Acetaminophen; Butalbital; Caffeine Interactions
- Acetaminophen
Antacids
Anti-retroviral protease inhibitors
Antineoplastic Agents
Anxiolytics, Sedatives, and Hypnotics
Barbiturates
- Buprenorphine
- Butorphanol
- Carbamazepine
- Chloramphenicol
- Citalopram
- Clozapine
Corticosteroids
- Cyclosporine
- Delavirdine
- Doxycycline
- Dronabinol, THC
- Efavirenz
- Escitalopram
Estrogens
- Ethanol
- Ethotoin
- Fluvoxamine
- food
- Fosphenytoin
- Galantamine
- grapefruit juice
Immunosuppressives
- Isoniazid, INH
- Lithium
- Methazolamide
Monoamine oxidase inhibitors (MAOIs)
- Nalbuphine
- Nevirapine
Opiate agonists
Oral contraceptives
- Pentazocine
Phenothiazines
- Phenytoin
- Pregabalin
Progestins
Psychostimulants
- Quinidine
- Quinine
Radiopaque Contrast Agents
- Ramelteon
- Rifampin
Sedating H1-blockers
Sympathomimetics
- Theophylline, Aminophylline
- Tramadol
Tricyclic antidepressants
- Valproic Acid, Divalproex Sodium
- Voriconazole
- Warfarin
Acetaminophen; Butalbital; Caffeine Interactions
NOTE: This monograph discusses the use of a combination product. Clinicians may wish to consult the individual monographs for more information about the specific drug interactions of each agent.
Many prescription and non-prescription medicines contain acetaminophen. Avoid concurrent use of products that contain acetaminophen as the maximum daily dose (i.e., 4 g/day for adults; 75 mg/kg/day for infants and children) may be exceeded leading to an increased risk of hepatotoxicity. Advise patients to carefully read the ingredients of any other medicines they are taking with acetaminophen; butalbital; caffeine combination products.
The butalbital portion of the acetaminophen-butalbital-caffeine combination products may induce the hepatic metabolism of anticonvulsant medications including carbamazepine, ethotoin, phenytoin or fosphenytoin. Conversely, phenytoin and valproic acid may inhibit the metabolism of butalbital, leading to increased CNS depression. Since anticonvulsant agents, such as carbamazepine, barbiturates, or phenytoin may induce cytochrome P450 isoenzymes 2E1 or 1A2, an increase in acetaminophen-induced hepatic toxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite. Potentiation of acetaminophen hepatotoxicity has occurred clinically with combinations of acetaminophen with phenobarbital co-administered chronically. However, this has not been reported with the occasional use of combinations containing acetaminophen and butalbital.
As an enzyme inducer, rifampin could induce the metabolism of acetaminophen, butalbital and/or caffeine, altering the clinical response. Hepatic failure and encephalopathy has been attributed to the combination of rifampin and acetaminophen in one report.
Isoniazid, INH, can induce the hepatic cytochrome P450 isoenzyme 2E1 and may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen’s hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity.
Antacids or food can delay and decrease the oral absorption of acetaminophen component of acetaminophen-butalbital-caffeine combination products. Grapefruit juice can inhibit enterocyte cytochrome P450 isoenzymes 2E1 or 1A2, which may decrease acetaminophen-induced hepatotoxicity. In addition, grapefruit juice can increase the serum concentrations and AUC of caffeine. This food-drug interaction might potentiate the clinical effects and duration of action of caffeine.
Agents which inhibit the hepatic cytochrome P450 (CYP) 2E1 or 1A2 isoenzymes may theoretically decrease the risk for hepatotoxicity from acetaminophen, by reducing the generation of acetaminophen’s toxic metabolites; however, the clinical significance of these interactions is not known. Agents that inhibit CYP2E1 or CYP1A2 and may decrease acetaminophen-induced hepatotoxicity include cimetidine; clarithromycin; erythromycin; fluvoxamine; ketoconazole; some quinolones, like ciprofloxacin and levofloxacin; omeprazole; and paroxetine. Enoxacin and, to a lesser extent, ciprofloxacin decrease the metabolism of caffeine via CYP1A2 and exaggerated effects of caffeine would be expected.
When an inducer and/or inhibitor of the cytochrome P450 enzyme system, such as anti-retroviral protease inhibitors, delavirdine, efavirenz, or nevirapine, is used with barbiturates a complex interaction occurs. Decreased efficacy of the anti-retroviral agent due to metabolism induction by the barbiturate may be noted. The anti-retroviral agent may cause changes in barbiturate efficacy or increased adverse reactions due to enzyme induction or inhibition. In addition, ritonavir may decrease the formation of toxic metabolites of acetaminophen due to inhibition of hepatic cytochrome P450 2E1 or 1A2 isoenzymes.
Barbiturates like butalbital can induce hepatic metabolism and, thus, reduce the sedative properties of tricyclic antidepressants or opiate agonists; however, this action would likely require several days of barbiturate administration. Additive drowsiness appears immediately and may be of a concern. Caution should be exercised during concomitant use of any CNS-depressant drugs and butalbital. Dosage reduction of the interacting medication may be necessary.
Ethanol can cause additive CNS depression when given in combination with acetaminophen-butalbital-caffeine combinations. In addition, chronic ethanol use increases acetaminophen-induced hepatotoxicity by inducing cytochrome P450 (CYP) 2E1 leading to increased formation of the hepatotoxic metabolite and by depleting liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in alcoholics or patients who consume ethanol regularly. However, acute ethanol ingestion may reduce acetaminophen-induced hepatotoxicity by substrate competition for CYP2E1.
The metabolism of xanthines, such as caffeine or theophylline, can be increased by concurrent use with barbiturates like butalbital. While it is clear that barbiturates can accelerate the clearance of theophylline, the magnitude of this interaction is uncertain. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to theophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by caffeine or theophylline. In the acetaminophen-butalbital-caffeine combination the interaction between butalbital and caffeine is used for beneficial effects.
Significant drug interaction may occur between acetaminophen-butalbital-caffeine combination products and warfarin. Butalbital may decrease the therapeutic effects of warfarin added to a stabilized warfarin regimen. If a barbiturate is discontinued during warfarin therapy, supratherapeutic INRs may result since the enzyme-inducing effects are no longer present. Acetaminophen has been shown to augment the hypoprothrombinemic response to warfarin in a dose-dependent manner when given in large doses for an extended period of time. Both INR prolongation and clinical bleeding have been reported during acetaminophen therapy. Clinicians should note that warfarin therapy may require dose adjustments during treatment with acetaminophen-butalbital-caffeine combination therapy.
Acetaminophen-butalbital-caffeine combination products may interact with antineoplastic agents and immunosuppressives. The acetaminophen component may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Butalbital may accelerate the conversion of cyclophosphamide and ifosfamide to their active alkylating metabolite, however, the clearance of this metabolite may also be enhanced. Although the clinical significance of this pharmacokinetic interaction is uncertain, patients receiving cyclophosphamide or ifosfamide with a barbiturate should be observed for leukopenia or hemorrhagic cystitis. In addition butalbital may increase the clearance of doxorubicin in humans and shorten the elimination half-life of doxorubicin in mice. The clinical significance of this pharmacokinetic interaction is uncertain. Although data are limited, barbiturates should be avoided in patients receiving cyclosporine. In a single case report, phenobarbital was shown to decrease cyclosporine concentrations.
The CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants. Caffeine should be avoided or used cautiously with amphetamine, dextroamphetamine, methylphenidate, nicotine, pemoline, pseudoephedrine, phenylpropanolamine, or beta2-agonists or other sympathomimetics. When combined with any of these medications, caffeine can cause nervousness, irritability, insomnia, and/or cardiac arrhythmias. The combination of caffeine and phenylpropanolamine has been associated with cerebrovascular accidents, so these agents should not be used together.
Caffeine appears to reduce serum lithium concentrations. Lithium ADRs have also been noted to increase simultaneously with a reduction in caffeine intake. Patients taking lithium should be counseled regarding their intake of caffeine.
Concurrent use of acetaminophen-butalbital-caffeine with MAOIs should be approached carefully due to potential interactions. Caffeine interacts with MAOIs (including furazolidone, procarbazine, and selegiline). Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine’s sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 - 2 weeks after discontinuation of any MAOI. MAOIs may prolong the effect of some barbiturates, although data are very limited. Until more data are available, barbiturates should be used cautiously in patients receiving MAOIs.
Acetaminophen-butalbital-caffeine should be used cautiously in patients receiving phenothiazines due to potential interactions with the butalbital component. Initially, additive drowsiness may occur. Alternatively, butalbital may induce the hepatic metabolism of phenothiazines, however data are limited. Although the clinical significance of this pharmacokinetic interaction is uncertain, chlorpromazine plasma concentrations have been reported to decrease when a barbiturate was added. Until more data are available, clinicians should be alert for a loss of chlorpromazine effect if a barbiturate is added. It is likely that additive drowsiness would occur immediately, while barbiturate-induced changes in phenothiazine clearance would require several days to be manifest.
Barbiturates have been shown to induce the metabolism of prednisone, dexamethasone, methylprednisolone, and prednisolone. Dose adjustments may be necessary in patients receiving both corticosteroids and combination products of acetaminophen-butalbital-caffeine. The effects of barbiturate therapy on the pharmacokinetics or clinical response to corticotropin, ACTH are unknown.
Barbiturates have been shown to affect the pharmacokinetics of doxycycline. Doxycycline half-life was decreased from 15.3 hours to 11.1 hours in a patient receiving phenobarbital. It is likely that other barbiturates, like butalbital, may exert the same effect. Clinicians should keep in mind that larger doses of doxycycline may be necessary in patients receiving barbiturates. This interaction may not apply to other tetracyclines since they are less dependent on hepatic metabolism for elimination.
Barbiturates like butalbital can accelerate the hepatic clearance of estrogens and progestins. As a result, the effectiveness of oral contraceptives can be lost. Barbiturates should be avoided in patients receiving oral contraceptives, or, if necessary, these patients should be instructed to use a different form of birth control. For patients taking estrogens for other indications, a higher dose of estrogen may be required during barbiturate therapy.
Additive CNS depression may occur if acetaminophen-butalbital-caffeine combination products are used concomitantly with buprenorphine, butorphanol, dronabinol, THC, nalbuphine, pentazocine, pregabalin, ramelteon, sedating H1-blockers, tramadol, or anxiolytics, sedatives, and hypnotics. Additionally, barbiturates are known hepatic enzyme inducers and may increase metabolism of ramelteon over a longer period of time, reducing ramelteon efficacy, although the additive CNS depressant effect might overrule.
Barbiturates can decrease the oral absorption of griseofulvin, however the clinical significance of this interaction is uncertain.
Barbiturates may reduce the serum concentrations of quinidine. Monitor quinidine therapy closely for decreased clinical efficacy if acetaminophen; butalbital; caffeine combination products are added. Dose adjustments for quinidine may be necessary if acetaminophen-butalbital-caffeine products are either added to discontinued during quinidine treatment.
Quinine may interfere with the hepatic metabolism of phenobarbital or other barbiturates. Phenobarbital peak concentrations and AUC were higher after quinine administration; however, the study design was flawed. Until more data are known, patients should be observed for increased barbiturate effect if barbiturates are administered to patients receiving quinine.
Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14% during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Barbiturates are inducers of the hepatic CYP3A4 isoenzyme, and use may lower the plasma levels of other medications metabolized through these pathways. The effectiveness of medications such as chloramphenicol, galantamine, or imatinib, STI-571 could theoretically be decreased; however, clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use.
Methazolamide can induce osteomalacia in patients treated chronically with barbiturates. Potential mechanisms for this interaction include a methazolamide-induced increase in the urinary excretion of calcium and effects resulting from metabolic acidosis. Methazolamide can also increase the rate of excretion of weakly acidic drugs such as barbiturates.
Citalopram and escitalopram are metabolized by CYP2C19 and CYP3A4. Barbiturates are inducers of the hepatic CYP3A4 isoenzyme, and use may lower the plasma levels of other medications metabolized through these pathways. Although no clinical data are available to support a clinically significant interaction, citalopram or escitalopram may need to be administered in higher doses in patients chronically taking barbiturates.
The manufacturer of voriconazole considers the concomitant use of long-acting barbiturates and voriconazole a contraindication; caution is advised in using voriconazole with short-acting barbiturates. Long-acting barbiturates, such as phenobarbital, are CYP3A4, CYP2C19 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for the CYP2C9 isoenzyme, and voriconazole (known to inhibit CYP2C9) may also theoretically increase the serum concentrations of the barbiturates.
Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine-containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
[ Last revised: 8/24/2005 1:34:00 PM ]
Related entries
Syndicate
|
