Acetaminophen; Butalbital; Caffeine; Codeine Phosphate (0022)
| Ingredients: |
Acetaminophen; Butalbital; Caffeine; Codeine Phosphate |
| Indications: |
Pain, mild to moderate |
| Pregnancy Category: |
C |
| FDA Approved: |
1992- 07- 01 |
| Classes: |
Analgesics, narcotic; Barbiturates; Xanthine derivatives |
| Brand Names: |
Fioricet with Codeine
-
US
;
Phrenilin with Caffeine and Codeine
-
US
;
|
| DEA schedules: |
Schedule III |
DESCRIPTION
|
| |
Fioricet with codeine is supplied in capsule form for oral administration.
Each Capsule Contains:
- Acetaminophen: 325 mg
- Butalbital: 50 mg
- Caffeine: 40 mg
- Codeine Phosphate: 30 mg
Codeine phosphate [morphine- 3- methyl ether phosphate (1:1) (salt) hemihydrate, C18 H24 NO7 P, anhydrous mw 397.37], is a narcotic analgesic and antitussive.
Butalbital (5- allyl- 5- isobutylbarbituric acid, C11 H16 N2 O3 , mw 224.26), is a short- to intermediate- acting barbiturate.
Caffeine (1, 3, 7- trimethylxanthine, C8 H10 N4 O2 , mw 194.19), is a central nervous system stimulant.
Acetaminophen (4′- hydroxyacetanilide, C8 H9 NO2 , mw 151.16), is a non- opiate, non- salicylate analgesic and antipyretic.
Active Ingredients: Codeine phosphate, butalbital, caffeine, and acetaminophen.
Inactive Ingredients: Black iron oxide, colloidal silicon dioxide, D&C red no. 7 (calcium lake), D&C red no. 33, FD&C blue no. 1, FD&C blue no.
1 (aluminum lake), gelatin, magnesium stearate, pregelatinized starch, red iron oxide, sodium lauryl sulfate, and titanium
dioxide.
May Also Include: Benzyl alcohol, butylparaben, carboxymethyl cellulose sodium, edetate calcium disodium, methylparaben, propylparaben, silicon
dioxide, and sodium propionate.
|
CLINICAL PHARMACOLOGY
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| |
Butalbital; acetaminophen; caffeine; codeine phosphate is a combination drug product intended as a treatment for tension headache.
Fioricet consists 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.
Codeine
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| |
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
(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.
|
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 the urine, 32% is conjugated.
The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 μg/ 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
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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- methyl- xanthine 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.
|
Acetaminophen
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| |
Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma
half- life is 1.25- 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.
|
|
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INDICATIONS AND USAGE
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Butalbital; acetaminophen; caffeine; codeine phosphate is indicated for the relief of the symptom complex of tension (or muscle
contraction) headache.
Evidence supporting the efficacy and safety of butalbital; acetaminophen; caffeine; codeine phosphate 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.
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CONTRAINDICATIONS
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Butalbital; acetaminophen; caffeine; codeine phosphate is contraindicated under the following conditions:
| • |
Hypersensitivity or intolerance to acetaminophen, caffeine, butalbital, or codeine.
|
| • |
Patients with porphyria.
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WARNINGS
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In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics
may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other
CNS depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries.
Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal
conditions.
Butalbital and codeine are both habit- forming and potentially abusable. Consequently, the extended use of butalbital; acetaminophen;
caffeine; codeine phosphate is not recommended.
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PRECAUTIONS
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| |
General
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Butalbital; acetaminophen; caffeine; codeine phosphate 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, head injuries, elevated
intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison's disease, or prostatic hypertrophy.
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Information for the Patient
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Butalbital; acetaminophen; caffeine; codeine phosphate 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 butalbital;
acetaminophen; caffeine; codeine phosphate.
Alcohol and other CNS depressants may produce an additive CNS depression, when taken with butalbital; acetaminophen; caffeine;
codeine phosphate, and should be avoided.
Codeine and 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.
For information on use in geriatric patients, see PRECAUTIONS, Geriatric Use.
|
Laboratory Tests
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In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/ or renal function
tests.
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Drug/Laboratory Test Interactions
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Codeine: Codeine may increase serum amylase levels.
Acetaminophen: Acetaminophen may produce false- positive test results for urinary 5- hydroxyindoleacetic acid.
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Carcinogenesis, Mutagenesis, and Impairment of Fertility
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No adequate studies have been conducted in animals to determine whether acetaminophen, codeine and butalbital have a potential
for carcinogenesis or mutagenesis. No adequate studies have been conducted in animals to determine whether acetaminophen and
butalbital have a potential for impairment of fertility.
|
Pregnancy, Teratogenic Effects, Pregnancy Category C
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Animal reproduction studies have not been conducted with butalbital; acetaminophen; caffeine; codeine phosphate. It is also
not known whether butalbital; acetaminophen; caffeine; codeine phosphate can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. Butalbital; acetaminophen; caffeine; codeine phosphate should be given to a pregnant
woman only when clearly needed.
|
Pregnancy, Nonteratogenic Effects
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Withdrawal seizures were reported in a 2- day- old male infant whose mother had taken 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.
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Labor and Delivery
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Use of codeine during labor may lead to respiratory depression in the neonate.
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Nursing Mothers
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Caffeine, barbiturates, acetaminophen and codeine 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; caffeine; codeine phosphate, 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
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Safety and effectiveness in pediatric patients have not been established.
|
Geriatric Use
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Butalbital; acetaminophen; caffeine; codeine phosphate 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 other 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.
|
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DRUG INTERACTIONS
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The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.
Butalbital; acetaminophen; caffeine; codeine phosphate 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.
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ADVERSE REACTIONS
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Frequently Observed
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The most frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath,
nausea, vomiting, abdominal pain, and intoxicated feeling.
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Infrequently Observed
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All adverse events tabulated below are classified as infrequent.
- Central Nervous: 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: 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.
The following adverse reactions have been voluntarily reported as temporally associated with butalbital; acetaminophen; caffeine;
codeine phosphate, a related product containing aspirin, butalbital, caffeine, and codeine:
- Central Nervous: Abuse, addiction, anxiety, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy,
psychosis, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo.
- Autonomic Nervous: Epistaxis, flushing, miosis, salivation.
- Gastrointestinal: Anorexia, appetite increased, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasms, hiccup, mouth burning, pyloric
ulcer.
- Cardiovascular: Chest pain, hypotensive reaction, palpitations, syncope.
- Skin: Erythema, erythema multiforme, exfoliative dermatitis, hives, rash, toxic epidermal necrolysis.
- Urinary: Kidney impairment, urinary difficulty.
- Miscellaneous: Allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema.
The following adverse drug events may be borne in mind as potential effects of the components of butalbital; acetaminophen;
caffeine; codeine phosphate. potential effects of high dosage are listed in OVERDOSAGE .
- Acetaminophen: Allergic reactions, rash, thrombocytopenia, agranulocytosis.
- Caffeine: Cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia.
- Codeine: Nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus.
|
Several cases of dermatological reactions, including toxic epidermal necrolysis and erythema multiforme, have been reported
for butalbital; acetaminophen; caffeine; codeine phosphate.
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DRUG ABUSE AND DEPENDENCE
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Controlled Substance
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Butalbital; acetaminophen; caffeine; codeine phosphate is controlled by the Drug Enforcement Administration and is classified
under Schedule III.
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Abuse and Dependence
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Codeine
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Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological
dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered
with the same degree of caution appropriate to the use of other oral narcotic medications.
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Butalbital
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Barbiturates May be Habit- Forming: 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 increases; tolerance to a fatal dosage, however, does not increase
more than twofold. 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.
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OVERDOSAGE
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Following an acute overdosage of butalbital; acetaminophen; caffeine; codeine phosphate, toxicity may result from the barbiturate,
the codeine, or the acetaminophen. Toxicity due to the caffeine is less likely, due to the relatively small amounts in this
formulation.
Signs and Symptoms
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Toxicity from barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; and hypovolemic shock. Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression of respiration, and loss of consciousness. Convulsions
may occur. 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 grams, or fatalities with less than 15 grams. Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium, tachycardia, and extrasystoles.
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Treatment
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A single or multiple overdose with butalbital; acetaminophen; caffeine; codeine phosphate 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. The value of vasopressor
agents such as norepinephrine or phenylephrine HCl in treating hypotension is questionable since they increase vasoconstriction
and decrease blood flow. However, if prolonged support of blood pressure is required, norepinephrine bitartrate may be given
IV with the usual precautions and serial blood pressure monitoring. 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.
Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Naloxone 0.4-
2 mg is given parenterally. Since the duration of action of codeine may exceed that of the naloxone, the patient should be
kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate
respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular
depression.
If the dose of acetaminophen may have exceeded 140 mg/ kg, N- acetyl- cysteine 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 IV administration.
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Toxic Doses (For Adults)
|
| |
- Butalbital: Toxic dose 1.0 g (20 capsules of butalbital; acetaminophen; caffeine; codeine phosphate).
- Acetaminophen: Toxic dose 10 g (30 capsules of butalbital; acetaminophen; caffeine; codeine phosphate).
- Caffeine: Toxic dose 1.0 g (25 capsules of butalbital; acetaminophen; caffeine; codeine phosphate).
- Codeine: Toxic dose 240 mg (8 capsules of butalbital; acetaminophen; caffeine; codeine phosphate).
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DOSAGE AND ADMINISTRATION
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1 or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules.
Extended and repeated use of this product is not recommended because of the potential for physical dependence.
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HOW SUPPLIED
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Fioricet with Codeine Capsules: Dark blue, opaque cap with a grey, opaque body. Cap is imprinted twice in light- blue with “FIORICET” and “CODEINE”. Body
is imprinted twice with four- head profile in red.
Storage: Below 30°C (86°F); tight container.
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PRODUCT LISTING - RATED THERAPEUTICALLY EQUIVALENT
|
| |
| capsule - oral - 325 mg- 50 mg- 40 mg- 30 mg -
|
| 100.0 |
$137.50 |
Phrenilin with Caffeine and Codeine
Amarin Pharmaceuticals Inc
|
65234006110 |
| 100.0 |
$149.00 |
GENERIC
West- Ward Pharmaceutical Corporation
|
00143300001 |
| 100.0 |
$220.86 |
Fioricet with Codeine
Novartis Pharmaceuticals
|
00078024305 |
|
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| capsule - oral - 325 mg- 50 mg- 40 mg- 30 mg -
|
| 30.0 |
$56.03 |
GENERIC
Direct Dispensing Inc
|
57866393801 |
| 100.0 |
$149.00 |
GENERIC
Qualitest Pharmaceuticals Inc
|
00603255321 |
| 100.0 |
$149.00 |
GENERIC
Able Laboratories Inc
|
53265024010 |
|
|