butalbital, aspirin, caffeine and codeine phosphate

Bryant Ranch Prepack
Bryant Ranch Prepack

butalbital, aspirin, caffeine and codeine phosphate capsule

FULL PRESCRIBING INFORMATION: CONTENTS*

• BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE DESCRIPTION
• CLINICAL PHARMACOLOGY
• INDICATIONS & USAGE
• BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE ADVERSE REACTIONS
• DRUG ABUSE AND DEPENDENCE
• OVERDOSAGE
• DOSAGE & ADMINISTRATION
• HOW SUPPLIED

FULL PRESCRIBING INFORMATION

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE 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

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

See OVERDOSAGE for toxicity information.

See OVERDOSAGE for toxicity information.

INDICATIONS & 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.

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE CONTRAINDICATIONS

ASCOMP^® with Codeine (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 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).
• 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.
• Peptic ulcer or other serious gastrointestinal lesions.
• 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

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.

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 PRECAUCTIONS, Nursing Mothers).

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).

In patients with severe hepatic or renal disease, 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.

ASCOMP^® with Codeine (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 ASCOMP^® with Codeine (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 addictive effects.
• 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.

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 may increase serum amylase levels.

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.

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.

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.

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE ADVERSE REACTIONS

DRUG ABUSE AND DEPENDENCE

ASCOMP^® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is controlled by the Drug Enforcement Administration and is classified under Schedule III.

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.

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.

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.

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^®.

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 & 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

ASCOMP^® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) are available as listed below:

NDC NBR                              CAPSULES PER BOTTLE

63629-2952-1                                 30

63629-2952-2                                 20

63629-2952-3                                 90

63629-2952-4                                 60

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

MM1