Each capsule for oral administration contains:

codeine phosphate, USP . . . . . . . . . . . . 30 mg (1/2 gr)
butalbital, USP . . . . . . . . . . . . . . . . . . . . . . . . . . 50 mg
caffeine, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 mg
aspirin, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 mg

Codeine phosphate occurs as fine, white, needle-shaped crystals, or white, crystalline powder. It is affected by light. Its chemical name is 7,8-didehydro-4,5α-epoxy-3-methoxy-17- methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate. Its molecular weight is 406.37 and its molecular formula is C18H21NO3•H3PO4•½H2O.

Butalbital, 5-allyl-5-isobutyl-barbituric acid, a white odorless crystalline powder, is a short- to intermediate-acting barbiturate. Its molecular weight is 224.26 and its molecular formula is C11H16N2O3.

Caffeine, 1,3,7-trimethylxanthine, is a central nervous stimulant which occurs as a white powder or white glistening needles. Its molecular weight is (anhydrous) 194.19 and its molecular formula is C8H10N4O2.

Aspirin is benzoic acid, 2-(acetyloxy)-, with a molecular formula of C9H8O4 and its molecular weight is 180.16.

Inactive Ingredients: D&C Yellow #10, D&C Yellow #10 Aluminum Lake, D&C Red #33, D&C Red #28, FD&C Blue #1, FD&C Blue #1 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Blue #10 Aluminum Lake, FD&C Red #40  Aluminum Lake, gelatin, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide, stearic acid, colloidal silicon dioxide.

Butalbital, Aspirin, Caffeine and Codeine Phosphate Capsules is a combination drug product intended as a treatment for tension headache.

Butalbital, Aspirin, Caffeine and Codeine Phosphate Capsules are indicated for the relief of the symptom complex of tension (or muscle contraction) headache.

Evidence supporting the efficacy of butalbital, aspirin, caffeine and codeine phosphate capsules is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: 1) butalbital, aspirin, caffeine and codeine; 2) codeine; 3) butalbital, aspirin and caffeine; 4) placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours. The combination product of butalbital, aspirin, caffeine and codeine proved statistically significantly superior to each of its components and to placebo on measures of pain relief.

Evidence supporting the efficacy and safety of butalbital, aspirin, caffeine and codeine 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.

This combination product is contraindicated under the following conditions:

1. Hypersensitivity or intolerance to aspirin, caffeine, butalbital or codeine.
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 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 the 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 this product is not recommended.

Results from epidemiologic studies indicate an association between aspirin and Reye Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu.

Commonly Observed

The most commonly reported adverse events associated with the use of butalbital, aspirin, caffeine and codeine 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 Butalbital, Aspirin, Caffeine and Codeine in controlled clinical trials, three (0.8%)  discontinued treatment 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 Butalbital, Aspirin, Caffeine and Codeine treated patients in controlled clinical trials comparing the combination product 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.

Other Adverse Events Reported During Controlled Clinical Trials

The listing that follows represents the proportion of the 382 patients exposed to butalbital, aspirin, caffeine and codeine while participating in 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 the combination product, the adverse events were not necessarily caused by butalbital, aspirin, caffeine and codeine.

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: headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells, numbness, and sluggishness.

Autonomic Nervous: 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 Butalbital, Aspirin, Caffeine and Codeine, that have been received since market introduction and that were not reported in clinical trials by the patients treated with the combination product, 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: Abuse, addiction, anxiety, depression, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sedation,sexual activity increase, slurred speech, twitching, unconsciousness, vertigo.

Autonomic Nervous: epitaxis, 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 this product. 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.

Butalbital, Aspirin, Caffeine and Codeine Phosphate Capsules are controlled by the Drug Enforcement Administration and is classified under Schedule III.

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 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.

The toxic effects of acute overdosage of Butalbital, Aspirin, Caffeine and Codeine Phosphate Capsules 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 this combination product is unlikely.

Signs and Symptoms

Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; 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 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 overdose with this combination product. 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. Correction of hypotension may require the administration of levarterenol bitartrate or phenylephrine hydrochloride by intravenous infusion. 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 mg 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.

Toxic and Lethal Doses

Butalbital: toxic dose 1 g (adult); lethal dose 2 g to 5 g

Aspirin: toxic blood level greater than 30 mg/100 mL; lethal dose 10 to 30 g (adult)

Caffeine: toxic dose greater than 1 g; lethal dose unknown

Codeine: lethal dose 0.5 to 1 g (adult)

1 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.

Each yellow and blue Butalbital, Aspirin, Caffeine and Codeine Phosphate Capsule USP 50 mg/325 mg/ 40 mg/30 mg is imprinted JSP 507

Bottles of 100 NDC 0527-1312-01
Bottles of 500 NDC 0527-1312-05

Store and Dispense

Below 25°C (77°F); in a tight, light resistant container.

Manufactured for:
Lannett Company, Inc.
Philadelphia, PA 19136

Manufactured by:
Jerome Stevens Pharmaceuticals, Inc.
Bohemia, NY 11716

Rev. 02/08
MG #11583

NDC 0527-1312-01

Lannett

BUTALBITAL,      CIII
ASPIRIN, CAFFEINE AND
CODEINE PHOSPHATE
CAPSULES USP,

50 mg/325 mg/40 mg/30 mg

Rx ONLY

100 CAPSULES