for Oral Administration Contains: Acetaminophen, 325 mg; Butalbital*, 50 mg; caffeine, 40 mg.
*WARNING: May be habit forming.
Active Ingredients: Acetaminophen, Butalbital and caffeine.
Fioricet Inactive Ingredients: Crospovidone, FD&C blue no. 1, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid.
Butalbital, 5-allyl-5-isobutylbarbituric acid, a white, odorless, crystalline powder having a slightly bitter taste, is a short- to intermediate-acting barbiturate.
Its molecular formula is C11H16N2O3, and its molecular weight is 224.26
Acetaminophen, 4’-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic, and antipyretic which occurs as a white, odorless, crystalline powder possessing a slightly bitter taste.
Its molecular formula is C8H9NO2, and its molecular weight 151.16.
Caffeine, 1, 3, 7-trimethylxanthine, is a central nervous system stimulant which occurs as a white powder or white glistening needles. It also has a bitter taste.
Its molecular formula is C8H10N4O2, and its molecular weights is 194.19.
CLINICAL PHARMACOLOGY
This combination drug product is intended as a treatment for tension headache.
It consists of a fixed combination of acetaminophen, Butalbital 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.
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.)
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 (59-88% 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 urine, 32% is conjugated.
The in vitro plasma protein binding of Butalbital is 45% over the concentration range of 0.5 to 20 ?g/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 OVERDOSAGE for toxicity information.)
Caffeine
Like most xanthines, caffeine is rapidly absorbed and distributed through most 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 biotrasformation 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
Acetaminophen, Butalbital 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
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.
PRECAUTIONS
General
Acetaminophen, Butalbital 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 the Patient
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.
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/Laboratory Test Interactions
Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.
Carcinogenesis, Mutagenesis, and 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, Teratogenic Effects, Pregnancy Category C
Animal reproduction studies have not been conducted with this combination product. It is also not known whether acetaminophen, Butalbital 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 2-day-old male infant whose mother had take a Butalbital-containing drug during the last 2 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, barbiurates 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 acetaminophen, Butalbital and caffeine, a decision should be made whether
to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in children below the age of 12 have not been established.
DRUG-INTERACTIONS
The CNS effects of Butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.
Acetaminophen, Butalbital 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.
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, excitement 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 listed in OVERDOSAGE.
- Acetaminophen: Allergic reactions, rash, thrombocytopenia, agranulocytosis.
- Caffeine: Cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia.
DRUG ABUSE AND DEPENDENCE
Butalbital
Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of
intoxication increase; tolerance to a fatal dosage, however, does not increase more than 2-fold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and
delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days.
Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patient’s regular dosage level and gradually decreasing the
daily dosage as tolerated by the patient.
OVERDOSAGE
Following an acute overdosage of acetaminophen, Butalbital and caffeine, toxicity may result from the barbiturate or the acetaminophen. Toxicity due to caffeine is less likely, due to the relatively small amounts in this formulation.
Signs and Symptoms
Toxicity from barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; and hypovolemic shock.
In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necroses, hypoglycemic coma and thrombocytopenia may also occur. Early symptoms following a potentially
hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48-72 hours post-ingestion. In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 g, or fatalities with less
than 15 g.
Acute caffeine poisoning may cause insomnia, restlessness, tremor, delirium, tachycardia and extrasystoles.
Treatment
A single or multiple overdose with this combination product is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended.
Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying.
The first dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required.
Hypotension is usually hypovolemic and should respond to fluids. Pressors should be avoided. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration. If renal function is normal, forced diuresis may aid in the
elimination of the barbiturate. Alkalinization of the urine increases renal excretion of some barbiturates, especially phenobarbital.
Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. If hypoprothrombinemia occurs due to acetaminophen overdose, vitamin K should be administered intravenously.
If the dose of acetaminophen may have exceeded 140 mg/kg, acetylcysteine should be administered as early as possible. Serum acetaminophen levels should be obtained, since levels 4 or more hours following ingestion help predict acetaminophen toxicity. Do not await acetaminophen assay results before initiating
treatment. Hepatic enzymes should be obtained initially, and repeated at 24 hour intervals.
Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration.
Toxic Doses (for adults)
- Acetaminophen: Toxic dose 10 g (30 tablets).
- Butalbital: Toxic dose 1 g (20 tablets).
- Caffeine: Toxic dose 1 g (25 tablets).
DOSAGE AND ADMINISTRATION
One tablet every 4 hours. Total daily dosage should not exceed 6 tablets.
Extended and repeated use of this product is not recommended because of the potential for physical dependence.
HOW SUPPLIED
Fioricet tablets are round, light blue tablets debossed with "FIORICET" and the Sandoz logo on one side and a different Sandoz logo on the other side.
Storage
Store below 30?C (86?F).
Protect from moisture.
Dispense in a tight, light-resistant container with a child-resistant closure.
Revision date: July 3, 2011
Last revised: by Tatiana Kuznetsova, D.M.D.
Drugs & Medications
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