Document
DailyMed Label: Butalbital, Aspirin, Caffeine and Codeine Phosphate
Title
DailyMed Label: Butalbital, Aspirin, Caffeine and Codeine Phosphate
Date
2010
Document type
DailyMed Prescription
Name
Butalbital, Aspirin, Caffeine and Codeine Phosphate
Generic name
Butalbital, Aspirin, Caffeine and Codeine Phosphate
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-1037
Product information
NDC: 54868-1037
Description
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules,
USP is supplied in capsule form for oral administration.
Each capsule contains the following active ingredients: butalbital, USP
……………………..50 mg aspirin, USP ……………………....325 mg caffeine, USP ………………………40
mg codeine phosphate, USP …………30 mg
Butalbital (5-allyl-5-isobutylbarbituric acid) is a short- to
intermediate-acting barbiturate. It has the following structural formula:
C 11 H 16 N 2 O 3 molecular weight
224.26
Aspirin (benzoic acid, 2-(acetyloxy)-) is an analgesic, antipyretic, and
anti-inflammatory. It has the following structural formula:
C 9 H 8 O 4 molecular weight
180.16
Caffeine (1,3,7-trimethylxanthine) is a central nervous system stimulant. It has
the following structural formula:
C 8 H 10 N 4 O 2 molecular weight 194.19
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:
C 18 H 24 NO 7 P anhydrous molecular weight
397.37
Inactive Ingredients: microcrystalline cellulose,
pregelatinized starch, talc. Gelatin capsules contain D&C Yellow No.10,
FD&C Blue No.1, FD&C Red No. 3, FD&C Yellow No. 6, gelatin, titanium
dioxide. The capsules are printed with edible ink containing red iron oxide.
image of butalbital chemical structure
image of aspirin chemical structure
image of caffeine chemical structure
image of codeine phosphate chemical structure
Indications
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules,
USP is indicated for the relief of the symptom complex of tension (or muscle
contraction) headache.
Evidence supporting the efficacy of butalbital, aspirin, caffeine, and
codeine phosphate capsules is derived from 2 multi-clinic trials that compared
patients with tension headache randomly assigned to 4 parallel treatments:
butalbital, aspirin, caffeine, and codeine phosphate capsules; codeine;
Butalbital, Aspirin, and Caffeine Capsules, USP; and placebo. Response was
assessed over the course of the first 4 hours of each of 2 distinct headaches,
separated by at least 24 hours. Butalbital, aspirin, caffeine, and codeine
phosphate capsules proved statistically significantly superior to each of its
components (Butalbital, Aspirin, and Caffeine Capsules, USP and codeine) and to
placebo on measures of pain relief.
Evidence supporting the efficacy and safety of Butalbital, Aspirin, Caffeine,
and Codeine Phosphate Capsules, USP 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.
Dosage
One 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.
Contraindications
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules,
USP is contraindicated under the following conditions:
Hypersensitivity or intolerance to aspirin, caffeine, butalbital
or codeine.
Patients with a hemorrhagic diathesis (e.g., hemophilia,
hypoprothrombinemia, von Willebrand’s disease, the thrombocytopenias,
thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe
vitamin K deficiency and severe liver damage).
Patients with the syndrome of nasal polyps, angioedema and
bronchospastic reactivity to aspirin or other nonsteroidal anti-inflammatory
drugs. Anaphylactoid reactions have occurred in such patients.
Peptic ulcer or other serious gastrointestinal lesions.
Patients with porphyria.
Precautions
General Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules,
USP should be prescribed with caution for certain special-risk patients such as
the elderly or debilitated, and those with severe impairment of renal or hepatic
function, coagulation disorders, or head injuries, elevated intracranial
pressure, acute abdominal conditions, hypothyroidism, urethral stricture,
Addison’s disease, prostatic hypertrophy, and peptic ulcer.
Aspirin should be used with caution in patients on anticoagulant therapy and
in patients with underlying hemostatic defects.
Precautions should be taken when administering salicylates to persons with
known allergies. Hypersensitivity to aspirin is particularly likely in patients
with nasal polyps, and relatively common in those with asthma.
Ultra-rapid Metabolizers of
Codeine
Some individuals may be ultra-rapid metabolizers due to a
specific CYP2D6*2x2 genotype. These individuals convert codeine into its active
metabolite, morphine, more rapidly and completely than other people. This rapid
conversion results in higher than expected serum morphine levels. Even at
labeled dosage regimens, individuals who are ultra-rapid metabolizers may
experience overdose symptoms such as extreme sleepiness, confusion or shallow
breathing.
The prevalence of this CYP2D6 phenotype varies widely and has been estimated
at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in
Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians
and Arabs. Data is not available for other ethnic groups.
When physicians prescribe codeine-containing drugs, they should choose the
lowest effective dose for the shortest period of time and should inform their
patients about these risks and the signs of morphine overdose. (See
PRECAUTIONS, Nursing
Mothers
)
Information for Patients Patients should be informed that Butalbital, Aspirin, Caffeine,
and Codeine Phosphate Capsules, USP contains aspirin and should not be taken by
patients with an aspirin allergy.
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may impair
the mental and/or physical abilities required for performance of potentially
hazardous tasks such as driving a car or operating machinery. Such tasks should
be avoided while taking Butalbital, Aspirin, Caffeine, and Codeine Phosphate
Capsules, USP.
Alcohol and other CNS depressants may produce an additive CNS depression when
taken with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP,
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, refer to
PRECAUTIONS, Geriatric Use
.
Caution patients that some people have a variation in a liver enzyme and
change codeine into morphine more rapidly and completely than other people.
These people are ultra-rapid metabolizers and are more likely to have
higher-than-normal levels of morphine in their blood after taking codeine which
can result in overdose symptoms such as extreme sleepiness, confusion, or
shallow breathing. In most cases, it is unknown if someone is an ultra-rapid
codeine metabolizer.
Nursing mothers taking codeine can also have higher morphine levels in their
breast milk if they are ultra-rapid metabolizers. These higher levels of
morphine in breast milk may lead to life-threatening or fatal side effects in
nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity
in their infants including increased sleepiness (more than usual), difficulty
breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to
talk to the baby's doctor immediately if they notice these signs and, if they
cannot reach the doctor right away, to take the baby to an emergency room or
call 911 (or local emergency services).
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 The CNS effects of butalbital may be enhanced by monoamine
oxidase (MAO) inhibitors.
In patients receiving concomitant corticosteroids and chronic use of aspirin,
withdrawal of corticosteroids may result in salicylism because corticosteroids
enhance renal clearance of salicylates and their withdrawal is followed by
return to normal rates of renal clearance.
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may
enhance the effects of:
Oral anticoagulants, causing bleeding by inhibiting prothrombin
formation in the liver and displacing anticoagulants from plasma protein binding
sites.
Oral antidiabetic agents and insulin, causing hypoglycemia by
contributing an additive effect, if dosage of Butalbital, Aspirin, Caffeine, and
Codeine Phosphate Capsules, USP exceeds maximum recommended daily
dosage.
6-mercaptopurine and methotrexate, causing bone marrow toxicity
and blood dyscrasias by displacing these drugs from secondary binding sites,
and, in the case of methotrexate, also reducing its excretion.
Non-steroidal anti-inflammatory agents, increasing the risk of
peptic ulceration and bleeding by contributing additive effects.
Other narcotic analgesics, alcohol, general anesthetics,
tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS
depressants, causing increased CNS depression.
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may
diminish the effects of:
Uricosuric agents such as probenecid and sulfinpyrazone, reducing their
effectiveness in the treatment of gout. Aspirin competes with these agents for
protein binding sites.
Drug/Laboratory Test Interactions
Aspirin: Aspirin may interfere
with the following laboratory determinations in blood: serum amylase, fasting
blood glucose, cholesterol, protein, serum glutamic-oxalacetic transaminase
(SGOT), uric acid, prothrombin time and bleeding time. Aspirin may interfere
with the following laboratory determinations in urine: glucose,
5-hydroxy-indoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), uric
acid, diacetic acid, and spectrophotometric detection of barbiturates.
Codeine: Codeine may increase serum amylase
levels.
Carcinogenesis, Mutagenesis, Impairment of
Fertility Adequate long-term studies have been conducted in mice and rats
with aspirin, alone or in combination with other drugs, in which no evidence of
carcinogenesis was seen. No adequate studies have been conducted in animals to
determine whether aspirin has a potential for mutagenesis or impairment of
fertility. No adequate studies have been conducted in animals to determine
whether butalbital has a potential for carcinogenesis, mutagenesis, or
impairment of fertility.
Usage in Pregnancy
Teratogenic Effects
Pregnancy Category C. Animal
reproduction studies have not been conducted with Butalbital, Aspirin, Caffeine,
and Codeine Phosphate Capsules, USP. It is also not known whether Butalbital,
Aspirin, Caffeine, and Codeine Phosphate Capsules, USP can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity.
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should be
given to a pregnant woman only when clearly needed.
Nonteratogenic Effects Although Butalbital, Aspirin, Caffeine, and Codeine Phosphate
Capsules, USP was not implicated in the birth defect, a female infant was born
with lissencephaly, pachygyria and heterotopic gray matter. The infant was born
8 weeks prematurely to a woman who had taken an average of 90 butalbital,
aspirin, caffeine, and codeine phosphate capsules each month from the first few
days of pregnancy. The child’s development was mildly delayed and from one year
of age she had partial simple motor seizures.
Withdrawal seizures were reported in a two-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.
Studies of aspirin use in pregnant women have not shown that aspirin
increases the risk of abnormalities when administered during the first trimester
of pregnancy. In controlled studies involving 41,337 pregnant women and their
offspring, there was no evidence that aspirin taken during pregnancy caused
stillbirth, neonatal death or reduced birth weight. In controlled studies of
50,282 pregnant women and their offspring, aspirin administration in moderate
and heavy doses during the first four lunar months of pregnancy showed no
teratogenic effect.
Reproduction studies have been performed in rabbits and rats at doses up to
150 times the human dose and have revealed no evidence of impaired fertility or
harm to the fetus due to codeine.
Therapeutic doses of aspirin in pregnant women close to term may cause
bleeding in mother, fetus, or neonate. During the last 6 months of pregnancy,
regular use of aspirin in high doses may prolong pregnancy and delivery.
Labor and Delivery Ingestion of aspirin prior to delivery may prolong delivery or
lead to bleeding in the mother or neonate. Use of codeine during labor may lead
to respiratory depression in the neonate.
Nursing Mothers Aspirin, caffeine, barbiturates 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, Aspirin, Caffeine, and Codeine Phosphate
Capsules, USP, 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.
Codeine is secreted into human milk. In women with normal codeine metabolism
(normal CYP2D6 activity), the amount of codeine secreted into human milk is low
and dose-dependent. Despite the common use of codeine products to manage
postpartum pain, reports of adverse events in infants are rare. However, some
women are ultra-rapid metabolizers of codeine. These women achieve
higher-than-expected serum levels of codeine's active metabolite, morphine,
leading to higher-than-expected levels of morphine in breast milk and
potentially dangerously high serum morphine levels in their breastfed infants.
Therefore, maternal use of codeine can potentially lead to serious adverse
reactions, including death, in nursing infants.
The prevalence of this CYP2D6 phenotype varies widely and has been estimated
at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in
Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians
and Arabs. Data is not available for other ethnic groups.
The risk of infant exposure to codeine and morphine through breast milk
should be weighed against the benefits of breastfeeding for both the mother and
baby. Caution should be exercised when codeine is administered to a nursing
woman. If a codeine containing product is selected, the lowest dose should be
prescribed for the shortest period of time to achieve the desired clinical
effect. Mothers using codeine should be informed about when to seek immediate
medical care and how to identify the signs and symptoms of neonatal toxicity,
such as drowsiness or sedation, difficulty breastfeeding, breathing
difficulties, and decreased tone, in their baby. Nursing mothers who are
ultra-rapid metabolizers may also experience overdose symptoms such as extreme
sleepiness, confusion or shallow breathing. Prescribers should closely monitor
mother-infant pairs and notify treating pediatricians about the use of codeine
during breastfeeding. (See
PRECAUTIONS, General, Ultra-rapid Metabolizers of Codeine
)
Pediatric Use Safety and effectiveness in pediatric patients have not been
established.
Geriatric Use Clinical studies of butalbital, aspirin, caffeine, and codeine
phosphate capsules 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.
Adverse reactions
The most commonly reported adverse events associated with the use
of butalbital, aspirin, caffeine, and codeine phosphate capsules and not
reported at an equivalent incidence by placebo-treated patients were nausea
and/or abdominal pain, drowsiness, and dizziness.
How supplied
Butalbital, Aspirin, Caffeine, and Codeine
Phosphate Capsules, USP
Blue cap with a yellow body. Cap is imprinted
with “WATSON” in red. Body is imprinted with “3546” in red. Supplied in:
bottles of 20 NDC 54868-1037-1
bottles of 30 NDC 54868-1037-3
bottles of 60 NDC 54868-1037-5
bottles of 120 NDC 54868-1037-4
which are supplied with child-resistant closures.
Store and Dispense Below 25°C (77°F); tight container. Protect from moisture.
Rx only
Watson Laboratories, Inc.
Corona, CA 92880 USA
Revised: January 2007
BASPCC01/07 S0107
Relabeling and Repackaging by: Physicians Total Care, Inc. Tulsa, OK 74146
Clinical pharmacology
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules,
USP is a combination drug product intended as a treatment for tension
headache.
Butalbital, Aspirin, and Caffeine Capsules, USP consists of a fixed
combination of caffeine 40 mg, butalbital 50 mg, and aspirin 325 mg. The role
each component plays in the relief of the complex of symptoms known as tension
headache is incompletely understood.
Pharmacokinetics
Bioavailability: The
bioavailability of the components of the fixed combination of Butalbital,
Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is identical to their
bioavailability when Butalbital, Aspirin, and Caffeine Capsules, USP and codeine
are administered separately in equivalent molar doses.
The behavior of the individual components is described below.
Aspirin The systemic availability of aspirin after an oral dose is highly
dependent on the dosage form, the presence of food, the gastric emptying time,
gastric pH, antacids, buffering agents, and particle size. These factors affect
not necessarily the extent of absorption of total salicylates but more the
stability of aspirin prior to absorption.
During the absorption process and after absorption, aspirin is mainly
hydrolyzed to salicylic acid and distributed to all body tissues and fluids,
including fetal tissues, breast milk, and the central nervous system (CNS).
Highest concentrations are found in plasma, liver, renal cortex, heart, and
lung. In plasma, about 50%-80% of the salicylic acid and its metabolites are
loosely bound to plasma proteins.
The clearance of total salicylates is subject to saturable kinetics; however,
first-order elimination kinetics are still a good approximation for doses up to
650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic
acid and/or total salicylates is about 3 hours.
The elimination of therapeutic doses is through the kidneys either as
salicylic acid or other biotransformation products. The renal clearance is
greatly augmented by an alkaline urine as is produced by concurrent
administration of sodium bicarbonate or potassium citrate.
The biotransformation of aspirin occurs primarily in the hepatocytes. The
major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides
of salicylate (15%), and gentisic and gentisuric acid (1%). The bioavailability
of the aspirin component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate
Capsules, USP is equivalent to that of a solution except for a slower rate of
absorption. A peak concentration of 8.8 mcg/mL was obtained at 40 minutes after
a 650 mg dose.
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
(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.
The bioavailability of the codeine component of Butalbital, Aspirin,
Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a
solution. Peak concentrations of 198 ng/mL were obtained at 1 hour after a 60 mg
dose.
See
OVERDOSAGE
for
toxicity information.
Butalbital Butalbital is well absorbed from the gastrointestinal tract and
is expected to distribute to most of the 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 included 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% was conjugated.
The bioavailability of the butalbital component of Butalbital, Aspirin,
Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a
solution except for a decrease in the rate of absorption. A peak concentration
of 2,020 ng/mL is obtained at about 1.5 hours after a 100 mg dose.
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
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 rapidly 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 has been recovered in the urine, only 3% was
unchanged drug.
The bioavailability of the caffeine component Butalbital, Aspirin, Caffeine,
and Codeine Phosphate Capsules, USP is equivalent to that of a solution except
for a slightly longer time to peak. A peak concentration of 1,660 ng/mL was
obtained in less than an hour for an 80 mg dose.
See
OVERDOSAGE
for
toxicity information.
Package label
Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules,
USP
50 mg/325 mg/40 mg/30 mg
image of package label
4 organizations
1 product
Organization
bryant ranch prepackOrganization
Amneal Pharmaceuticals of New York, LLCOrganization
Jerome Stevens Pharmaceuticals, Inc.Organization
Physicians Total Care, Inc.