BUTALBITAL, ASPIRIN, AND CAFFEINE - butalbital, aspirin, and caffeine capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
BUTALBITAL (UNII: KHS0AZ4JVK) (BUTALBITAL - UNII:KHS0AZ4JVK), ASPIRIN (UNII: R16CO5Y76E) (ASPIRIN - UNII:R16CO5Y76E), CAFFEINE (UNII: 3G6A5W338E) (CAFFEINE - UNII:3G6A5W338E)
Available from:
STAT RX USA LLC
INN (International Name):
BUTALBITAL
Composition:
BUTALBITAL 50 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Butalbital, Aspirin, and Caffeine Capsules, USP is 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, USP 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, USP is contraindicated under the following conditions: - Hypersensitivity or intolerance to aspirin, caffeine, or butalbital. Hypersensitivity or intolerance to aspirin, caffeine, or butalbital. - 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 a hemorrhagic diathesis (e.g., hemophilia, hypoprothrombinemia, von Willebrand’s disease, the thrombocytopenias,
Product summary:
Butalbital, Aspirin, and Caffeine Capsules, USP Green cap with a yellow body. Cap is imprinted with “WATSON” in red. Body is imprinted with “3219” in red. Bottles of 100 are supplied with child-resistant closures. Store and Dispense Below 25°C (77°F); tight container. Protect from moisture. Rx only Address medical inquiries to: WATSON Medical Communications P.O. Box 1953 Morristown, NJ 07962-1953 800-272-5525 Watson Laboratories, Inc . Corona, CA 92880 USA Revised: June 2009 190110 S0609
Authorization status:
New Drug Application Authorized Generic
Authorization number:
16590-911-30, 16590-911-60, 16590-911-72, 16590-911-90

BUTALBITAL, ASPIRIN, AND CAFFEINE - butalbital, aspirin, and caffeine capsule

STAT RX USA LLC

----------

Butalbital, Aspirin, and Caffeine Capsules, USP C-III

Revised: June 2009

Rx only

1901100609

DESCRIPTION

Butalbital, Aspirin, and Caffeine 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

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

following structural formula:

H N O molecular weight 224.26

Aspirin (benzoic acid, 2-(acetyloxy)-) is an analgesic, antipyretic, and anti-inflammatory. It has the

following structural formula:

C H O molecular weight 180.16

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

formula:

C H N O molecular weight 194.19

Inactive Ingredients: microcrystalline cellulose, pregelatinized starch, and talc. Gelatin capsules contain

D&C Yellow No. 10, FD&C Green No. 3, and gelatin. The capsules are printed with edible ink

containing red iron oxide.

CLINICAL PHARMACOLOGY

Pharmacologically, Butalbital, Aspirin, and Caffeine Capsules, USP 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 was shown to have significantly superior clinical effects to either

component alone.

Pharmacokinetics

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, and Caffeine

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.

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, and Caffeine 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 for Butalbital, Aspirin, and Caffeine 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.

INDICATIONS

Butalbital, Aspirin, and Caffeine Capsules, USP is 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, USP in the treatment of multiple recurrent headaches is unavailable.

Caution in this regard is required because butalbital is habit-forming and potentially abusable.

CONTRAINDICATIONS

Butalbital, Aspirin, and Caffeine Capsules, USP is contraindicated under the following conditions:

1. Hypersensitivity or intolerance to aspirin, caffeine, or butalbital.

2. 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).

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.

WARNINGS

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, USP 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.

PRECAUTIONS

General

Butalbital, Aspirin, and Caffeine 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, 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, USP contains aspirin and

should not be taken by patients with an aspirin allergy.

Butalbital, Aspirin, and Caffeine 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, and Caffeine Capsules, USP.

Alcohol and other CNS depressants may produce an additive CNS depression when taken with

Butalbital, Aspirin, and Caffeine Capsules, USP 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 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, and Caffeine Capsules, USP may enhance the effects of:

1. Oral anticoagulants, causing bleeding by inhibiting prothrombin formation in the liver and displacing

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, USP exceeds maximum recommended daily

dosage.

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

its excretion.

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, 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-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

Teratogenic Effects:

Pregnancy Category C. Animal reproduction studies have not been conducted with Butalbital, Aspirin,

and Caffeine Capsules, USP. It is also not known whether Butalbital, Aspirin, and Caffeine Capsules,

USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Butalbital, Aspirin, and Caffeine Capsules, USP should be given to a pregnant woman only when clearly

needed.

Nonteratogenic Effects:

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.

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.

Nursing Mothers

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, 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

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

Controlled Substance

Butalbital, Aspirin, and Caffeine Capsules, USP is controlled by the Drug Enforcement Administration

and is classified under Schedule III.

Abuse and Dependence

Butalbital

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 two-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

The toxic effects of acute overdosage of Butalbital, Aspirin, and Caffeine Capsules, USP 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, USP 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

extrasystoles.

Treatment

Treatment consists 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 (for adults)

Butalbital: toxic dose 1 g (20 capsules)

Aspirin: toxic blood level greater than 30 mg/100 mL; lethal dose 10-30 g

Caffeine: toxic dose 1 g (25 capsules)

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.

HOW SUPPLIED

Butalbital, Aspirin, and Caffeine Capsules, USP

Green cap with a yellow body. Cap is imprinted with “WATSON” in red. Body is imprinted with “3219”

in red. Bottles of 100 are supplied with child-resistant closures.

Store and Dispense

Below 25°C (77°F); tight container. Protect from moisture.

Rx only

Address medical inquiries to:

WATSON

Medical Communications

P.O. Box 1953

Morristown, NJ 07962-1953

800-272-5525

Watson Laboratories, Inc.

Corona, CA 92880 USA

Revised: June 2009

190110

S0609

PACKAGE LABEL

BUTAL-ASP-CAF LABEL IMAGE

BUTALBITAL, ASPIRIN, AND CAFFEINE

butalbital, aspirin, and caffeine capsule

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code (Source )

NDC:16 59 0 -

9 11(NDC:0 59 1-3219 )

Route of Administration

ORAL

DEA Sche dule

CIII

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

BUTALBITAL (UNII: KHS0 AZ4JVK) (BUTALBITAL - UNII:KHS0 AZ4JVK)

BUTALBITAL

50 mg

ASPIRIN (UNII: R16 CO5Y76 E) (ASPIRIN - UNII:R16 CO5Y76 E)

ASPIRIN

325 mg

CAFFEINE (UNII: 3G6 A5W338 E) (CAFFEINE - UNII:3G6 A5W338 E)

CAFFEINE

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

STAT RX USA LLC

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

D&C YELLO W NO . 10 (UNII: 35SW5USQ3G)

FD&C GREEN NO . 3 (UNII: 3P3ONR6 O1S)

GELATIN (UNII: 2G8 6 QN327L)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

Product Characteristics

Color

green (GREEN) , yello w (YELLOW)

S core

no sco re

S hap e

CAPSULE

S iz e

29 mm

Flavor

Imprint Code

WATSON;3219

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 59 0 -9 11-30

30 in 1 BOTTLE

2

NDC:16 59 0 -9 11-6 0

6 0 in 1 BOTTLE

3

NDC:16 59 0 -9 11-72

120 in 1 BOTTLE

4

NDC:16 59 0 -9 11-9 0

9 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA autho rized generic

NDA0 17534

0 5/0 4/19 76

Labeler -

ST AT RX USA LLC (786036330)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

STAT RX USA LLC

78 6 0 36 330

repack, relabel

Revised: 9/2010

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