Pill Identifier App

Barbiturates and Analgesics (Systemic)

This monograph includes information on the following:

1) Butalbital and Acetaminophen 
2) Butalbital, Acetaminophen, Caffeine, and Codeine  
3) Butalbital and Aspirin
4) Butalbital, Aspirin, Caffeine, and Codeine
5) Phenobarbital, ASA, and Codeine *

Pharmacy Equivalent Name (PEN):
Butalbital, Acetaminophen, and Caffeine
Co-bucafAPAP

INN:
Acetaminophen— Paracetamol

VA CLASSIFICATION
Butalbital and Acetaminophen
Primary: CN103

Butalbital, Acetaminophen, Caffeine, and Codeine
Primary: CN101

Butalbital and Aspirin
Primary: CN103

Butalbital, Aspirin, Caffeine, and Codeine
Primary: CN101

Phenobarbital, ASA, and Codeine
Primary: CN101


Note: Controlled substance classification—

Note: Controlled substances in the U.S. and Canada as follows:



Butalbital, Acetaminophen, Caffeine and Codeine:
  U.S.—III.
  Canada—Not available.
Butalbital and Aspirin:
  U.S.—III.
  Canada—C.
Butalbital, Aspirin, Caffeine, and Codeine:
  U.S.—III.
  Canada—N.
Phenobarbital, ASA , and Codeine:
  U.S.—Not available.
  Canada—N.
 In Canada, Aspirin is a brand name; acetylsalicylic acid is the generic name. ASA, a commonly used designation for aspirin (or acetylsalicylic acid) in both the U.S. and Canada, is the term used in Canadian product labeling.
Commonly used brand name(s): Amaphen1; Anolor-3001; Anoquan1; Arcet1; Ascomp with Codeine No.34; Axotal3; Bancap1; Bucet1; Butace1; Butalbital Compound with Codeine4; Butalgen3; Butinal with Codeine No.34; Conten1; Dolmar1; Endolor1; Esgic1; Esgic-Plus1; Ezol1; Femcet1; Fiorgen3; Fioricet1; Fioricet with Codeine2; Fiorinal3; Fiorinal with Codeine No.34; Fiorinal-C 1/24; Fiorinal-C 1/44; Fiormor3; Fortabs3; Idenal with Codeine4; Isobutal3; Isobutyl3; Isocet1; Isolin3; Isollyl3; Isollyl with Codeine4; Laniroif3; Lanorinal3; Marnal3; Medigesic1; Pacaps1; Pharmagesic1; Phenaphen with Codeine No.35; Phrenilin1; Phrenilin Forte1; Repan1; Sedapap1; Tecnal3; Tecnal-C 1/24; Tecnal-C 1/44; Tencet1; Tencon1; Triad1; Triaprin1; Two-Dyne1; Vibutal3.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Analgesic.—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Headache, tension-type (treatment)—Barbiturate and analgesic combinations are indicated for relief of the symptoms of occasional tension-type (muscle contraction) headache. {01} {02} {03} {04} {05} {06} {07} {08} {09} {10} {29}

[Headache, migraine (treatment)]—Barbiturate and analgesic combinations are indicated to relieve occasional migraine1{09} {11} {12} and coexisting migraine and tension-type headaches (``mixed'' headache syndrome). {04} {05} {06} {07} {08} {09} {11} {12}

Note: Because of the risk of habituation, barbiturate and analgesic combinations are not recommended for treatment of frequent, especially daily, headaches. {10} {11}
To reduce analgesic use, underlying problems that may contribute to tension-type headaches, such as inflammation or structural abnormalities in the cervical or temporomandibular areas, should be identified and treated. {09} {11} In some patients, application of heat, muscle relaxants, and/or physical therapy may be helpful. {10} Other medications having the potential to cause habituation (e.g., benzodiazepines) should be used as infrequently as possible. {09} {10} {11}
Chronic tension-type headaches and severe migraines that occur more frequently than twice a month may require additional prophylactic treatment to reduce the frequency, severity, and/or duration of the headaches. {09} {10} {11} {13} {14} The prophylactic agents most commonly used for tension-type headaches are tricyclic antidepressants, especially amitriptyline, and/or beta-adrenergic blocking agents, especially propranolol. {09} {10} {11} For migraines, beta-adrenergic blocking agents, calcium channel blocking agents, tricyclic antidepressants, monoamine oxidase inhibitors, methysergide, pizotyline (not commercially available in the U.S.), and sometimes cyproheptadine (especially in children) are used for prophylaxis. {09} {11} {13} {14} The combination of amitriptyline plus propranolol has been found superior to either agent used alone in preventing ``mixed'' headaches. {12} {15}
Identification and avoidance of precipitating factors is also important in the overall management of the patient with migraine headaches. {11} {14} Relaxation and/or biofeedback techniques may also be helpful in controlling migraine headaches, and may reduce the need for medication. {14}


[Pain (treatment)]—Barbiturate and analgesic combinations are also indicated for relief of pain other than headache, especially when an antianxiety or relaxant effect is desired. {04} {05} {06} {07} {08}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
{16}    Butalbital: 224.26 {30}
    Phenobarbital: 232.24
    Acetaminophen: 151.16
    Aspirin: 180.16 {30}
    Codeine phosphate: 406.37 {30}
    Caffeine (anhydrous): 194.19 {30}

pKa—
    Aspirin: 3.5 {30}

Mechanism of action/Effect:


Butalbital or:


Phenobarbital—

Butalbital is a short- to intermediate-acting barbiturate; phenobarbital is a long-acting barbiturate. Barbiturates are nonselective depressants of the central nervous system (CNS). They are used in analgesic combinations for their antianxiety and relaxant effects.




Acetaminophen or:


Aspirin—

The mechanism of analgesic action has not been fully determined. Acetaminophen and aspirin may act by inhibiting prostaglandin synthesis in the CNS and through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of the synthesis of prostaglandins or to inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation. Acetaminophen may act predominantly in the CNS, whereas aspirin may produce analgesia predominantly via peripheral actions.




Codeine:

Opioid analgesics bind with stereospecific receptors at many sites within the CNS to alter processes affecting both the perception of pain and the emotional response to pain. Precise sites and mechanisms of action have not been fully determined. It has been proposed that there are multiple subtypes of opioid receptors, each mediating various therapeutic and/or side effects of opioids. The actions of an opioid analgesic may therefore depend upon its binding affinity for each type of receptor and whether it acts as a full agonist or a partial agonist or is inactive at each type of receptor. At least two of these types of receptors (mu and kappa) mediate analgesia. Codeine probably produces its effects via agonist actions at the mu receptor.



Caffeine:

Caffeine-induced constriction of cerebral blood vessels, which leads to a decrease in cerebral blood flow and in the oxygen tension of the brain, may contribute to relief of some types of headache. Also, it has been suggested that the addition of caffeine to acetaminophen and/or aspirin may provide a more rapid onset of action and/or enhanced pain relief with lower doses of analgesics. However, the FDA has not accepted caffeine as an effective analgesic adjuvant.



Other actions/effects:


Butalbital:


Phenobarbital—

Barbiturates have dose-dependent respiratory depressant effects.

Phenobarbital is a potent inducer of the activity of the hepatic p-450 microsomal enzyme system and may alter the metabolism and efficacy of many other medications that are metabolized via this enzyme system. Butalbital may also have some enzyme-inducing activity. {01} {02} {03}

Phenobarbital also has anticonvulsant activity.




Acetaminophen:

Has antipyretic activity.



Aspirin:

Has antipyretic, anti-inflammatory, and platelet aggregation–inhibiting actions.



Codeine:

Has CNS depressant, respiratory depressant, antidiarrheal, and antitussive actions.



Caffeine:

Has CNS stimulating activity and may therefore inhibit sleep. Because sleep contributes to relief of migraine headaches, this action may be detrimental to the patient. {11}


Absorption:


Butalbital:

Well absorbed from the gastrointestinal tract. {03}



Acetaminophen:

Rapid and almost complete; may be decreased if the medication is taken following a high-carbohydrate meal.



Aspirin:

Generally rapid and complete but may vary according to factors such as tablet dissolution rate and gastric or intraluminal pH. Concurrent administration with food decreases the rate, but not the extent, of absorption.



Caffeine:

Well absorbed from the gastrointestinal tract.

Note: Gastric stasis that accompanies migraine headaches tends to inhibit absorption of orally administered medications, which may result in alteration of some of the pharmacokinetic values reported below. Consequently, the onset of action of these medications may be delayed and/or their efficacy decreased, especially if they are taken after a migraine is well established. {11}



Distribution:


In breast milk:


Acetaminophen—

Peak concentrations of 10 to 15 mcg per mL (mcg/mL) (66.2 to 99.3 micromoles/L) have been measured 1 to 2 hours following maternal ingestion of a single 650-mg dose.



Aspirin (as salicylate)—

Peak salicylate concentrations of 173 to 483 mcg/mL (17.3 to 48.3 mg per 100 mL; 1.25 to 3.5 mmol/L) have been measured 5 to 8 hours after maternal ingestion of a single 650-mg dose.



Codeine—

Small quantities of codeine are distributed into breast milk.



Caffeine—

Small quantities of caffeine are distributed into breast milk.




Protein binding:


Phenobarbital:

Low to moderate (20 to 45%).



Acetaminophen:

Not significant with usual analgesic doses.



Salicylate (from aspirin):

High (to albumin); decreases as plasma salicylate concentration increases, with reduced plasma albumin concentration or renal dysfunction, and during pregnancy.



Codeine:

Very low.



Caffeine:

Low.


Biotransformation:


Phenobarbital and probably butalbital:

Hepatic, primarily by the hepatic microsomal enzyme system.



Acetaminophen:

Approximately 90 to 95% of a dose is metabolized in the liver, primarily by conjugation with glucuronic acid, sulfuric acid, and cysteine. An intermediate metabolite is hepatotoxic and possibly nephrotoxic.



Aspirin:

Largely hydrolyzed in the gastrointestinal tract, liver, and blood to salicylate, which also has analgesic activity. Salicylate is further metabolized, primarily in the liver.



Codeine:

Hepatic; about 10% of a dose is demethylated to morphine, which may contribute to the therapeutic actions.



Caffeine:

Hepatic.


Half-life:


Butalbital:

About 35 hours {03}.



Phenobarbital:

May range between 53 and 118 hours (mean, 79 hours).



Acetaminophen:

1 to 4 hours; does not change with renal failure but may be prolonged in some forms of hepatic disease, in overdose, in the elderly, and in the neonate; may be somewhat shortened in children.

In breast milk: 1.35 to 3.5 hours.



Aspirin:

15 to 20 minutes (for intact molecule); rapidly hydrolyzed to salicylate.

In breast milk (as salicylate): 3.8 to 12.5 hours (average, 7.1 hours) following a single 650-mg dose.



Salicylate (from aspirin):

Dependent on dose and urinary pH; about 2 to 3 hours with usual analgesic doses.



Codeine:

2.5 to 4 hours



Caffeine:

3 to 4 hours


Onset of action:


Phenobarbital:

1 hour or longer.


Codeine—

30 to 45 minutes.



Time to peak concentration:


Butalbital:

About 1.5 hours following a 100-mg dose. {03}



Acetaminophen:

0.5 to 2 hours.



Aspirin:

Generally 1 to 2 hours with single doses.


Peak serum concentration


Butalbital:

About 2 mcg/mL (8.9 micromoles/L), following a 100-mg dose. {03}



Acetaminophen:

5 to 20 mcg/mL (33.1 to 132.4 micromoles/L), with doses up to 650 mg.


Therapeutic plasma concentration


Aspirin (as salicylate):

25 to 50 mcg/mL (2.5 to 5 mg per 100 mL [0.18 to 0.36 mmol/L]); these concentrations are generally reached with doses of 325 to 650 mg.


Time to peak effect


Acetaminophen:

1 to 3 hours.



Codeine:

1 to 2 hours.


Duration of action:


Phenobarbital:

10 to 12 hours.



Acetaminophen:

3 to 4 hours.



Codeine:

4 to 6 hours {29}.


Elimination:


Butalbital—
        Primarily via hepatic metabolism, followed by renal excretion of metabolites; 50 to 88% of a dose is excreted in the urine, about 3.6% of a dose being excreted as unchanged butalbital and the remainder as metabolites. {03}



Phenobarbital—
        Renal; 25 to 50% of a dose is eliminated as unchanged phenobarbital.



Acetaminophen—
        Renal, as metabolites, primarily conjugates; 3% of a dose may be excreted unchanged.


In dialysis—
        Hemodialysis—120 mL per minute (for unmetabolized drug); metabolites also cleared rapidly.
        Hemoperfusion—200 mL per minute.
        Peritoneal dialysis—< 10 mL per minute.




Aspirin—
        Renal, primarily as free salicylic acid and conjugated metabolites. There are large interindividual variations in elimination kinetics. Also, the rate of excretion of total salicylate and the quantity of free salicylic acid eliminated are increased in alkaline urine and decreased in acidic urine.


In dialysis: As salicylate—
        Hemodialysis: Clearances of 35 to 100 mL per minute have been reported.
        Peritoneal dialysis: Removed more slowly than with hemodialysis; clearances of 45 to 90 mL per hour have been reported in infants.




Codeine—
        Renal, primarily as metabolites (10% as unchanged or conjugated morphine); 5 to 15% of a dose may be excreted as unchanged codeine.



Caffeine—
        Renal, primarily as metabolites. About 10% of a dose is excreted unchanged.



Precautions to Consider

Note: Information regarding precautions applying to the use of the individual ingredients in these combination medications is limited to brief summaries of the major precautions that may apply to occasional use of recommended doses. For more complete information that may apply, especially if these agents are ingested frequently or in higher-than-recommended doses, see—Butalbital: Barbiturates (Systemic) . Although butalbital is not specifically mentioned in that monograph, general precautions applying to all barbiturates may apply to butalbital also.
Phenobarbital: Barbiturates (Systemic) .
Acetaminophen: Acetaminophen (Systemic) .
Aspirin: Salicylates (Systemic) .
Codeine: Opioid (Narcotic) Analgesics (Systemic) .
Caffeine: Caffeine (Systemic) .


Cross-sensitivity and/or related problems


Butalbital and Phenobarbital

Patients sensitive to other barbiturates may be sensitive to butalbital and phenobarbital also.



Acetaminophen

Patients sensitive to aspirin are usually not sensitive to acetaminophen; however, mild bronchospastic reactions with acetaminophen have been reported in some aspirin-sensitive patients (fewer than 5% of those tested).



Aspirin

Patients sensitive to one salicylate, including methyl salicylate (oil of wintergreen), may be sensitive to aspirin also. However, patients sensitive to aspirin may not necessarily be sensitive to salicylamide.

Patients sensitive to other nonsteroidal anti-inflammatory drugs (NSAIDs) may be sensitive to aspirin also.


Pregnancy/Reproduction
Fertility—

Acetaminophen

Chronic toxicity studies in animals have shown that high doses of acetaminophen cause testicular atrophy and inhibition of spermatogenesis; the relevance of this finding to use in humans is not known.


Pregnancy—
Reproduction studies have not been done in humans or in animals with any of the butalbital and analgesic combinations. There is no information about the use of phenobarbital, aspirin, and codeine combination during pregnancy. However, the following information is available for individual ingredients in these formulations.


First trimester


Butalbital and Phenobarbital—

Barbiturates readily cross the placenta and are distributed throughout fetal tissues. The highest concentrations are found in the placenta and in the fetal liver and brain. Prenatal exposure to barbiturates has been reported to increase the risk of fetal abnormalities and of brain tumors.



Acetaminophen—

Problems in humans have not been documented. Although controlled studies have not been done, it is known that acetaminophen crosses the placenta.



Aspirin—

Salicylate readily crosses the placenta. It has been reported that aspirin use during pregnancy may increase the risk of birth defects in humans. However, controlled studies using usual therapeutic doses of aspirin have not shown proof of teratogenicity.

Studies in animals have shown that aspirin causes increased fetal resorptions and birth defects, including fissure of the spine and skull; facial clefts; eye defects; and malformations of the CNS, viscera, and skeleton (especially the vertebrae and ribs).



Codeine—

Codeine crosses the placenta. Although teratogenic effects in humans have not been documented, controlled studies have not been done.

Studies in animals have not shown that codeine causes teratogenic effects in doses up to 150 times the human dose. However, a single dose of 100 mg per kg of body weight (mg/kg) caused delayed ossification in mice, and doses of 120 mg/kg caused increased resorptions in rats.



Caffeine—

Caffeine crosses the placenta and achieves fetal blood and tissue concentrations similar to maternal concentrations. Studies in humans have not shown that caffeine causes birth defects. However, excessive intake of caffeine by pregnant women has resulted in fetal arrhythmias.

Studies in animals have shown that caffeine causes skeletal abnormalities in the digits and phalanges (when given in doses equivalent to the caffeine content of 12 to 24 cups of coffee daily throughout pregnancy or in very large single doses, i.e., 50 to 100 mg/kg) and retarded skeletal development (when given in lower doses).




Third trimester


Butalbital and Phenobarbital—

Ingestion of a barbiturate shortly prior to delivery may cause respiratory depression in the neonate.



Aspirin—

Problems attributed to use of aspirin during the third trimester include prolonged gestation, increased risk of postmaturity syndrome, reduced birthweight, increased risk of stillbirth or neonatal death (possibly resulting from prepartum maternal or fetal hemorrhage or from premature closure of the fetal ductus arteriosus), and prolonged labor and complicated deliveries when the medication is used during the last few weeks of pregnancy. Although these problems have occurred with chronic, high-dose use or abuse of aspirin, it is recommended that pregnant women not take aspirin during the last trimester unless aspirin therapy is prescribed and monitored by a physician.

Ingestion of aspirin during the last 2 weeks of pregnancy may increase the risk of maternal, fetal, or neonatal hemorrhage.



Codeine—

Ingestion of codeine shortly prior to delivery may cause respiratory depression in the neonate, especially the premature neonate.

FDA Pregnancy Category C (butalbital, aspirin, and codeine combination). {03}



Breast-feeding


Butalbital and Phenobarbital:

Barbiturates are distributed into breast milk and may cause CNS depression in the infant.



Acetaminophen:

Problems in humans have not been documented. Although peak concentrations of 10 to 15 mcg/mL (66.2 to 99.3 micromoles/L) have been measured in breast milk 1 to 2 hours following maternal ingestion of one 650-mg dose, neither acetaminophen nor its metabolites were detected in the urine of the nursing infants. The half-life in breast milk is 1.35 to 3.5 hours.



Aspirin:

Problems in humans with usual analgesic doses have not been documented; however, salicylate is distributed into breast milk. In one study, peak salicylate concentrations of 173 to 483 mcg/mL (17.3 to 48.3 mg per 100 mL [1.25 to 3.5 mmol/L]) were measured in breast milk 5 to 8 hours after maternal ingestion of one 650-mg dose of aspirin. The half-life in breast milk was 3.8 to 12.5 hours (average 7.1 hours).



Codeine:

Problems in humans have not been documented; however, codeine is distributed into breast milk in low concentrations.



Caffeine:

Caffeine is distributed into breast milk in very small amounts; at recommended doses of caffeine-containing analgesic combinations, concentration in the infant is considered insignificant. However, it is recommended that breast-feeding mothers limit their total daily intake of caffeine to 360 mg. Accumulation of caffeine in the infant, leading to signs of caffeine stimulation such as hyperactivity and wakefulness, may occur when a breast-feeding mother ingests large quantities of caffeine.


Pediatrics


Butalbital and Phenobarbital:

Some children react to barbiturates with paradoxical excitement.



Acetaminophen:

Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of acetaminophen in children.



Aspirin:

Aspirin usage may be associated with the development of Reye's syndrome in children with acute febrile illnesses, especially influenza and varicella. It is recommended that aspirin not be administered to febrile pediatric patients until after the presence of such an illness has been ruled out. Other pediatric patients, especially those with fever and dehydration, may also be more susceptible to the toxic effects of salicylates.



Codeine:

Some children react to opioids with paradoxical excitement.



Caffeine:

Appropriate studies on the relationship of age to the effects of caffeine have not been performed in children up to 12 years of age. However, no pediatrics-specific problems have been documented to date.




Adolescents


Aspirin

Aspirin usage may be associated with the development of Reye's syndrome in adolescents with acute febrile illnesses, especially influenza and varicella. It is recommended that aspirin not be administered to febrile adolescent patients until after the presence of such an illness has been ruled out.



Geriatrics



Butalbital and Phenobarbital:

Geriatric patients may react to usual doses of barbiturates with excitement, confusion, or depression. Also, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving barbiturates.



Acetaminophen:

Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of acetaminophen in the elderly.



Aspirin:

Geriatric patients may be more susceptible to the toxic effects of salicylates. Also, elderly patients may be more likely to have age-related renal function impairment, which may require caution in patients receiving aspirin.



Codeine:

Geriatric patients may be more susceptible to the effects, especially the respiratory depressant effects, of opioid analgesics such as codeine. Elderly patients tend to eliminate opioid analgesics more slowly than younger adults. Lower doses and/or longer intervals between doses may be required, and are usually effective, for these patients. Also, elderly patients are more likely to have age-related renal function impairment and/or prostatic hypertrophy or obstruction; opioid-induced urinary retention may be detrimental to these patients.



Caffeine:

No information is available on the relationship of age to the effects of caffeine in geriatric patients.


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For barbiturates
Addictive medications, other, especially CNS depressants with habituating potential    (caution in concurrent use is recommended because of the increased risk of habituation)


» Alcohol or
» CNS depression-producing medications, other (see Appendix II )    (concurrent use with a barbiturate may cause additive CNS depression; caution is recommended and dosage reduction of either or both medications may be needed)


Any medication that may be rendered less effective, because of accelerated metabolism, by hepatic enzyme induction, especially:
» Anticoagulants, coumarin- or indandione-derivative
» Carbamazepine
» Contraceptives, estrogen-containing, oral
» Corticosteroids, glucocorticoid and mineralocorticoid
» Corticotropin    (caution in concurrent use is recommended, especially with phenobarbital)


» Divalproex sodium or
» Valproic acid    (these agents may decrease barbiturate metabolism, possibly leading to increased barbiturate serum concentrations and risk of toxicity)

    (concurrent use with a barbiturate may also increase the half-life and risk of hepatotoxicity of valproic acid)


For acetaminophen
» Alcohol, especially chronic abuse of or
Hepatic enzyme inducers (see Appendix II ) or
Hepatotoxic medications, other (see Appendix II )    (risk of hepatotoxicity with single toxic doses of acetaminophen may be increased in alcoholics or in patients regularly taking other hepatotoxic medications or hepatic enzyme inducers)

    (chronic use of barbiturates or primidone has been reported to decrease the therapeutic effects of acetaminophen, probably because of increased metabolism resulting from induction of hepatic microsomal enzyme activity; the possibility should be considered that similar effects may occur with other hepatic enzyme inducers; however, such problems have not been reported with occasional use of combination formulations containing butalbital and acetaminophen {17})


For aspirin
Acidifiers, urinary, such as:
Ammonium chloride
Ascorbic acid
Potassium or sodium phosphates    (acidification of the urine by these medications decreases salicylate [from aspirin] excretion, leading to increased salicylate plasma concentrations)


» Alkalizers, urinary, such as:
Carbonic anhydrase inhibitors
Citrates or
Antacids, chronic high-dose use, especially calcium- or magnesium-containing or sodium bicarbonate    (alkalinization of the urine by these agents increases salicylate [from aspirin] excretion, leading to decreased salicylate plasma concentrations, reduced effectiveness, and shortened duration of analgesic action)

    (carbonic anhydrase inhibitors may also increase the risk of salicylate intoxication in patients receiving large doses of aspirin because metabolic acidosis induced by carbonic anhydrase inhibitors may increase penetration of salicylate into the brain; the increased risk of severe metabolic acidosis and salicylate toxicity must be considered if acetazolamide is used to produce forced alkaline diuresis in the treatment of aspirin overdose)


» Anticoagulants, coumarin- or indandione-derivative or
» Heparin or
» Thrombolytic agents, such as:
Alteplase
Anistreplase
Streptokinase
Urokinase    (because aspirin inhibits platelet aggregation and may induce gastrointestinal ulceration and/or bleeding, which may be hazardous to patients receiving anticoagulant or thrombolytic therapy, it is recommended that aspirin not be administered to patients receiving these agents except as part of a prescribed and monitored antithrombotic regimen)


Furosemide    (in addition to an increased risk of ototoxicity, concurrent use of furosemide with high doses of aspirin may lead to salicylate toxicity because of competition for renal excretory sites)


Laxatives, cellulose-containing    (concurrent use may reduce the salicylate effect because of physical binding or other absorptive hindrance; medications should be administered 2 hours apart)


» Methotrexate    (aspirin may displace methotrexate from its binding sites and decrease its renal clearance, leading to toxic plasma concentrations of methotrexate; if used concurrently, methotrexate dosage should be decreased, the patient observed for signs of toxicity, and/or methotrexate plasma concentration monitored; also, it is recommended that aspirin not be administered for 24 to 48 hours prior to administration of a high-dose methotrexate infusion, or until plasma methotrexate concentrations have decreased to a nontoxic level following the infusion [usually at least 12 hours])


Ototoxic medications, other (see Appendix II ), especially
» Vancomycin    (concurrent or sequential administration of these medications with aspirin should be avoided because the potential for ototoxicity may be increased; hearing loss may occur and may progress to deafness even after discontinuation of the medication; these effects may be reversible, but usually are permanent)


» Probenecid or
» Sulfinpyrazone    (uricosuric effects of probenecid or sulfinpyrazone may be decreased by doses of aspirin that produce serum salicylate concentrations above 50 mcg/mL [5 mg per 100 mL; 0.36 mmol/L]; also, probenecid may decrease renal clearance and increase plasma concentrations of salicylate, thereby increasing the risk of toxicity)

    (sulfinpyrazone may decrease salicylate [from aspirin] excretion and/or displace salicylate from its protein binding sites, possibly leading to increased salicylate concentrations and toxicity)


For codeine
Addictive medications, other, especially CNS depressants with habituating potential    (increased risk of habituation)


» Alcohol or
» CNS depression-producing medications, other (see Appendix II ), including other opioid analgesics    (concurrent use with codeine may lead to additive CNS depression; caution is recommended and dosage reduction of either or both medications may be needed)


Anticholinergics, especially atropine and related compounds    (concurrent use with codeine may result in increased risk of severe constipation, possibly leading to paralytic ileus, and/or urinary retention)


Antidiarrheals, antiperistaltic    (risk of constipation, which may lead to paralytic ileus, as well as the risk of CNS and/or respiratory depression, may be increased)


Antihypertensives, especially ganglionic blocking agents such as guanadrel, guanethidine, and mecamylamine or
Diuretics or
Hypotension-producing medications, other (see Appendix II )    (codeine may potentiate the hypotensive effects of these medications, leading to an increased risk of orthostatic hypotension)


Metoclopramide    (codeine may antagonize the effects of metoclopramide on gastrointestinal motility)


Monoamine oxidase inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use with codeine should be undertaken with caution because concurrent use with meperidine has resulted in unpredictable, severe, and sometimes fatal reactions, including immediate excitation, sweating, rigidity, and severe hypertension or, in some patients, hypotension, severe respiratory depression, coma, seizures, hyperpyrexia, and cardiovascular collapse; it is recommended that codeine be administered in reduced dosage to patients receiving an MAO inhibitor)


Naloxone    (antagonizes the analgesic, CNS, and respiratory depressant effects of codeine and may precipitate withdrawal symptoms in physically dependent patients; dosage of the antagonist should be carefully titrated when used to treat codeine overdose in dependent patients)


» Naltrexone    (codeine should not be administered as an analgesic to patients receiving naltrexone, which blocks the therapeutic effects of opioids; also, naltrexone therapy should not be initiated in patients receiving codeine for therapeutic purposes)

    (administration of naltrexone to a patient physically dependent on codeine will precipitate withdrawal symptoms; symptoms may appear within 5 minutes of naltrexone administration, persist for up to 48 hours, and be difficult to reverse)


Opioid analgesics, other    (concurrent use with codeine may result in additive CNS depressant, respiratory depressant, and hypotensive effects)

    (opioid agonist/antagonist analgesics [butorphanol, nalbuphine, or pentazocine] may partially antagonize the therapeutic and CNS depressant effects of codeine; also, nalbuphine and pentazocine may precipitate withdrawal symptoms in patients who are physically dependent on codeine)


For caffeine
CNS stimulation–producing medications, other (see Appendix II )    (concurrent use with caffeine may result in excessive CNS stimulation, leading to unwanted effects such as nervousness, irritability, insomnia, or possibly convulsions or cardiac arrhythmias; close observation is recommended)


Lithium    (caffeine increases urinary excretion of lithium, and may thereby reduce its therapeutic effect)


Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (the sympathomimetic side effects of caffeine may lead to cardiac arrhythmias or severe hypertension when large amounts of caffeine are used concurrently with MAO inhibitors; even small doses may cause tachycardia and a slight increase in blood pressure)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results

For barbiturates:
Cyanocobalamin Co 57 test for pernicious anemia or vitamin B 12 deficiency    (absorption of radioactive cyanocobalamin may be impaired by phenobarbital)


Metyrapone test for pituitary function    (induction of hepatic microsomal enzymes may increase metabolism of metyrapone, leading to a decreased response to the diagnostic agent)


Phentolamine test for pheochromocytoma    (barbiturates may cause false-positive test results; it is recommended that barbiturates not be administered for at least 24 hours, and preferably 48 to 72 hours, prior to the test)


For acetaminophen:
Glucose, blood, determinations    (values may be falsely decreased by acetaminophen when measured by the glucose oxidase/peroxidase method but probably not when measured by the hexokinase/glucose-6-phosphate dehydrogenase [G6PD] method)

    (values may be falsely increased when certain instruments are used in glucose analysis if high acetaminophen concentrations are present; consult manufacturer's instruction manual)


5-Hydroxyindoleacetic acid (5-HIAA), serum, determinations    (acetaminophen may cause false-positive results in qualitative screening tests using nitrosonaphthol reagent; the quantitative test is unaffected)


Pancreatic function determinations using bentiromide    (administration of acetaminophen prior to the bentiromide test will invalidate test results because acetaminophen is also metabolized to an arylamine and will thus increase the apparent quantity of para-aminobenzoic acid [PABA] recovered; it is recommended that acetaminophen be discontinued at least 3 days prior to administration of bentiromide)


Uric acid, serum, determinations    (falsely increased values may occur when the phosphotungstate uric acid test method is used)


For aspirin:
Aceto-acetic acid, urine, via Gerhard test    (interference may occur because reaction with ferric chloride produces a reddish color that persists after boiling)


Glucose, urine, determinations using copper sulfate    (false-positive test results may occur with chronic use of 2.4 grams or more a day)


Glucose, urine, enzymatic determinations    (false-negative test results may occur with chronic use of 2.4 grams or more a day)


5-Hydroxyindoleacetic acid (5-HIAA), urine, determinations    (aspirin may alter results when fluorescent method is used)


Renal function test using phenolsulfonphthalein (PSP)    (salicylate [from aspirin] may competitively inhibit renal tubular secretion of PSP, thereby decreasing urinary PSP concentration and invalidating test results)


Thyroid imaging, radionuclide    (chronic aspirin administration may depress thyroid function; aspirin therapy should be discontinued at least 1 week prior to administration of the radiopharmaceutical; however, a rebound effect may occur following discontinuation of salicylate therapy, resulting in a period of 3 to 10 days of increased thyroidal uptake)


Thyroid-stimulating hormone (TSH) release, determined via protirelin stimulation    (TSH response to protirelin may be decreased by 2 to 3.6 grams of aspirin daily; peak TSH concentrations occur at the same time after administration, but are reduced)


Vanillylmandelic acid (VMA), urine, determinations    (values may be falsely increased or decreased, depending on method used)


For codeine:
Gastric emptying studies    (codeine may delay gastric emptying, thereby invalidating test results)


Hepatobiliary imaging using technetium Tc 99m disofenin    (delivery of technetium Tc 99m disofenin may be prevented because of codeine-induced constriction of the sphincter of Oddi and increased biliary tract pressure; these actions result in delayed visualization and thus resemble obstruction of the common bile duct)


For caffeine:
Myocardial perfusion studies, dipyridamole-assisted    (caffeine may inhibit the effects of dipyridamole on myocardial blood flow, thereby interfering with test results; patients should be advised to avoid caffeine for at least 12 hours prior to the test)

With physiology/laboratory test values

For barbiturates
Bilirubin, serum    (concentrations may be decreased in patients with congenital nonhemolytic unconjugated hyperbilirubinemia and in epileptics; this effect is presumably due to induction of glucuronyl transferase, the enzyme responsible for bilirubin conjugation)


For acetaminophen
Bilirubin, serum and
Lactate dehydrogenase, serum and
Prothrombin time and
Transaminase, serum    (values may be increased indicating acetaminophen-induced hepatotoxicity, especially in alcoholics, patients taking hepatic enzyme–inducing agents, or those with pre-existing hepatic disease, when single toxic doses [>8–10 grams] are taken or with prolonged use of lower doses [>3–5 grams a day])


For aspirin
Bleeding time    (may be prolonged by aspirin for 4 to 7 days because of suppressed platelet aggregation; as little as 40 mg of aspirin affects platelet function for at least 96 hours following administration; however, clinical bleeding problems have not been reported with small doses [150 mg or less])


Potassium, serum    (concentrations may be decreased because of increased potassium excretion caused by direct effect on renal tubules)


Uric acid, serum    (concentrations may be increased with doses producing plasma salicylate concentrations below 100 to 150 mcg/mL [10 to 15 mg per 100 mL; 0.724 to 1.09 mmol/L] or decreased with doses producing plasma salicylate concentrations higher than 100 to 150 mcg/mL [10 to 15 mg per 100 mL; 0.724 to 1.09 mmol/L])


For codeine
Amylase, plasma and
Lipase, plasma    (values may be increased because codeine can cause contractions of the sphincter of Oddi and increased biliary tract pressure; the diagnostic utility of determinations of these enzymes may be compromised for up to 24 hours after medication has been given)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical conditions exist:

For barbiturates:
» Porphyria, acute intermittent or variegata or history of    (barbiturates may aggravate symptoms by inducing enzymes responsible for porphyrin synthesis)


For aspirin:
» Angioedema, anaphylaxis or other severe allergic reaction induced by aspirin or other NSAIDs, history of    (high risk of recurrence)


» Bleeding ulcers or
» Hemorrhagic states, other active    (may be exacerbated)


» Hemophilia or other bleeding problems, including coagulation or platelet function disorders    (increased risk of hemorrhage)


» Nasal polyps associated with aspirin-induced asthma or other allergies    (high risk of severe allergic reactions)


For codeine:
» Diarrhea caused by poisoning or antibiotic therapy, until toxic material has been eliminated from the gastrointestinal tract    (codeine may slow elimination of toxic material)


» Respiratory depression, acute    (may be exacerbated)


Risk-benefit should be considered when the following medical problems exist

For barbiturates:
» Allergic reaction to a barbiturate, history of
Asthma, history of    (increased risk of bronchospastic allergic reactions)


Diabetes mellitus, especially with phenobarbital
» Drug abuse or dependence, history of    (patient predisposed to habituation and dependence)


» Hepatic coma, premonitory signs of or
Hepatic function impairment    (barbiturates metabolized in liver; caution and a reduction in barbiturate dosage is recommended)


Hyperkinesis    (increased risk of barbiturate-induced paradoxical excitement)


Hyperthyroidism    (symptoms may be exacerbated because barbiturates displace thyroxine from plasma proteins)


Mental depression or
Suicidal tendencies    (condition may be exacerbated, especially in elderly patients)


Renal function impairment    (barbiturates excreted via kidneys; reduction in barbiturate dosage may be necessary)


» Respiratory disease involving dyspnea or obstruction, particularly status asthmaticus    (serious ventilatory depression may occur)


Caution is also recommended in geriatric or debilitated patients, who may be more sensitive to the effects of barbiturates and may react to usual doses of a barbiturate with excitement, depression, and confusion and in pediatric patients, who are especially susceptible to paradoxical excitement during barbiturate therapy.
For acetaminophen:
» Alcohol abuse, current or
» Hepatic disease or
» Viral hepatitis    (increased risk of hepatotoxicity)


Renal function impairment, severe    (risk of adverse renal effects may be increased with prolonged use of high doses; occasional use is acceptable)


Sensitivity to acetaminophen, history of    (increased risk of allergic reaction)


For aspirin:
» Asthma    (increased risk of bronchospastic allergic reactions)


» Gastritis, erosive or
» Peptic ulcer    (may be exacerbated because of ulcerogenic effects; risk of gastrointestinal bleeding is increased)


Gout    (aspirin may increase serum uric acid concentrations; also, may interfere with efficacy of uricosuric agents)


Hepatic function impairment    (salicylates metabolized in liver; also, in severe hepatic impairment, inhibition of platelet function by aspirin may increase risk of hemorrhage)


Hypoprothrombinemia or
Vitamin K deficiency    (increased risk of bleeding because of antiplatelet action of aspirin)


Mild sensitivity reaction to aspirin, history of    (increased risk of severe allergic reactions)


Renal function impairment    (salicylates excreted via kidneys)


For codeine:
Allergic reaction to codeine, history of
» Asthma, acute attack or
» Respiratory impairment or disease, chronic    (codeine may decrease respiratory drive and increase airway resistance)


Cardiac arrhythmias or
Convulsions, history of    (may be induced or exacerbated)


Drug abuse or dependence, history of or
Emotional instability or
Suicidal ideation or attempts    (increased risk of abuse)


Gallbladder disease or gallstones    (codeine may cause biliary tract spasm)


Head injury or
Increased intracranial pressure, pre-existing or
Intracranial lesions    (risk of respiratory depression and further elevation of cerebrospinal fluid is increased; also, codeine may cause sedation and pupillary changes which may obscure clinical course of head injury)


Hepatic function impairment    (codeine metabolized in liver; may accumulate)


Hypothyroidism    (increased risk of respiratory depression and prolonged CNS depression)


» Inflammatory bowel disease, severe    (risk of toxic megacolon may be increased, especially with repeated dosing)


Prostatic hypertrophy or obstruction or
Urethral stricture    (codeine may cause urinary retention)


Renal function impairment    (codeine excreted primarily via kidneys; also, may cause urinary retention)


Caution is also advised in administration to very young, elderly, or very ill or debilitated patients, who may be more sensitive to the effects, especially the respiratory depressant effects, of codeine.
For caffeine:
Cardiac disease, severe    (high doses of caffeine may increase risk of tachycardia or extrasystoles, which may lead to heart failure)


Sensitivity to caffeine, history of    (risk of allergic reaction)




Side/Adverse Effects

Note: Barbiturates and codeine may cause dependence, especially following prolonged use of high doses, in any patient. The characteristics of dependence include: a strong desire or need to continue taking the medication; a tendency to increase the dose; a psychological dependence on the effects of the medication; and a physical dependence on the effects of the medication requiring its presence for maintenance of homeostasis and resulting in an abstinence syndrome when the medication is discontinued. With codeine, the severity of withdrawal symptoms depends upon the abruptness of withdrawal and the extent to which dependence has developed. However, codeine has lower dependence liability and potential for abuse than most other opioid agonists because of its relatively weak agonist activity with usual analgesic doses.
Frequent use of any analgesic for treatment of headaches (including analgesics that do not contain a barbiturate or an opioid) may lead to tolerance, {09} an increased dosage requirement, {09} {18} dependence, {09} {11} {18} withdrawal (rebound) headaches, {09} {11} {13} {14} {18} and further use of the medication. {11} {14} {18} Eventually, chronic (daily or near-daily) headaches may occur. {11} {14} {18} This type of dependence may occur only in headache-prone patients; withdrawal headaches have not been reported in patients who take analgesics frequently for other types of pain. {18} Chronic daily use of caffeine may also result in the development of physical dependence, leading to withdrawal headaches and medication abuse. {18} {19} {20} {21} {22}
Aspirin-induced bronchospasm is most likely to occur in patients with the triad of aspirin-induced asthma, allergies, and nasal polyps. Aspirin-induced angioedema or urticaria may be more likely to occur in patients with a history of recurrent idiopathic angioedema or urticaria.
The side/adverse effects listed below are those that may occur with occasional use of recommended doses of these combination medications (including those that may result from an allergic or idiosyncratic response to individual ingredients in the formulations) or with an acute overdose. For additional information on side/adverse effects that may occur with individual ingredients in these medications, especially if these agents are ingested frequently or in higher-than-recommended doses, see—
For butalbital: Barbiturates (Systemic) . Although butalbital is not specifically mentioned in that monograph, side effects that are likely to occur with other barbiturates may occur with butalbital also.
For phenobarbital: Barbiturates (Systemic) .
For acetaminophen: Acetaminophen (Systemic) .
For aspirin: Salicylates (Systemic) .
For codeine: Opioid (Narcotic) Analgesics (Systemic) .
For caffeine: Caffeine (Systemic) .

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
For barbiturates
    
Agranulocytosis (fever with or without chills; sores, ulcers, or white spots on lips or in mouth; sore throat)
    
angioedema (large, hive-like swellings on eyelids, face, lips, and/or tongue)
    
bronchospastic allergic reaction ( shortness of breath; troubled breathing ; tightness in chest; wheezing)
    
CNS (Central Nervous System) effects ( confusion; hallucinations; mental depression; unusual tiredness or weakness)—confusion or mental depression especially likely to occur in geriatric or debilitated patients
    
CNS stimulation, paradoxical (unusual excitement)— especially likely to occur in pediatric, geriatric, or debilitated patients
    
dermatitis, allergic (skin rash or hives)
    
dermatitis, exfoliative (fever with or without chills; red, thickened, or scaly skin; swollen and/or painful glands; unusual bruising)
    
erythema multiforme (fever with or without chills ; muscle cramps or pain; skin rash; sores, ulcers, or white spots on lips or in mouth)
    
hypotension ( decreased blood pressure)—usually asymptomatic, but may lead to tiredness or weakness if severe
    
Stevens-Johnson syndrome (bleeding or crusting sores on lips; chest pain; fever with or without chills; muscle cramps or pain; skin rash; sores, ulcers, or white spots in mouth; sore throat)
    
thrombocytopenia (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)

For acetaminophen
    
Agranulocytosis (fever with or without chills; sores, ulcers, or white spots on lips or in mouth; sore throat)
    
dermatitis, allergic (skin rash, hives, or itching )
    
thrombocytopenia (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)

For aspirin
    
Anaphylaxis (bluish discoloration or flushing or redness of skin; coughing; difficulty in swallowing; dizziness or feeling faint, severe; skin rash, hives [may include giant urticaria], and/or itching; stuffy nose; large, hive-like swellings on eyelids, face, lips, and/or tongue; tightness in chest, troubled breathing, and/or wheezing, especially in asthmatic patients)
    
bronchospastic allergic reaction (shortness of breath, troubled breathing, tightness in chest, and/or wheezing)
    
dermatitis, allergic ( skin rash, hives, or itching)
    
necrolysis, toxic epidermal ( redness, tenderness, itching, burning, or peeling of skin; sore throat; fever with or without chills)

For codeine
    
Angioedema (large, hive-like swellings on face, eyelids, mouth, lips, and/or tongue)
    
bronchoconstriction, laryngeal edema, or laryngospasm, allergic ( shortness of breath, troubled breathing, tightness in chest, or wheezing)
    
CNS toxicity (convulsions, hallucinations, trembling, and/or uncontrolled muscle movements; mental depression)
    
dermatitis, allergic (skin rash, itching, or hives)




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
For all barbiturate and analgesic combinations
    
CNS effects (dizziness, drowsiness, or lightheadedness, mild )
    
gastrointestinal irritation (bloated or "gassy" feeling, mild stomach pain, heartburn or indigestion, nausea with or without vomiting)—especially likely with formulations containing aspirin.






Overdose
For specific information on the agents used in the management of barbiturates and analgesics overdose, see: For acetaminophen

   • Acetylcysteine (Systemic) monograph; and/or
   • Vitamin K— Phytonadione 1 (Systemic) in Vitamin K (Systemic) monograph.For aspirin

   • Vitamin K— Phytonadione 1 (Systemic) in Vitamin K (Systemic) monograph.For codeine

   • Naloxone (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
For barbiturates
Acute
    
Confusion
    
severe drowsiness or weakness
    
shortness of breath or unusually slow or troubled breathing
    
slow heartbeat
    
slurred speech
    
staggering
    
unusual movements of the eyes

Note: In acute barbiturate overdosage, CNS and respiratory depression may lead to Cheyne-Stokes respiration, areflexia, slight pupillary constriction (in severe toxicity, pupils may be dilated), oliguria, tachycardia, lowered body temperature, and coma . Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.
In extreme barbiturate overdosage, all electrical activity in the brain may cease. In this case an electroencephalogram (EEG) may be “flat,” but this does not necessarily indicate clinical death since, unless hypoxic damage occurs, this effect is fully reversible.
Complications in barbiturate overdosage such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur.



For acetaminophen
Acute
    
Diarrhea
    
increased sweating
    
loss of appetite
    
nausea or vomiting
    
stomach cramps or pain — may occur within 6 to 14 hours after ingestion of the overdose and persist for about 24 hours

Note: Early signs and symptoms often do not occur.


Chronic
    
Hepatotoxicity (pain, tenderness, and/or swelling in upper abdominal area)—may occur 2 to 4 days after the overdose is ingested

Note: The first indications of overdosage may be signs and symptoms of possible liver damage and abnormalities in liver function tests, which may not occur until 2 to 4 days after ingestion of the overdose. Maximal changes in liver function tests usually occur 3 to 5 days after ingestion of the overdose.
Overt hepatic disease or failure may occur 4 to 6 days after ingestion of the overdose. Hepatic encephalopathy (with mental changes, confusion, agitation, or stupor), convulsions, respiratory depression, coma, cerebral edema, coagulation defects, gastrointestinal bleeding, disseminated intravascular coagulation, hypoglycemia, metabolic acidosis, renal tubular necrosis leading to renal failure (signs include bloody or cloudy urine and sudden decrease in amount of urine), cardiac arrhythmias, and cardiovascular collapse may occur.



For aspirin
Acute and chronic
[Mild overdose] Salicylism
    
Continuing ringing or buzzing in ears, or hearing loss
    
confusion
    
severe or continuing diarrhea, stomach pain, and/or headache
    
dizziness or lightheadedness
    
severe drowsiness
    
fast or deep breathing
    
continuing nausea and/or vomiting
    
uncontrollable flapping movements of the hands, especially in elderly patients
    
increased thirst
    
vision problems


Severe overdose
    
Bloody urine
    
convulsions
    
hallucinations
    
severe nervousness, excitement, or confusion
    
shortness of breath or troubled breathing
    
unexplained fever

Note: In young children, the only signs of an overdose may be changes in behavior, severe drowsiness or tiredness, and/or fast or deep breathing.
Laboratory findings in overdose may indicate encephalographic abnormalities; alterations in acid-base balance, especially respiratory alkalosis and metabolic acidosis; hyperglycemia or hypoglycemia, especially in children; ketonuria; hyponatremia; hypokalemia; and proteinuria.




For codeine
Acute and chronic
    
CNS toxicity (confusion, convulsions, severe dizziness, severe drowsiness, severe nervousness or restlessness, unconsciousness, severe weakness )
    
cold, clammy skin
    
low blood pressure
    
pinpoint pupils of eyes
    
respiratory depression (shortness of breath or unusually slow or troubled breathing)
    
slow heartbeat


For caffeine
Acute and chronic
    
CNS toxicity (agitation, anxiety, excitement, or restlessness ; confusion or delirium; increased sensitivity to touch or pain; irritability; ringing or other sounds in ears; seeing flashes of “zig-zag” lights; seizures, usually tonic-clonic; trouble in sleeping)
    
dehydration
    
fast or irregular heartbeat
    
fever
    
frequent urination
    
gastrointestinal effects (abdominal or stomach pain ; nausea and vomiting, sometimes with blood)
    
headache
    
muscle trembling or twitching




Treatment of overdose


For all barbiturate and analgesic combinations:
To decrease absorption—Inducing emesis with ipecac syrup if the patient is conscious and has not lost the gag reflex. Care should be taken to prevent pulmonary aspiration of vomitus. If emesis is contraindicated, performing gastric lavage with a cuffed endotracheal tube in place with the patient face down.

After emesis is completed, administering activated charcoal in a glass of water or sorbitol to prevent absorption and increase excretion of the barbiturate. It is usually recommended that activated charcoal be left in the stomach. Also, a saline cathartic may be administered.

To enhance elimination—If renal function is normal, inducing forced diuresis, which may help to eliminate the barbiturate. Alkalinization of the urine increases renal excretion of some barbiturates.

Instituting hemodialysis or hemoperfusion in severe barbiturate poisoning or if the patient is anuric or in shock. However, hemodialysis or hemoperfusion is not recommended as a routine procedure.

Specific treatment—Administering fluid therapy and other standard treatment for shock, if necessary. A vasopressor may be required if hypotension occurs. Fluid or sodium overload should be avoided, especially if cardiovascular status is decreased.

Administering chest physiotherapy. If pneumonia is suspected, appropriate cultures should be taken and antibiotics should be administered. Also, appropriate care should be taken to prevent hypostatic pneumonia, decubiti, aspiration, and other complications that may occur with altered states of consciousness.

Supportive care—Maintaining an adequate airway, with assisted respiration and administration of oxygen as needed.

Monitoring vital signs and fluid balance.



For acetaminophen:
To enhance elimination—Instituting hemodialysis or hemoperfusion to remove acetaminophen from the circulation may be beneficial if acetylcysteine administration cannot be instituted within 24 hours following ingestion of a massive acetaminophen overdose. However, the efficacy of this treatment in preventing acetaminophen-induced hepatotoxicity is not known.

Specific treatment—Because activated charcoal may interfere with absorption of oral acetylcysteine (antidote used to protect against acetaminophen-induced hepatotoxicity), removal of activated charcoal via gastric lavage may be advisable prior to acetylcysteine administration. See the package insert or Acetylcysteine (Systemic) for specific dosing guidelines for use of this product.

Administering acetylcysteine. It is recommended that acetylcysteine administration be instituted as soon as possible after ingestion of an overdose has been reported, without waiting for the results of plasma acetaminophen determinations or other laboratory tests. Acetylcysteine is most effective if treatment is started within 10 to 12 hours after ingestion of the overdose; however, it may be of some benefit if treatment is started within 24 hours.

Administering vitamin K 1 (if prothrombin time ratio exceeds 1.5) and fresh frozen plasma or clotting factor concentrate (if prothrombin time ratio exceeds 3.0). See the package insert or Phytonadione in Vitamin K (Systemic) for specific dosing guidelines for use of this product.

Monitoring—Determining plasma acetaminophen concentration at least 4 hours following ingestion of the overdose. Determinations performed prior to this time are not reliable for assessing potential hepatotoxicity. Initial plasma concentrations above 150 mcg per mL (mcg/mL) (993 micromoles/L) at 4 hours, 100 mcg/mL (662 micromoles/L) at 6 hours, 70 mcg/mL (463.4 micromoles/L) at 8 hours, 50 mcg/mL (331 micromoles/L) at 10 hours, 20 mcg/mL (132.4 micromoles/L) at 15 hours, 8 mcg/mL (53 micromoles/L) at 20 hours, or 3.5 mcg/mL (23.2 micromoles/L) at 24 hours postingestion indicate possible hepatotoxicity and the need for completing the full course of acetylcysteine treatment. If the initial determination indicates a plasma concentration below those listed at the times indicated, cessation of acetylcysteine therapy can be considered. However, some clinicians advise that more than one determination should be performed to ascertain peak absorption and half-life of acetaminophen prior to considering discontinuation of acetylcysteine.

Performing liver function tests (serum aspartate aminotransferase [AST; SGOT], serum alanine aminotransferase [ALT; SGPT], prothrombin time, and bilirubin) at 24-hour intervals for at least 96 hours postingestion if the plasma acetaminophen concentration indicates potential hepatotoxicity. If no abnormalities are detected within 96 hours, further determinations are not needed.

Monitoring renal and cardiac function and administering appropriate therapy as required.

Supportive care—Instituting supportive treatment, including maintaining fluid and electrolyte balance, and correcting hypoglycemia.



For aspirin:
To enhance elimination—Inducing forced alkaline diuresis to increase salicylate excretion. However, bicarbonate should not be administered orally for this purpose because salicylate absorption may be increased. Also, if acetazolamide is used, the increased risk of severe metabolic acidosis and salicylate toxicity (caused by increased penetration of salicylate into the brain because of metabolic acidosis) must be considered. Some emergency care practitioners recommend that acetazolamide not be used at all in the treatment of salicylate overdose. Others state that acetazolamide may be used, provided that precautions are taken to prevent systemic metabolic acidosis, such as concurrent administration of an alkaline intravenous solution, e.g., one that contains sodium bicarbonate or sodium lactate.

Institution of exchange transfusion, hemodialysis, peritoneal dialysis, or hemoperfusion as needed in severe overdose.

Administering blood or vitamin K 1 if necessary to treat hemorrhaging. See the package insert or Phytonadione (Systemic) in Vitamin K (Systemic) for specific dosing guidelines for use of this product.

Monitoring—Monitoring serum salicylate concentration until it is apparent that the concentration is decreasing to the nontoxic range. Salicylate concentrations of 500 mcg/mL (50 mg per 100 mL; 3.62 mmol/L) 2 hours after ingestion indicate serious toxicity; salicylate concentrations above 800 mcg/mL (80 mg per 100 mL; 5.79 mmol/L) 2 hours after ingestion indicate possible fatality. In addition, prolonged monitoring may be necessary in massive overdosage because absorption may be delayed; if a determination performed prior to 6 hours after ingestion fails to show a toxic salicylate concentration, the determination should be repeated. Salicylate concentrations indicative of varying degrees of toxicity are as follows:

Time After
Ingestion
Salicylate Concentration
mcg/mL
mg/100 mL
mmol/L
Mild toxicity
     
6 hr
450–650
45–65
3.26–4.71
12 hr
350–550
35–55
2.53–3.98
Moderate toxicity
     
6 hr
650–900
65–90
4.71–6.52
12 hr
550–750
55–75
3.98–5.43
Severe toxicity
     
6 hr
> 900
> 90
> 6.52
12 hr
> 750
> 75
> 5.43


Monitoring for pulmonary edema and instituting appropriate therapy if required.

Supportive care—Correcting hyperthermia; fluid, electrolyte, and acid-base imbalances; ketosis; and plasma glucose concentration as needed.



For codeine:
Specific treatment—Administering the opioid antagonist naloxone. See the package insert or Naloxone (Systemic) for specific dosing guidelines for use of this product.

Monitoring—Continuing to monitor the patient (mandatory because the duration of action of the opioid analgesic may exceed that of naloxone) so that additional antagonist may be administered as needed. Alternatively, initial treatment may be followed by continuous intravenous infusion of naloxone, with the rate of infusion being adjusted according to patient response. The fact that naloxone may also antagonize the analgesic actions of opioid analgesics and may precipitate withdrawal symptoms in physically dependent patients must be kept in mind.

Supportive care—Establishing adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled respiration.

Administration of intravenous fluids, vasopressors, and other supportive measures as needed.


Note: Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation

Table 1. Patient Consultation



As an aid to patient consultation, refer to Advice for the Patient, Butalbital and Acetaminophen (Systemic); Advice for the Patient, Butalbital and Aspirin (Systemic); Advice for the Patient, Butalbital, Acetaminophen, Caffeine, and Codeine (Systemic); or Advice for the Patient, Barbiturates, Aspirin, and Codeine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Legend:
I=Butalbital and Acetaminophen
II=Butalbital, Acetaminophen, and Caffeine
III=Butalbital and Aspirin

IV=Butalbital, Aspirin, and Caffeine
V=Butalbital, Aspirin, Caffeine, and Codeine
VI=Phenobarbital, Aspirin, and Codeine
VII=Butalbital, Acetaminophen, Caffeine and Codeine
 
II  III  IV  VI  VII 
Before using this medication
» Conditions affecting use, especially:
Sensitivity to—
Butalbital, phenobarbital, or other barbiturates








Acetaminophen


       
Aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs)
   



 
Codeine
       


Caffeine
 
 

 
Pregnancy—
Barbiturates cross the placenta; may cause fetal abnormalities and/or an increased risk of brain tumors in the neonate; may also cause breathing problems in the neonate if taken shortly before delivery







Aspirin crosses the placenta; should not be taken during third trimester unless prescribed by physician; chronic, high-dose use may cause adverse effects on the circulation in fetus or neonate, bleeding in fetus and/or mother, prolonged gestation, and complicated deliveries
   



 
Codeine crosses the placenta; may cause breathing problems in the neonate if taken just before delivery
       


Caffeine crosses the placenta; total daily intake should be limited because of risk of fetal arrhythmias
 
 

 
Breast-feeding—
Barbiturates distributed into breast milk; may cause CNS depression in the infant







Caffeine distributed into breast milk; total daily intake should be limited because of risk of CNS stimulation in the infant
 
 

 
Use in children—
Possibility of barbiturate-induced paradoxical excitement







Not giving aspirin to children with symptoms of viral illness (especially influenza or varicella) without physician's permission because of risk of Reye's syndrome; children without a viral illness are also more susceptible to aspirin-induced toxicity
   



 
Possibility of codeine-induced paradoxical excitement
       


Use in teenagers—Checking with physician before giving to teenagers with symptoms of acute febrile illness, especially influenza or varicella, because of the risk of Reye's syndrome
   



 
Use in the elderly—
Increased sensitivity to barbiturates; may react to usual doses with confusion, depression, or excitement







Increased susceptibility to toxic effects of aspirin
   



 
Increased susceptibility to respiratory depressant and other adverse effects of opioid analgesics
       


Other medications, especially:
             
Alcohol







Alkalizers, urinary
   



 
Anticoagulants, coumarin- or indandione-derivative







Carbamazepine







Contraceptives, estrogen-containing, oral







Corticosteroids, glucocorticoid and mineralocorticoid







Corticotropin







CNS depressants







Divalproex sodium







Heparin
   



 
Methotrexate
   



 
Naltrexone
       


Probenecid
   



 
Sulfinpyrazone
   



 
Valproic acid







Vancomycin
   



 
Other medical problems, especially:
Alcohol abuse


       
Asthma







Bleeding ulcers, or other bleeding problems or coagulation defects
   



 
Diarrhea caused by antibiotics or poisoning
       


Drug abuse or history of







Gastritis (erosive) or peptic ulcer, history of
   



 
Inflammatory bowel disease, severe
       


Liver disease







Porphyria







Respiratory disease







Viral hepatitis


       
Proper use of this medication
» Taking with food or a full glass (240 mL) of water to minimize stomach irritation
   



 
»Not taking medication if it has a strong vinegar-like odor
   



 
»Importance of not taking more medication than the amount prescribed because of danger of:
Habituation







Hepatotoxicity


       
Overdose







»For relief of headache:
Most effective when taken as soon as headache appears or at first sign of migraine attack (prodromal stage)







Lying down in a quiet, dark room for a while after taking







Compliance with prophylactic therapy, if prescribed







» Proper dosing







Missed dose (if on scheduled dosing regimen): Taking as soon as possible; not taking if almost time for next dose; not doubling doses







» Proper storage







Precautions while using this medication
» Checking with physician if effectiveness of medication decreases and/or frequency of headaches increases; possibility that tolerance to or physical dependence on the medication, leading to withdrawal headaches, has developed







» Risk of overdose if taking other medications containing:
Barbiturates







Acetaminophen


       
Aspirin or other salicylates
   



 
Codeine or other opioids
       


»Avoiding alcohol or other CNS depressants unless prescribed or otherwise approved by physician







Alcohol consumption may increase probability of stomach problems
   




Alcohol consumption may increase risk of hepatotoxicity, with high doses or prolonged use


       
»Caution if dizziness, lightheadedness, drowsiness, or a false sense of well-being occurs







Caution when getting up suddenly from a lying or sitting position
       


Lying down if nausea or vomiting, or dizziness or lightheadedness occurs
       


Need to inform physician or dentist of use of medication if any kind of surgery (including dental surgery) or emergency treatment is required







Caution if any kind of surgery is required; aspirin should be discontinued 5 days prior to surgery unless otherwise directed by physician
   



 
Diabetics: May cause false urine sugar test results with prolonged use of 8 or more capsules or tablets per day
   



 
Caution if any laboratory tests required
Possible interference with laboratory test results







Not taking caffeine for 8 to 12 hours prior to dipyridamole-assisted myocardial perfusion studies
 
 

 
»Checking with physician before discontinuing medication following prolonged use; gradual reduction in dosage may be required to reduce risk of withdrawal symptoms







» Suspected overdose: Getting emergency help at once







Side/adverse effects
Signs and symptoms of potential side effects, especially:
Agranulocytosis







Anaphylaxis
   




Angioedema







Bronchospastic allergic reaction







CNS adverse effects







CNS stimulation (paradoxical)







Dermatitis, allergic







Dermatitis, exfoliative







Erythema multiforme







Laryngeal edema, allergic
       


Laryngospasm, allergic
       


Stevens-Johnson syndrome







Thrombocytopenia







Toxic epidermal necrolysis
   



 


General Dosing Information
When used for relief of headache, especially a migraine headache, a barbiturate and analgesic combination will be most effective if administered when the first symptoms appear (during the prodrome, for migraine with aura). {09} {14}

After the first dose has been administered, it is recommended that the patient lie down and relax in a quiet, darkened room, because this contributes to relief of headaches. {11}

A reduction in dosage may be required for elderly or debilitated patients, who may react to usual doses of barbiturates with excitement, confusion, or depression. This is particularly important for the codeine-containing combinations, because these patients are also more sensitive to the respiratory depressant effects of codeine.

Tolerance may occur with repeated administration of large doses of barbiturates or codeine. Also, patients who are tolerant to the effects of other opioids may be at least partially cross-tolerant to the effects of codeine, and vice versa.

Prolonged uninterrupted use of codeine or barbiturates may result in psychic or physical dependence; in patients taking these medications for relief of pain other than headache pain, gradual withdrawal may be required to reduce the risk of precipitating withdrawal symptoms.

In headache-prone individuals, frequent use of analgesics may cause physical dependence, {09} {11} leading to both analgesic abuse {11} {14} {18} and chronic (daily or near-daily) headaches. {18} {24} {25} {26} {27} Chronic daily use of caffeine may also result in the development of physical dependence, leading to withdrawal (rebound) headaches when the medication is stopped and to further ingestion of caffeine-containing analgesics. {18} {19} {20} {21} {22} {23} Patients who experience frequent headaches may be dependent on a variety of medications, including opioid analgesics, nonopioid analgesics such as acetaminophen or aspirin, ergotamine-containing headache suppressants, and antianxiety agents or sedatives, as well as barbiturate and analgesic combinations. {11} {14} {24} {27}

Chronic headaches resulting from overmedication may be difficult to relieve, especially if the patient continues to take ergotamine-containing headache suppressants {24} {27} and/or analgesics. {24} {25} {27} If such headaches occur, it is recommended that these medications be discontinued. {11} {24} {25} {26} {27} In-patient treatment may be necessary during detoxification. {25} {26} Naproxen, alone {09} or together with amitriptyline {24}, may reduce the severity of the headaches. Repetitive intravenous administration of dihydroergotamine (in conjunction with metoclopramide [to control dihydroergotamine-induced nausea and vomiting]) is recommended by some headache specialists to relieve this type of headache. {25} {26} Appropriate treatment for symptoms of withdrawal from other substances frequently used or abused by chronic headache patients may also be needed. {25} {26} In addition, appropiate prophylactic treatment should be initiated or adjusted to reduce the frequency and severity of future headaches. {25} {26} {27}

BUTALBITAL AND ACETAMINOPHEN

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effect—Butalbital: A short- to intermediate-acting barbiturate.

Biotransformation—Acetaminophen: An intermediate metabolite is hepatotoxic and possibly nephrotoxic.



Precautions:
Cross-sensitivity and/or related problems—Acetaminophen: Low risk of cross-sensitivity with aspirin.

Drug interactions and/or related problems—

Butalbital: May be less likely than phenobarbital to cause significant interference with medications adversely affected by hepatic enzyme induction.

Acetaminophen: Caution required with hepatic enzyme inducers and with other hepatotoxic medications.

Laboratory value alterations—Acetaminophen: Interferes with blood glucose determinations, blood 5-hydroxyindoleacetic acid determinations, pancreatic function determinations using bentiromide, serum uric acid determinations. Hepatic function studies may indicate hepatotoxicity.

Medical considerations/contraindications—Acetaminophen: Increased risk of hepatotoxicity in alcoholics and patients with hepatic disease or viral hepatitis.



Oral Dosage Forms

BUTALBITAL AND ACETAMINOPHEN CAPSULES

Usual adult and adolescent dose
Analgesic
Oral, 1 or 2 capsules containing 50 mg of butalbital and 325 mg of acetaminophen every four hours as needed, not to exceed 6 capsules a day; or
Oral, 1 capsule containing 50 mg of butalbital and 650 mg of acetaminophen every four hours as needed, not to exceed 4 capsules a day.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital and 325 mg of acetaminophen (Rx) [Bancap] [Triaprin]


50 mg of butalbital and 650 mg of acetaminophen (Rx) [Bucet] [Conten] [Phrenilin Forte] [Tencon]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • May be habit-forming.


BUTALBITAL AND ACETAMINOPHEN TABLETS

Usual adult and adolescent dose
Analgesic
Oral, 1 or 2 tablets containing 50 mg of butalbital and 325 mg of acetaminophen every four hours as needed, not to exceed 6 tablets a day; or
Oral, 1 tablet containing 50 mg of butalbital and 650 mg of acetaminophen every four hours as needed, not to exceed 4 tablets a day.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital and 325 mg of acetaminophen (Rx) [Phrenilin ( scored)][Generic]


50 mg of butalbital and 650 mg of acetaminophen (Rx) [Sedapap ( scored)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • May be habit-forming.


BUTALBITAL, ACETAMINOPHEN, AND CAFFEINE CAPSULES USP

Usual adult and adolescent dose
Analgesic—Oral, 1 or 2 capsules every four hours as needed, not to exceed 6 capsules a day.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital, 325 mg of acetaminophen, and 40 mg of caffeine (Rx) [Amaphen] [Anolor-300] [Anoquan] [Butace] [Dolmar] [Endolor] [Esgic] [Ezol] [Femcet] [Medigesic] [Pacaps] [Repan] [Tencet] [Triad] [Two-Dyne]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • May be habit-forming.


BUTALBITAL, ACETAMINOPHEN, AND CAFFEINE TABLETS USP

Usual adult and adolescent dose
Analgesic
Oral, 1 or 2 tablets containing 50 mg of butalbital and 325 mg of acetaminophen every four hours as needed, not to exceed 6 tablets a day; or
Oral, 1 tablet containing 50 mg of butalbital and 500 mg of acetaminophen every four hours as needed, not to exceed 6 tablets a day. {28}


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital, 325 mg of acetaminophen, and 40 mg of caffeine (Rx) [Arcet] [Dolmar] [Esgic (scored)] [Fioricet] [Isocet] [Medigesic] [Pharmagesic] [Repan][Generic]


50 mg of butalbital, 500 mg of acetaminophen, and 40 mg of caffeine (Rx) [Esgic-Plus{28} (scored)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • May be habit-forming.


BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effect—Butalbital: A short- to intermediate-acting barbiturate.

Other actions/effects—Codeine: Also has antidiarrheal and antitussive actions.

Biotransformation—Acetaminophen: An intermediate metabolite is hepatotoxic and possibly nephrotoxic.



Precautions:
Cross-sensitivity and/or related problems—Acetaminophen: Low risk of cross-sensitivity with aspirin.

Pregnancy—Codeine: Ingestion shortly prior to delivery may cause neonatal respiratory depression, especially in premature neonates.

Geriatrics—Codeine: Increased susceptibility to respiratory depressant effects.

Drug interactions and/or related problems—

Butalbital: May be less likely than phenobarbital to cause significant interference with medications adversely affected by hepatic enzyme induction.

Acetaminophen: Caution is required with hepatic enzyme inducers and with other hepatotoxic medications.

Codeine: Caution is also required with anticholinergics, antiperistaltic antidiarrheals, agents that may reduce blood pressure, metoclopramide, monoamine oxidase inhibitors, naloxone, naltrexone, and other opioid analgesics.

Laboratory value alterations—

Acetaminophen: Interferes with blood glucose determinations, blood 5-hydroxyindoleacetic acid determinations, pancreatic function determinations using bentiromide, serum uric acid determinations. Hepatic function studies may indicate hepatotoxicity.

Codeine: Interferes with gastric emptying studies and hepatobiliary imaging (radionuclide). Also, may increase plasma amylase and/or lipase concentrations.

Medical considerations/contraindications—

Acetaminophen: Increased risk of hepatotoxicity in alcoholics and patients with hepatic disease or viral hepatitis.

Codeine: Should not be used if the patient has diarrhea caused by poisoning or by antibiotic therapy, or in the presence of acute respiratory depression. Caution is also required in patients with asthma, chronic respiratory disease, and severe inflammatory bowel disease.



Side/adverse effects:
Codeine: May also cause laryngospasm or laryngeal edema.



Oral Dosage Forms

BUTALBITAL, ACETAMINOPHEN, CAFFEINE AND CODEINE PHOSPHATE CAPSULES

Usual adult and adolescent dose
Analgesic
Oral, 1 or 2 capsules every four hours as needed, not to exceed 6 capsules a day {29}.


Usual pediatric dose
Dosage has not been established {29}.

Strength(s) usually available
U.S.—


50 mg of butalbital, 325 mg of acetaminophen, 40 mg of caffeine, and 30 mg of codeine phosphate (Rx) [Fioricet with Codeine ( propylparaben ) (carboxymethylcellulose) ( silicone dioxide and/or sodium propionate)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (86 °F). Store in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • May be habit-forming.


BUTALBITAL AND ASPIRIN

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effect—Butalbital: A short- to intermediate-acting barbiturate.

Other actions/effects—Aspirin: Also has platelet aggregation–inhibiting actions.



Precautions:
Cross-sensitivity and/or related problems—Aspirin: Risk of cross-sensitivity with other nonsteroidal anti-inflammatory drugs (NSAIDs); slight risk of cross-sensitivity with acetaminophen.

Pregnancy/reproduction—Aspirin:

First trimester—Reports of possible birth defects in humans, but teratogenicity not found in controlled studies with usual therapeutic doses.

Third trimester—Use not recommended; chronic, high-dose use has caused complications (including stillbirth or neonatal death) associated with prolonged gestation, premature closure of the fetal ductus arteriosus, prolonged labor, complicated deliveries, and maternal, fetal or neonatal bleeding.

Pediatrics—Aspirin: Risk of Reye's syndrome in children with acute febrile illness, especially influenza and varicella; febrile, dehydrated patients also more susceptible to other forms of salicylate toxicity.

Adolescents—Aspirin: Risk of Reye's syndrome in adolescents with acute febrile illness, especially influenza and varicella.

Geriatrics—Aspirin: Increased susceptibility to salicylate toxicity.

Drug interactions and/or related problems—

Butalbital: May be less likely than phenobarbital to cause significant interference with medications adversely affected by hepatic enzyme induction.

Aspirin: Caution also required with urinary acidifiers or alkalizers; anticoagulants; methotrexate; ototoxic medications; probenecid; sulfinpyrazone; and thrombolytic agents.

Laboratory value alterations—Aspirin: Interferes with determinations of urine aceto-acetic acid (Gerhard test), urine glucose (copper sulfate or enzymatic tests), urine 5-hydroxyindoleacetic acid, renal function test (phenolsulfonphthalein), thyroid imaging (radionuclide), thyroid-stimulating hormone release (protirelin-stimulated), vanillylmandelic acid. May also prolong bleeding time, decrease serum potassium concentrations, and cause dose-dependent increase or decrease in serum uric acid concentration.

Medical considerations/contraindications—Aspirin: Should not be used in patients with severe allergic or asthmatic reaction to aspirin or other NSAIDs (history of), bleeding ulcers or other active bleeding states, or hemophilia or other coagulation or platelet function defects. Caution also required in patients with gastrointestinal ulceration, gout, hypoprothrombinemia, and vitamin K deficiency.

Side/adverse effects: Aspirin—May also cause anaphylaxis and toxic epidermal necrolysis.



Additional Dosing Information
See also General Dosing Information .

Medications containing aspirin should be administered with food or a full glass (240 mL) of water to lessen gastric irritation.

Dosage of aspirin should be reduced if fever or illness causes fluid depletion, especially in children.

In general, it is recommended that aspirin therapy be discontinued 5 days before surgery to reduce the risk of bleeding problems.


Oral Dosage Forms

BUTALBITAL AND ASPIRIN TABLETS USP

Usual adult and adolescent dose
Analgesic
Oral, 1 tablet every four hours as needed, not to exceed 6 tablets a day.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital and 650 mg of aspirin (Rx) [Axotal]

Canada—
Not commercially available.

Packaging and storage:
Store below 30 °C (86 °F), protected from moisture, unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Take with food or with a full glass of water.

Note: Not a federally controlled substance in the U.S.; however, state regulations may apply.



BUTALBITAL, ASPIRIN, AND CAFFEINE CAPSULES USP

Usual adult and adolescent dose
Analgesic
Oral, 1 or 2 capsules every four hours as needed, not to exceed 6 capsules a day.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital, 325 mg of aspirin, and 40 mg of caffeine (Rx) [Butalgen] [Fiorinal (sodium bisulfite)] [Isobutal] [Isollyl] [Laniroif] [Lanorinal] [Marnal][Generic]

Canada—


50 mg of butalbital, 330 mg of ASA, and 40 mg of caffeine (Rx) [Fiorinal] [Tecnal]

Note: Because Aspirin is a brand name in Canada, ASA is the term used in Canadian product labeling.


Packaging and storage:
Store below 25 °C (77 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Take with food or with a full glass of water.

Note: Controlled substance in both the U.S. and Canada.



BUTALBITAL, ASPIRIN, AND CAFFEINE TABLETS USP

Usual adult and adolescent dose
Analgesic
Oral, l or 2 tablets containing 50 mg of butalbital, 325 mg of aspirin, and 40 mg of caffeine every four hours as needed, not to exceed 6 tablets a day.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital, 325 mg of aspirin, and 40 mg of caffeine (Rx) [Butalgen] [Fiorgen] [Fiorinal (lactose)] [Fiormor] [Fortabs] [Isobutal] [Isobutyl] [Isolin] [Isollyl] [Laniroif] [Lanorinal] [Marnal] [Vibutal][Generic]

Canada—


50 mg of butalbital, 330 mg of ASA, and 40 mg of caffeine (Rx) [Fiorinal] [Tecnal]

Note: Because Aspirin is a brand name in Canada, ASA is the term used in Canadian product labeling.


Packaging and storage:
Store below 30 °C (86 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Take with food or with a full glass of water.

Note: Products containing 325 mg of aspirin and 50 mg of butalbital per tablet are controlled substances in both the U.S. and Canada.



BUTALBITAL, ASPIRIN, CAFFEINE, AND CODEINE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effect—Butalbital: A short- to intermediate-acting barbiturate.

Other actions/effects—

Aspirin: Also has platelet aggregation–inhibiting actions.

Codeine: Also has antidiarrheal and antitussive actions.



Precautions:
Cross-sensitivity and/or related problems—Aspirin: Risk of cross-sensitivity with other nonsteroidal anti-inflammatory drugs (NSAIDs); slight risk of cross-sensitivity with acetaminophen.

Pregnancy/reproduction—

First trimester: Aspirin—Reports of possible birth defects in humans, but teratogenicity not found in controlled studies with usual therapeutic doses.

Third trimester:

Aspirin—Use not recommended; chronic, high-dose use has caused complications (including stillbirth or neonatal death) associated with prolonged gestation, premature closure of the fetal ductus arteriosus, prolonged labor, complicated deliveries, and maternal, fetal or neonatal bleeding.

Codeine—Ingestion shortly prior to delivery may cause neonatal respiratory depression, especially in premature neonates.

Pediatrics—Aspirin: Risk of Reye's syndrome in children with acute febrile illness, especially influenza and varicella; febrile, dehydrated patients also more susceptible to other forms of salicylate toxicity.

Adolescents—Aspirin: Risk of Reye's syndrome in adolescents with acute febrile illness, especially influenza and varicella.

Geriatrics—

Aspirin: Increased susceptibility to salicylate toxicity.

Codeine: Increased susceptibility to respiratory depressant effects.

Drug interactions and/or related problems—

Butalbital: May be less likely than phenobarbital to cause significant interference with medications adversely affected by hepatic enzyme induction.

Aspirin: Caution also required with urinary acidifiers or alkalizers; anticoagulants; methotrexate; ototoxic medications; probenecid; sulfinpyrazone; and thrombolytic agents.

Codeine: Caution also required with anticholinergics, antiperistaltic antidiarrheals, agents that may reduce blood pressure, metoclopramide, monoamine oxidase inhibitors, naloxone, naltrexone, and other opioid analgesics.

Laboratory value alterations—

Aspirin: Interferes with determinations of urine aceto-acetic acid (Gerhard test), urine glucose (copper sulfate or enzymatic tests), urine 5-hydroxyindoleacetic acid, renal function test (phenolsulfonphthalein), thyroid imaging (radionuclide), thyroid-stimulating hormone release (protirelin-stimulated), vanillylmandelic acid. May also prolong bleeding time, decrease serum potassium concentrations, and cause dose-dependent increase or decrease in serum uric acid concentration.

Codeine: Interferes with gastric emptying studies and hepatobiliary imaging (radionuclide). Also, may increase plasma amylase and/or lipase concentrations.

Medical considerations/contraindications

Aspirin: Should not be used in patients with severe allergic or asthmatic reaction to aspirin or other NSAIDs (history of), bleeding ulcers or other active bleeding states (current), or hemophilia or other coagulation or platelet function defects. Caution also required in patients with gastrointestinal ulceration, gout, hypoprothrombinemia, and vitamin K deficiency.

Codeine: Should not be used if the patient has diarrhea caused by poisoning or by antibiotic therapy, or in the presence of acute respiratory depression. Caution also required in patients with asthma, chronic respiratory disease, and severe inflammatory bowel disease.



Side/adverse effects:
Aspirin: May also cause anaphylaxis and toxic epidermal necrolysis.

Codeine: May also cause laryngospasm or laryngeal edema.



Additional Dosing Information
See also General Dosing Information .

Medications containing aspirin should be administered with food or a full glass (240 mL) of water to lessen gastric irritation.

Dosage of aspirin should be reduced if fever or illness causes fluid depletion, especially in children.

In general, it is recommended that aspirin therapy be discontinued 5 days before surgery to reduce the risk of bleeding problems.


Oral Dosage Forms

BUTALBITAL, ASPIRIN, CAFFEINE, AND CODEINE PHOSPHATE CAPSULES USP

Usual adult and adolescent dose
Analgesic
Oral, 1 or 2 capsules every four hours as needed, not to exceed 6 capsules a day.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital, 325 mg of aspirin, 40 mg of caffeine, and 30 mg of codeine phosphate (Rx) [Ascomp with Codeine No.3] [Butalbital Compound with Codeine] [Butinal with Codeine No.3] [Fiorinal with Codeine No.3] [Idenal with Codeine] [Isollyl with Codeine][Generic]

Canada—


50 mg of butalbital, 330 mg of ASA, 40 mg of caffeine, and 15 mg of codeine phosphate (Rx) [Fiorinal-C 1/4 (lactose)] [Tecnal-C 1/4]


50 mg of butalbital, 330 mg of ASA, 40 mg of caffeine, and 30 mg of codeine phosphate (Rx) [Fiorinal-C 1/2 (lactose)] [Tecnal-C 1/2]

Note: Because Aspirin is a brand name in Canada, ASA is the term used in Canadian product labeling.


Packaging and storage:
Store below 25 °C (77 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Take with food or with a full glass of water.
   • May be habit-forming.

Note: Controlled substance in both the U.S. and Canada.



BUTALBITAL, ASPIRIN, CAFFEINE, AND CODEINE PHOSPHATE TABLETS

Usual adult and adolescent dose
See Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules USP .

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of butalbital, 325 mg of aspirin, 30 mg of codeine phosphate, and 40 mg of caffeine (Rx) [Idenal with Codeine][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 25 °C (77 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Take with food or with a full glass of water.
   • May be habit-forming.

Note: Controlled substance in the U.S.



PHENOBARBITAL, ASA, AND CODEINE

Summary of Differences


Pharmacology/pharmacokinetics:
Mechanism of action/effect—Phenobarbital: A long-acting barbiturate.

Other actions/effects—

Phenobarbital: Also has anticonvulsant activity.

Aspirin: Also has platelet aggregation–inhibiting actions.

Codeine: Also has antidiarrheal and antitussive actions.



Precautions:
Cross-sensitivity and/or related problems—Aspirin: Risk of cross-sensitivity with other nonsteroidal anti-inflammatory drugs (NSAIDs); slight risk of cross-sensitivity with acetaminophen.

Pregnancy/reproduction—

First trimester: Aspirin—Reports of possible birth defects in humans, but teratogenicity not found in controlled studies with usual therapeutic doses.

Third trimester: Aspirin—Use not recommended; chronic, high-dose use has caused complications (including stillbirth or neonatal death) associated with prolonged gestation, premature closure of the fetal ductus arteriosus, prolonged labor, complicated deliveries, and maternal, fetal or neonatal bleeding.

Pediatrics—Aspirin: Risk of Reye's syndrome in children with acute febrile illness, especially influenza and varicella; febrile, dehydrated patients also more susceptible to other forms of salicylate toxicity.

Adolescents—Aspirin: Risk of Reye's syndrome in adolescents with acute febrile illness, especially influenza and varicella.

Geriatrics—

Aspirin: Increased susceptibility to salicylate toxicity.

Codeine: Increased susceptibility to respiratory depressant effects.

Drug interactions and/or related problems—

Phenobarbital: More likely than butalbital to cause significant interference with medications adversely affected by hepatic enzyme induction.

Aspirin: Caution also required with urinary acidifiers or alkalizers; anticoagulants; methotrexate; ototoxic medications; probenecid; sulfinpyrazone; and thrombolytic agents.

Codeine: Caution also required with anticholinergics, antiperistaltic antidiarrheals, agents that may reduce blood pressure, metoclopramide, monoamine oxidase inhibitors, naloxone, naltrexone, and other opioid analgesics.

Laboratory value alterations—

Aspirin: Interferes with determinations of urine aceto-acetic acid (Gerhard test), urine glucose (copper sulfate or enzymatic tests), urine 5-hydroxyindoleacetic acid, renal function test (phenolsulfonphthalein), thyroid imaging (radionuclide), thyroid-stimulating hormone release (protirelin-stimulated), vanillylmandelic acid. May also prolong bleeding time, decrease serum potassium concentrations, and cause dose-dependent increase or decrease in serum uric acid concentration.

Codeine: Interferes with gastric emptying studies and hepatobiliary imaging (radionuclide). Also, may increase plasma amylase and/or lipase concentrations.

Medical considerations/contraindications

Aspirin: Should not be used in patients with severe allergic or asthmatic reaction to aspirin or other NSAIDs (history of), bleeding ulcers or other active bleeding states (current), or hemophilia or other coagulation or platelet function defects. Caution also required in patients with gastrointestinal ulceration, gout, hypoprothrombinemia, and vitamin K deficiency.

Codeine: Should not be used if the patient has diarrhea caused by poisoning or by antibiotic therapy, or in the presence of acute respiratory depression. Caution also required in patients with asthma, chronic respiratory disease, and severe inflammatory bowel disease.



Side/adverse effects:
Aspirin—May also cause anaphylaxis and toxic epidermal necrolysis.

Codeine—May also cause laryngospasm or laryngeal edema.



Additional Dosing Information
See also General Dosing Information .

Medications containing aspirin should be administered with food or a full glass (240 mL) of water to lessen gastric irritation.

Dosage of aspirin should be reduced if fever or illness causes fluid depletion, especially in children.

In general, it is recommended that aspirin therapy be discontinued 5 days before surgery to reduce the risk of bleeding problems.


Oral Dosage Forms

PHENOBARBITAL, ASA, AND CODEINE PHOSPHATE CAPSULES

Usual adult and adolescent dose
Analgesic
Oral, 1 or 2 capsules containing 16.2 mg of phenobarbital, 325 mg of ASA, and 16.2 or 32.4 mg of codeine phosphate every three or four hours; or
Oral, 1 capsule containing 16.2 mg of phenobarbital, 325 mg of ASA, and 64.8 mg of codeine phosphate every three or four hours.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


16.2 mg of phenobarbital, 325 mg of ASA, and 32.4 mg of codeine phosphate (Rx) [Phenaphen with Codeine No.3]{31}

Note: Because Aspirin is a brand name in Canada, ASA is the term used in Canadian product labeling.


Packaging and storage:
Store below 30 °C (86 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Take with food or with a full glass of water.

Note: Controlled substance in Canada.




Revised: 08/26/2002



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Prescribing information Fioricet, Sandoz (U.S.), in: Physician's desk reference 46th ed. Montvale: Medical Economics Data; 1992: 2006-7.
  1. Prescribing information Fiorinal, Sandoz (U.S.), in: Physician's desk reference 46th ed. Montvale: Medical Economics Data; 1992: 2007-8.
  1. Prescribing information Fiorinal with Codeine, Sandoz (U.S.), in: Physician's desk reference 46th ed. Montvale: Medical Economics Data; 1992: 2008-9.
  1. Prescribing information Fiorinal, Sandoz (Canada.), in: Krogh CME, ed. Compendium of pharmaceuticals and specialties, 26th ed. Ottawa: Canadian Pharmaceutical Association; 1991: 469.
  1. Prescribing information Fiorinal C, Sandoz (Canada.), in: Krogh CME, ed. Compendium of pharmaceuticals and specialties, 26th ed. Ottawa: Canadian Pharmaceutical Association; 1991: 469-70.
  1. Prescribing information Tecnal, Technilab (Canada.), in: Krogh CME, ed. Compendium of pharmaceuticals and specialties, 26th ed. Ottawa: Canadian Pharmaceutical Association; 1991: 1186-7.
  1. Prescribing information Tecnal C, Technilab (Canada.), in: Krogh CME, ed. Compendium of pharmaceuticals and specialties, 26th ed. Ottawa: Canadian Pharmaceutical Association; 1991: 1187.
  1. Prescribing information Phenaphen with Codeine, Ayerst (Canada), in: Krogh CME, ed. Compendium of pharmaceuticals and specialties, 26th ed. Ottawa: Canadian Pharmaceutical Association; 1991: 933.
  1. AMA drug evaluations (Subscription). Chicago: American Medical Association; 1990 (summer update): Section 2, 2: 1-2: 11.
  1. Kunkel RS. Diagnosis and treatment of muscle contraction (tension-type) headaches. Med Clin N Amer 1991; 75: 595-603.
  1. Couch JR. Headache. In: Rakel RE, ed. Conn's current therapy. Philadelphia: W.B. Saunders; 1991: 830-41.
  1. Baumel B., Eisner LS. Diagnosis and treatment of headache in the elderly. Med Clin N Amer 1991; 75: 661-75.
  1. Anthony M. The treatment of migraine and other headaches. Curr Opin Neurol Neurosurg 1991; 4: 245-52.
  1. Diamond S. Migraine headache. Med Clin N Amer 1991; 75: 545-66.
  1. Mathew NT. Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 1991; 21: 105-9.
  1. Fleeger CA, ed. USAN and the USP dictionary of drug names. Rockville: The U.S. Pharmacopeial Convention, Inc.; 1992.
  1. Data on file, Forest Pharmaceuticals.
  1. Elkind AH. Drug abuse and headache. Med Clin N Amer 1991; 75: 717-32.
  1. Gennaro AR, ed. Remington's pharmaceutical sciences, 17th ed. Easton: Mack; 1985.
  1. Griffiths RR, et al. Low-dose caffeine physical dependence in humans. J Pharmacol Exp Ther 1990; 255: 1123-32.
  1. Panelist comment, Caffeine (Systemic) monograph, in progress.
  1. Greden JG, Victor BS, Fontaine P, Lubetsky M. Caffeine-withdrawal headache: a clinical profile. Psychosomatics 1980; 21: 411-3, 417-8.
  1. Smith R. Caffeine withdrawal headache. J Clin Pharm Ther 1987; 12: 53-7.
  1. Hering R, Steiner TJ. Abrupt outpatient withdrawal of medication in analgesic-abusing migraineurs. Lancet 1991; 337: 1442-3.
  1. Silberstein SD, Schulman EA, Hopkins M. Repetitive intravenous DHE in the treatment of refractory headache. Headache 1990; 30: 334-9.
  1. Sands GH. A protocol for butalbital, aspirin, and caffeine (BAC) detoxification in headache patients. Headache 1990; 30: 491-6.
  1. Mathew NT, Kurman R, Perez F. Drug induced refractory headache—clinical features and management. Headache 1990; 30: 634-8.
  1. Prescribing information Esgic-Plus, Forest (U.S.), in Physician's desk reference 46th ed. Montvale: Medical Economics Data; 1992: 1002-3.
  1. Fiorecet with Codeine package insert (Sandoz—US), Rev 2/96, Rec 6/97.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1996. p.18.
  1. Health Canada: Therapeutic Products Programme. August 17, 2002. Available at: http://www.hc-sc.gc.ca/hpb/drugs-dpd/index.html
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