y 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, caffeine and codeine 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.

uired because codeine and butalbital are habit-forming and potentially abusable.

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.

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 in 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 )

he 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 treated patients during placebo controlled clinical trials incidence rate of adverse events body system/ adverse event butalbital, aspirin, caffeine and codeine (n=382) placebo n=(377) central nervous drowsiness 2.4% 0.5% dizziness/lightheadedness 2.6% 0.5% intoxicated feeling 1.0% 0% gastrointestinal 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 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.

y 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, caffeine and codeine 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.

s 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.

ncluding 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 3.0 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 hepatcytes. 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 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. 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 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 component of butalbital, aspirin, caffeine and codeine phosphate capsules is equivalent to that of a solution except for a decrease in the rate of absorption. a peak concentration of 2020 ng/ml is obtained at about 1.5 hours after a 100 mg dose. 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-methyl-xanthine 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 component of butalbital, aspirin, caffeine and codeine phosphate capsules is equivalent to that of a solution except for a slightly longer time to peak. a peak concentration of 1660 ng/ml was obtained in less than an hour for an 80 mg dose. see overdosage for toxicity information.

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 3.0 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 hepatcytes. 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 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. 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 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 component of butalbital, aspirin, caffeine and codeine phosphate capsules is equivalent to that of a solution except for a decrease in the rate of absorption. a peak concentration of 2020 ng/ml is obtained at about 1.5 hours after a 100 mg dose. 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-methyl-xanthine 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 component of butalbital, aspirin, caffeine and codeine phosphate capsules is equivalent to that of a solution except for a slightly longer time to peak. a peak concentration of 1660 ng/ml was obtained in less than an hour for an 80 mg dose. see overdosage for toxicity information.

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).