BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE- butalbital, aspirin, caffeine and codeine phosphate 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), CODEINE PHOSPHATE (UNII: GSL05Y1MN6) (CODEINE ANHYDROUS - UNII:UX6OWY2V7J)
Available from:
Bryant Ranch Prepack
INN (International Name):
BUTALBITAL
Composition:
BUTALBITAL 50 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
ASCOMP® with Codeine (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 ASCOMP® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: ASCOMP® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), 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. ASCOMP® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) proved statistically significantly superior to each of its components ASCOMP® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) and to placebo on measures of pain relief.
Product summary:
Product: 63629-2952 NDC: 63629-2952-1 30 CAPSULE in a BOTTLE NDC: 63629-2952-2 20 CAPSULE in a BOTTLE NDC: 63629-2952-3 90 CAPSULE in a BOTTLE NDC: 63629-2952-4 60 CAPSULE in a BOTTLE NDC: 63629-2952-5 40 CAPSULE in a BOTTLE NDC: 63629-2952-6 18 CAPSULE in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-2952-1, 63629-2952-2, 63629-2952-3, 63629-2952-4, 63629-2952-5, 63629-2952-6

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE- butalbital, aspirin,

caffeine and codeine phosphate capsule

Bryant Ranch Prepack

----------

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE

Rx Only

DESCRIPTION

ASCOMP with Codeine (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:

H N O

224.26

5-Allyl-5-isobutylbarbituric acid is a short-to intermediate-acting barbiturate.

Aspirin:

C H O

180.16

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

Caffeine:

C H N O

194.19

1,3,7-trimethylxanthine, is a central nervous system stimulant which occurs as a white powder or white

glistening needles.

Codeine phosphate:

H NO P

397.37 (Anhydrous)

7,8-didehydro-4, 5α-epoxy-3- methoxy-I7-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate, is

a narcotic analgesic and antitussive, occurs as fine, white, needle-shaped crystals, or white, crystalline

powder and affects by light.

Inactive Ingredients: Corn Starch, D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, FD&C

Red No. 40, Gelatin, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Stearic Acid, Talc, and

Titanium Dioxide.

CLINICAL PHARMACOLOGY

ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is a

combination drug product intended as a treatment for tension headache. ASCOMP with Codeine

(Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) consists of a fixed combination

of caffeine 40mg, butalbital 50mg, aspirin 325mg, and codeine phosphate 30mg. The role each

component plays in the relief of the complex of symptoms known as tension headache is not completely

understood.

Pharmacokinetics

Bioavailability

The bioavailability of the components of the fixed combination of ASCOMP with Codeine (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 is equivalent to that of a solution except for a slower rate of absorption. A

peak concentration of 8.80 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 ASCOMP with Codeine (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 ASCOMP with Codeine (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% 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.

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 ASCOMP with Codeine (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.

INDICATIONS AND USAGE

ASCOMP with Codeine (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 ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and

Codeine Phosphate Capsules, USP) is derived from 2 multi-clinic trials that compared patients with

tension headache randomly assigned to 4 parallel treatments: ASCOMP with Codeine (Butalbital,

Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), 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. ASCOMP with Codeine (Butalbital, Aspirin,

Caffeine, and Codeine Phosphate Capsules, USP) proved statistically significantly superior to each of

its components ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate

Capsules, USP) and to placebo on measures of pain relief.

Evidence supporting the efficacy and safety of ASCOMP with Codeine (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.

CONTRAINDICATIONS

ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is

contraindicated under the following conditions:

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

2. Patients with hemorrhagic diathesis (e.g., hemophilia, hypoprothrombin emia, 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 non-steroidal 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 pre-operatively may prolong the bleeding time.

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 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 ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate 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

ASCOMP with Codeine (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

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 this combination product contains aspirin and should not be taken by

patients with an aspirin allergy.

ASCOMP with Codeine (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 ASCOMP with

Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP).

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

ASCOMP with Codeine (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.

ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) 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 ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate

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 addictive effects.

5. Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide,

sedative-hypnotics, or other CNS depressants, causing increased CNS depression.

ASCOMP with Codeine (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. It is also not known whether this combination product can cause fetal harm when

administered to a pregnant woman or can affect reproduction capacity. This product should be given to a

pregnant woman only when clearly needed.

Nonteratogenic Effects

Although ASCOMP with Codeine (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 ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP)

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 ASCOMP with Codeine (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 ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate

Capsules, USP) 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

Commonly Observed

The most commonly reported adverse events associated with the use of ASCOMP with Codeine

(Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) and not reported at an equivalent

incidence by placebo-treated patients were nausea and/or abdominal pain, drowsiness and dizziness.

Associated with Treatment Discontinuation

Of the 382 patients treated with ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine

Phosphate Capsules, USP) in controlled clinical trials, three (0.8%) discontinued treatment with

ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP)

because of adverse events. One patient each discontinued treatment for the following reasons:

gastrointestinal upset; lightheadedness and heavy eyelids; and drowsiness and generalized tingling.

Incidence in Controlled Clinical Trials

The following table summarizes the incidence rates of the adverse events reported by at least 1% of the

ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) treated

patients in controlled clinical trials comparing ASCOMP with Codeine (Butalbital, Aspirin, Caffeine,

and Codeine Phosphate Capsules, USP) to placebo, and provides a comparison to the incidence rates

reported by the placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of side

effects in the course of usual medical practice where patient characteristics and other factors differ

from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with

figures obtained from other clinical investigations involving different treatments, uses, and

investigators.

Adverse Events Reported by at Least 1% of Butalbital, Aspirin, Caffeine, and

Codeine Phosphate, USP Treated Patients During Placebo Controlled Clinical

T rials

Incidence Rate of Adverse Events

Body System/Adverse Event

Butalbital, Aspirin,

Caffeine, and Codeine

Phosphate, USP

(N=382)

Placebo

(N=377)

Central Nervous

Drowsiness

2.4%

0.5%

Dizziness/Lightheadedness

2.6%

0.5%

Intoxicated Feeling

1.0%

Gas trointes tinal

Nausea/Abdominal Pain

3.7%

0.8%

Other Adverse Events Reported During Controlled Clinical Trials

The listing that follows represents the proportion of the 382 patients exposed to ASCOMP with

Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) while participating in

the controlled clinical trials who reported, on at least one occasion, an adverse event of the type cited.

All reported adverse events, except those already presented in the previous table, are included. It is

important to emphasize that, although the adverse events reported did occur while the patient was

receiving ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules,

USP), the adverse events were not necessarily caused by ASCOMP with Codeine (Butalbital, Aspirin,

Caffeine, and Codeine Phosphate Capsules, USP).

Adverse events are classified by body system and frequency, "Frequent" is defined as an adverse event

which occurred in at least 1/100 (1%) of the patients; all adverse events listed in the previous table are

frequent.

"Infrequent" is defined as an adverse event that occurred in less than 1/100 patients but at least 1/1000

patients. All adverse events tabulated below are classified as infrequent.

Central Nervous System: headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids,

high energy, hot spells, numbness and sluggishness.

Autonomic Nervous System: dry mouth and hyperhidrosis.

Gastrointestinal: vomiting, difficulty swallowing, and heartburn.

Cardiovascular: tachycardia.

Musculoskeletal: leg pain and muscle fatigue.

Genitourinary: diuresis.

Miscellaneous: pruritus, fever, earache, nasal congestion, and tinnitus.

Voluntary reports of adverse drug events, temporally associated with ASCOMP with Codeine

(Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), that have been received since

market introduction and that were not reported in clinical trials by the patients treated with ASCOMP

with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), are listed below.

Many or most of these events may have no causal relationship with the drug and are listed according to

body system.

Central Nervous System: abuse, addiction, anxiety, depression, disorientation, hallucination,

hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sedation, sexual activity

increase, slurred speech, twitching, unconsciousness, vertigo.

Autonomic Nervous System: epistaxis, flushing, miosis, salivation.

Gastrointestinal: anorexia, appetite increased, constipation, diarrhea, esophagitis, gastroenteritis,

gastrointestinal spasm, 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

ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP).

Potential effects of high dosage are listed in the OVERDOSAGE section of this insert.

Aspirin: occult blood loss, hemolytic anemia, iron deficiency anemia, gastric distress, heartburn,

nausea, peptic ulcer, prolonged bleeding time, acute airway obstruction, renal toxicity when taken in

high doses for prolonged periods, impaired urate excretion, hepatitis.

Caffeine: cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia.

Codeine: nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is

controlled by the Drug Enforcement Administration and is classified under Schedule III.

Abuse and Dependence

Codeine

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.

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

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.

OVERDOSAGE

The toxic effects of acute overdosage of ASCOMP with Codeine (Butalbital, Aspirin, Caffeine, and

Codeine Phosphate Capsules, USP) are attributable mainly to the barbiturate and codeine components,

and, to a lesser extent, aspirin. Because toxic effects of caffeine occur in very high dosages only, the

possibility of significant caffeine toxicity from ASCOMP with Codeine (Butalbital, Aspirin, Caffeine,

and Codeine Phosphate 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. Symptoms of acute codeine poisoning include the opioid triad of: pinpoint pupils,

marked depression of respiration, and loss of consciousness. Convulsions may occur.

Treatment

The following paragraphs describe one approach to the treatment of overdosage with ASCOMP with

Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP). However, because

strategies for the management of an overdose continually evolve, consultation with a regional poison

control center is strongly encouraged.

Treatment consists primarily of management of barbiturate intoxication, reversal of the effects of

codeine, 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 and 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.

Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous

administration.

Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid

overdose. Typically, a dose of 0.4 to 2 mg is given parenterally and may be repeated if an adequate

response is not achieved. Since the duration of action of codeine may exceed that of the antagonist, the

patient should be kept under continued 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.

Up-to-date information about the treatment of overdose can 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); lethal dose 2-5 g

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

Caffeine: toxic dose greater than 1 g; (25 capsules); lethal dose unknown

Codeine: toxic dose 240 mg (8 capsules); lethal dose 0.5-1 g

DOSAGE AND ADMINISTRATION

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.

HOW SUPPLIED

Product: 63629-2952

NDC: 63629-2952-1 30 CAPSULE in a BOTTLE

NDC: 63629-2952-2 20 CAPSULE in a BOTTLE

NDC: 63629-2952-3 90 CAPSULE in a BOTTLE

NDC: 63629-2952-4 60 CAPSULE in a BOTTLE

NDC: 63629-2952-5 40 CAPSULE in a BOTTLE

NDC: 63629-2952-6 18 CAPSULE in a BOTTLE

Manufactured By:

Nexgen Pharma, Inc.

Irvine, CA 92614

Distributed by:

Breckenridge Pharmaceutical, Inc.

Boca Raton, FL 33487

#6094 Rev. 12/08B

Levophed

is a registered trademark of Hospira, Inc.

ButAspCaffCod (CIII) 50/325/40/30mg

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE

butalbital, aspirin, caffeine and codeine phosphate capsule

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -

29 52(NDC:519 9 1-0 74)

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

CO DEINE PHO SPHATE (UNII: GSL0 5Y1MN6 ) (CODEINE ANHYDROUS - UNII:UX6 OWY2V7J)

CODEINE PHOSPHATE 30 mg

Inactive Ingredients

Ingredient Name

Stre ng th

Sta rch, Co rn (UNII: O8 232NY3SJ)

D&C Red No . 2 8 (UNII: 76 7IP0 Y5NH)

D&C Yello w No . 10 (UNII: 35SW5USQ3G)

FD&C Blue No . 1 (UNII: H3R47K3TBD)

FD&C Red No . 4 0 (UNII: WZB9 127XOA)

GELATIN, UNSPECIFIED (UNII: 2G8 6 QN327L)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

So dium La uryl Sulfa te (UNII: 36 8 GB5141J)

Stea ric Acid (UNII: 4ELV7Z6 5AP)

Ta lc (UNII: 7SEV7J4R1U)

Tita nium Dio xide (UNII: 15FIX9 V2JP)

Product Characteristics

Color

BLUE, YELLOW

S core

no sco re

S hap e

CAPSULE

S iz e

22mm

Flavor

Imprint Code

B0 74

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -29 52-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/0 1/20 0 9

2

NDC:6 36 29 -29 52-2

20 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/0 1/20 0 9

3

NDC:6 36 29 -29 52-3

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/0 1/20 0 9

4

NDC:6 36 29 -29 52-4

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/0 1/20 0 9

5

NDC:6 36 29 -29 52-5

40 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/0 1/20 0 9

6

NDC:6 36 29 -29 52-6

18 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/0 1/20 0 9

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 75231

0 5/0 1/20 0 9

Labeler -

Bryant Ranch Prepack (171714327)

Bryant Ranch Prepack

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -29 52) , RELABEL(6 36 29 -29 52)

Revised: 10/2017

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