BUTALBITAL, ASPIRIN, AND CAFFEINE CAPSULES USP   CIII

Each butalbital, aspirin, and caffeine capsule for oral administration contains: butalbital, USP, 50 mg; aspirin, USP, 325 mg; caffeine, USP, 40 mg.

Butalbital, 5-allyl-5-isobutyl-barbituric acid, has a molecular formula of C₁₁H₁₆N₂O₃ and a molecular weight of 224.26.

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

Caffeine, 1, 3, 7-trimethylxanthine, has a molecular formula of C₈H₁₀N₄O₂ and a molecular weight of 194.19.

Active Ingredients: aspirin, USP, butalbital, USP, and caffeine, USP.

Inactive Ingredients: alginic acid, corn starch, pregelatinized starch, sodium lauryl sulfate, and talc. The capsule contains: FD&C Blue #2, FDA/E172 yellow iron oxide, gelatin and titanium dioxide. The imprinting ink contains: D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, and propylene glycol.

Pharmacologically, butalbital, aspirin, and caffeine capsules combines the analgesic properties of aspirin with the anxiolytic and muscle relaxant properties of butalbital.

The clinical effectiveness of butalbital, aspirin and caffeine capsules in tension headache has been established in double-blind, placebo-controlled, multi-clinic trials. A factorial design study compared butalbital, aspirin and caffeine capsules with each of its major components. This study demonstrated that each component contributes to the efficacy of butalbital, aspirin, and caffeine capsules in the treatment of the target symptoms of tension headache (headache pain, psychic tension, and muscle contraction in the head, neck, and shoulder region). For each symptom and the symptom complex as a whole, butalbital, aspirin, and caffeine capsules were shown to have significantly superior clinical effects to either component alone.

The behavior of the individual components is described below.

Butalbital aspirin, and caffeine capsules are indicated for the relief of the symptom complex of tension (or muscle contraction) headache. Evidence supporting the efficacy and safety of butalbital, aspirin, and caffeine capsules in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because butalbital is habit-forming and potentially abusable.

Butalbital, aspirin, and caffeine capsules are contraindicated under the following conditions:

• Hypersensitivity or intolerance to aspirin, caffeine, or butalbital.
• 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).
• 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.
• Peptic ulcer or other serious gastrointestinal lesions.
• Patients with porphyria.

Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking.

Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders. Aspirin administered preoperatively may prolong the bleeding time. Butalbital is habit-forming and potentially abusable. Consequently, the extended use of butalbital, aspirin, and caffeine capsules is not recommended. Results from epidemiologic studies indicate an association between aspirin and Reye's Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu.

Butalbital, aspirin, and caffeine capsules should be prescribed with caution for certain special-risk patients such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, coagulation disorders, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison's disease, or prostatic hypertrophy.

Aspirin should be used with caution in patients on anticoagulant therapy and in patients with underlying hemostatic defects, and extreme caution in the presence of peptic ulcer.

Precautions should be taken when administering salicylates to persons with known allergies. Hypersensitivity to aspirin is particularly likely in patients with nasal polyps, and relatively common in those with asthma.

Patients should be informed that butalbital, aspirin, and caffeine capsules contain aspirin and should not be taken by patients with an aspirin allergy.

Butalbital, aspirin, and caffeine capsules may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking butalbital, aspirin, and caffeine capsules.

Alcohol and other CNS depressants may produce an additive CNS depression when taken with butalbital, aspirin, and caffeine capsules and should be avoided.

Butalbital may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

In patients with severe hepatic or renal disease, the effects of therapy should be monitored with serial liver and/or renal function tests.

The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.

In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance.

Butalbital, aspirin, and caffeine capsules may enhance the effects of:

• 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 butalbital, aspirin, and caffeine capsules exceed maximum recommended daily dose.
• 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 additive effects.
• Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression.

Butalbital, aspirin, and caffeine capsules may diminish the effects of:

Uricosuric agents such as probenecid and sulfinpyrazone, reducing the effectiveness in the treatment of gout. Aspirin competes with these agents for protein binding sites.

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.

Ingestion of aspirin prior to delivery may prolong delivery or lead to bleeding in the mother or neonate.

Aspirin, caffeine, and barbiturates are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of potential for serious adverse reactions in nursing infants from butalbital, aspirin, and caffeine capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

The most frequent adverse reactions are drowsiness and dizziness. Less frequent adverse reactions are lightheadedness and gastrointestinal disturbances including nausea, vomiting and flatulence. A single incidence of bone marrow suppression has been reported with the use of butalbital, aspirin, and caffeine capsules. Several cases of dermatological reactions including toxic epidermal necrolysis and erythema multiforme have been reported.

Butalbital, aspirin, and caffeine capsules are controlled by the Drug Enforcement Administration and are classified under Schedule III.

The toxic effects of acute overdosage of butalbital, aspirin, and caffeine capsules are attributable mainly to its barbiturate component, and, to a lesser extent, aspirin. Because toxic effects of caffeine occur in very high dosages only, the possibility of significant caffeine toxicity from butalbital, aspirin, and caffeine capsules overdosage is unlikely.

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 consists of primarily of management of barbiturate intoxication and the correction of the acid-base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis, alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through administration of intravenous fluids such as 1% sodium bicarbonate in 5% dextrose in water. Meticulous attention should be given to maintaining adequate pulmonary ventilation. The value of vasopressor agents such as Norepinephrine or Phenylephrine Hydrochloride in treating hypotension is questionable since they increase vasoconstriction and decrease blood flow. However, if prolonged support of blood pressure is required, Norepinephrine Bitartrate (Levophed^®)Levophed is a registered Trademark of Sanofi Winthrop Pharmaceuticals. 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 uled in the Physicians' Desk Reference^®Trademark of Medical Economics Company, Inc..

Butalbital: toxic dose 1 g (20 capsules of butalbital, aspirin, and caffeine)

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

Caffeine: toxic dose 1 g (25 capsules of butalbital, aspirin, and caffeine)

One or 2 capsules every 4 hours. Total daily dose should not exceed 6 capsules. Extended and repeated use of this product is not recommended because of the potential for physical dependence.

Butalbital, aspirin, and caffeine capsules, USP are supplied as follows:

Butalbital 50 mg, aspirin 325 mg, caffeine 40 mg capsules are green opaque/white opaque, imprinted MUTUAL/779, on both the cap and the body.