United States - English - NLM (National Library of Medicine)
BUTALBITAL, ASPIRIN, AND CAFFEINE- butalbital, aspirin, and caffeine capsule
MUTUAL PHARMACEUTICAL COMPANY, INC.
BUTALBITAL, ASPIRIN, AND CAFFEINE CAPSULES USP CIII
Each butalbital, aspirin, and caffeine capsule for oral administration contains: butalbital, USP, 50 mg;
aspirin, USP, 325 mg; caffeine, USP, 40 mg.
Butalbital, 5-allyl-5-isobutyl-barbituric acid, has a molecular formula of C
H N O and a molecular
weight of 224.26.
Aspirin, benzoic acid, 2-(acetyloxy)-, has a molecular formula of C H O and a molecular weight of
Caffeine, 1, 3, 7-trimethylxanthine, has a molecular formula of C H N O and a molecular weight of
Active Ingredients: aspirin, USP, butalbital, USP, and caffeine, USP.
Inactive Ingredients: alginic acid, corn starch, pregelatinized starch, sodium lauryl sulfate, and talc. The
capsule contains: FD&C Blue #2, FDA/E172 yellow iron oxide, gelatin and titanium dioxide. The
imprinting ink contains: D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide
black, and propylene glycol.
Pharmacologically, butalbital, aspirin, and caffeine capsules combines the analgesic properties of
aspirin with the anxiolytic and muscle relaxant properties of butalbital.
The clinical effectiveness of butalbital, aspirin and caffeine capsules in tension headache has been
established in double-blind, placebo-controlled, multi-clinic trials. A factorial design study compared
butalbital, aspirin and caffeine capsules with each of its major components. This study demonstrated that
each component contributes to the efficacy of butalbital, aspirin, and caffeine capsules in the treatment
of the target symptoms of tension headache (headache pain, psychic tension, and muscle contraction in
the head, neck, and shoulder region). For each symptom and the symptom complex as a whole, butalbital,
aspirin, and caffeine capsules were shown to have significantly superior clinical effects to either
The behavior of the individual components is described below.
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.
The 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% to 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, and caffeine
capsules 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.
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% to 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
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, and caffeine capsules is equivalent
to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2020 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 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.
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
The bioavailability of the caffeine component for butalbital, aspirin, and caffeine capsules is equivalent
to that of a solution except for a slightly longer time to peak. A peak concentration of 1660 ng/mL was
obtained in less than an hour for an 80 mg dose.
See OVERDOSAGE for toxicity information.
INDICATIONS AND USAGE
Butalbital aspirin, and caffeine capsules are indicated for the relief of the symptom complex of tension
(or muscle contraction) headache. Evidence supporting the efficacy and safety of butalbital, aspirin, and
caffeine capsules in the treatment of multiple recurrent headaches is unavailable. Caution in this regard
is required because butalbital is habit-forming and potentially abusable.
Butalbital, aspirin, and caffeine capsules are contraindicated under the following conditions:
1. Hypersensitivity or intolerance to aspirin, caffeine, or butalbital.
2. Patients with 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).
3. 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.
4. Peptic ulcer or other serious gastrointestinal lesions.
5. Patients with porphyria.
Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should
be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking.
Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal
lesions, and in patients with bleeding disorders. Aspirin administered preoperatively may prolong the
bleeding time. Butalbital is habit-forming and potentially abusable. Consequently, the extended use of
butalbital, aspirin, and caffeine capsules is not recommended. Results from epidemiologic studies
indicate an association between aspirin and Reye's Syndrome. Caution should be used in administering
this product to children, including teenagers, with chicken pox or flu.
Butalbital, aspirin, and caffeine capsules 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, head injuries, elevated intracranial pressure, acute abdominal conditions,
hypothyroidism, urethral stricture, Addison's disease, or prostatic hypertrophy.
Aspirin should be used with caution in patients on anticoagulant therapy and in patients with underlying
hemostatic defects, and extreme caution in the presence of peptic ulcer.
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.
Information for Patients
Patients should be informed that butalbital, aspirin, and caffeine capsules contain aspirin and should not
be taken by patients with an aspirin allergy.
Butalbital, aspirin, and caffeine capsules 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, and caffeine capsules.
Alcohol and other CNS depressants may produce an additive CNS depression when taken with
butalbital, aspirin, and caffeine capsules 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.
In patients with severe hepatic or renal disease, the effects of therapy should be monitored with serial
liver and/or renal function tests.
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, and caffeine capsules may enhance the effects of:
1. Oral anticoagulants, causing bleeding by inhibiting prothrombin formation in the liver and displacing
anticoagulants from plasma protein binding sites.
2. Oral antidiabetic agents and insulin, causing hypoglycemia by contributing an additive effect, if
dosage of butalbital, aspirin, and caffeine capsules exceed maximum recommended daily dose.
3. 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
4. Non-steroidal anti-inflammatory agents, increasing the risk of peptic ulceration and bleeding by
contributing additive effects.
5. Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide,
sedative-hypnotics, or other CNS depressants, causing increased CNS depression.
Butalbital, aspirin, and caffeine capsules may diminish the effects of:
Uricosuric agents such as probenecid and sulfinpyrazone, reducing the effectiveness in the treatment of
gout. Aspirin competes with these agents for protein binding sites.
Drug/Laboratory Test Interactions
Aspirin may interfere with the following laboratory determinations in blood: serum amylase, fasting
blood glucose, cholesterol, protein, serum glutamic-oxaloacetic transaminase (SGOT), uric acid,
prothrombin time and bleeding time. Aspirin may interfere with the following laboratory determinations
in urine: glucose, 5-hydroxyindoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), uric acid,
diacetic acid, and spectrophotometric detection of barbiturates.
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
Pregnancy Category C. Animal reproduction studies have not been conducted with butalbital, aspirin,
and caffeine capsules. It is also not known whether butalbital, aspirin, and caffeine capsules can cause
fetal harm when administered to a pregnant woman or can affect reproduction capacity. Butalbital,
aspirin, and caffeine capsules should be given to a pregnant woman only when clearly needed.
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 5mg/kg, which was tapered without further seizure or other withdrawal
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.
Therapeutic doses of aspirin in pregnant women close to term may cause bleeding in the 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.
Aspirin, caffeine, and barbiturates 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, and caffeine capsules, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the
Safety and effectiveness in pediatric patients have not been established.
The most frequent adverse reactions are drowsiness and dizziness. Less frequent adverse reactions are
lightheadedness and gastrointestinal disturbances including nausea, vomiting and flatulence. A single
incidence of bone marrow suppression has been reported with the use of butalbital, aspirin, and caffeine
capsules. Several cases of dermatological reactions including toxic epidermal necrolysis and erythema
multiforme have been reported.
DRUG ABUSE AND DEPENDENCE
Butalbital, aspirin, and caffeine capsules are controlled by the Drug Enforcement Administration and are
classified under Schedule III.
Abuse and Dependence
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 1,500 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.
The toxic effects of acute overdosage of butalbital, aspirin, and caffeine capsules are attributable
mainly to its barbiturate component, and, to a lesser extent, aspirin. Because toxic effects of caffeine
occur in very high dosages only, the possibility of significant caffeine toxicity from butalbital, aspirin,
and caffeine capsules overdosage is unlikely.
Signs and Symptoms
Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma;
respiratory depression; hypotension; hypovolemic shock. Symptoms attributable to acute aspirin
poisoning include hyperpnea; acid-base disturbances with development of metabolic acidosis; vomiting
and abdominal pain; tinnitus; hyperthermia; hypoprothrombinemia; restlessness; delirium; convulsions.
Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium, tachycardia and
Treatment consists of primarily of management of barbiturate intoxication and the correction of the acid-
base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the
conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if
less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before
gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis,
alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through
administration of intravenous fluids such as 1% sodium bicarbonate in 5% dextrose in water. Meticulous
attention should be given to maintaining adequate pulmonary ventilation. The value of vasopressor
agents such as Norepinephrine or Phenylephrine Hydrochloride in treating hypotension is questionable
since they increase vasoconstriction and decrease blood flow. However, if prolonged support of blood
pressure is required, Norepinephrine Bitartrate (Levophed
) may be given I.V. with the usual
precautions and serial blood pressure monitoring. In severe cases of intoxication, peritoneal dialysis,
hemodialysis, or exchange transfusion may be lifesaving. Hypoprothrombinemia should be treated with
Vitamin K, intravenously.
Up-to-date information about the treatment of overdose can often be obtained from a Certified Regional
Poison Control Center. Telephone numbers of Certified Regional Poison Control Centers are listed in
the Physicians' Desk Reference
Toxic and Lethal Doses
Levophed is a registered Trademark of Sanofi Winthrop Pharmaceuticals.
Trademark of Medical Economics Company, Inc.
Butalbital: toxic dose 1 g (20 capsules of butalbital, aspirin, and caffeine)
Aspirin: toxic blood level greater than 30 mg/100mL; lethal dose 10 to 30 g
Caffeine: toxic dose 1 g (25 capsules of butalbital, aspirin, and caffeine)
DOSAGE AND ADMINISTRATION
One or 2 capsules every 4 hours. Total daily dose should not exceed 6 capsules. Extended and repeated
use of this product is not recommended because of the potential for physical dependence.
Butalbital, aspirin, and caffeine capsules, USP are supplied as follows:
Butalbital 50 mg, aspirin 325 mg, caffeine 40 mg capsules are green opaque/white opaque, imprinted
MUTUAL/779, on both the cap and the body.
Bottles of 30
Bottles of 60
Bottles of 100
Bottles of 250
Bottles of 500
Bottles of 1000
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature].
Protect from moisture.
DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
MUTUAL PHARMACEUTICAL COMPANY, INC.
Philadelphia, PA 19124 USA
Revised: September 2006S
BUTALBITAL, ASPIRIN, AND CAFFEINE
butalbital, aspirin, and caffeine capsule
Product T ype
HUMAN PRESCRIPTION DRUG
Ite m Code (Source )
NDC:5348 9 -6 22
Route of Administration
DEA Sche dule
Active Ingredient/Active Moiety
Basis of Strength
Stre ng th
buta lbita l (UNII: KHS0 AZ4JVK) (butalbital - UNII:KHS0 AZ4JVK)
a spirin (UNII: R16 CO5Y76 E) (aspirin - UNII:R16 CO5Y76 E)
ca ffeine (UNII: 3G6 A5W338 E) (caffeine - UNII:3G6 A5W338 E)
MUTUAL PHARMACEUTICAL COMPANY, INC.
Stre ng th
Alg inic a cid ()
co rn sta rch ()
preg ela tinized sta rch ()
so dium la uryl sulfa te (UNII: 36 8 GB5141J)
ta lc (UNII: 7SEV7J4R1U)
FD&C Blue #2 ()
FDA/E17 2 yello w iro n o xide ()
g ela tin (UNII: 2G8 6 QN327L)
tita nium dio xide (UNII: 15FIX9 V2JP)
D&C Yello w #10 ()
FD&C Blue #1 ()
FD&C Red #4 0 ()
iro n o xide bla ck ()
pro pylene g lyco l (UNII: 6 DC9 Q16 7V3)
GREEN (green o paque) , WHITE (white o paque)
no sco re
S hap e
S iz e
S ymb ol
Marketing Start Date
Marketing End Date
NDC:5348 9 -6 22-0 7
30 in 1 BOTTLE, PLASTIC
NDC:5348 9 -6 22-0 6
6 0 in 1 BOTTLE, PLASTIC
NDC:5348 9 -6 22-0 1
10 0 in 1 BOTTLE, PLASTIC
NDC:5348 9 -6 22-0 3
250 in 1 BOTTLE, PLASTIC
NDC:5348 9 -6 22-0 5
50 0 in 1 BOTTLE, PLASTIC
NDC:5348 9 -6 22-10
10 0 0 in 1 BOTTLE, PLASTIC
MUT UAL PHARMACEUT ICAL COMPANY, INC.