Aspirin, ASA; Butalbital; Caffeine Interactions
- Acetaminophen
- Acetazolamide
- Alendronate
Aminoglycosides
- Amoxapine
- Amphotericin B
Angiotensin II receptor antagonists
Angiotensin-converting enzyme inhibitors (ACE inhibitors)
Anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Anti-retroviral protease inhibitors
Anticoagulants
Antidiabetic Agents
Antineoplastic Agents
- Antithymocyte Globulin
Anxiolytics, Sedatives, and Hypnotics
- Aspirin, ASA
- Bacitracin
Barbiturates
Beta-blockers
- Carbamazepine
- Carisoprodol
- Cidofovir
- Cimetidine
- Ciprofloxacin
- Cisplatin
- Clomipramine
- Clozapine
Corticosteroids
- Cyclophosphamide
Diuretics
- Dronabinol, THC
- Droperidol
- Echinacea
- Enoxacin
- Entacapone
Estrogens
- Ethanol
- Ethotoin
- Flaxseed
- food
- Foscarnet
- Fosphenytoin
- Furazolidone
General Anesthetics
- Ginkgo, Ginkgo biloba
- grapefruit juice
- Haloperidol
- Ifosfamide
- Imatinib, STI-571
Immunosuppressives
- Linezolid
- Lithium
- Maprotiline
- Mercaptopurine, 6-MP
- Methocarbamol
- Methotrexate
- Mexiletine
- Mirtazapine
Mixed Opiate Agonists/Antagonists
- Molindone
Monoamine oxidase inhibitors (MAOIs)
- Nefazodone
- Nicotine
Nonsteroidal antiinflammatory drugs (NSAIDs)
- Olanzapine
Opiate agonists
Oral contraceptives
Phenothiazines
- Phenytoin
- Pimozide
Platelet Inhibitors
- Pramipexole
- Pregabalin
- Probenecid
- Procarbazine
Progestins
Psychostimulants
- Psyllium
- Quetiapine
- Quinidine
Radiopaque Contrast Agents
- Ranolazine
- Rifampin
- Rifapentine
- Risperidone
- Ropinirole
Sedating H1-blockers
Selective serotonin reuptake inhibitors (SSRIs)
Skeletal Muscle Relaxants
- Strontium-89 Chloride
- Sulfinpyrazone
Sympathomimetics
- Tacrine
- Theophylline, Aminophylline
- Tolcapone
- Tramadol
- Trazodone
Tricyclic antidepressants
- Valerian, Valeriana officinalis
- Valproic Acid, Divalproex Sodium
- Vancomycin
- Varicella Virus Vaccine Live
- Voriconazole
- Zileuton
Aspirin, ASA; Butalbital; Caffeine Interactions
NOTE: This monograph discusses the use of aspirin; butalbital; caffeine combination products. Clinicians may wish to consult the individual monographs for more information about the specific drug interactions of aspirin and caffeine.
Many prescription and non-prescription medicines contain aspirin, ASA. Avoid concurrent use of aspirin; butalbital; caffeine with products that contain aspirin and in patients who are taking aspirin on a regular basis. Advise patients to carefully read the ingredients of any other medicines they are taking with aspirin; butalbital; caffeine combination products.
Avoid concurrent use of NSAIDs and aspirin; butalbital; caffeine. The use of aspirin together with nonsalicylate NSAIDs (e.g., indomethacin) can lead to additive GI toxicity. Also, increased bleeding or decreased renal function may occur.
Use caution when combining aspirin, ASA; butalbital; caffeine combinations with other barbiturates, due to duplicative pharmacotherapy. Caution should be exercised during concomitant use of any CNS-depressant drugs and aspirin; butalbital; caffeine; codeine. Dosage reduction of aspirin; butalbital; caffeine; codeine may be necessary.
The use of ginkgo biloba and aspirin; butalbital; caffeine may increase the risk for clinically significant bleeding. Ginkgo can produce clinically-significant antiplatelet effects; a compound found in ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of ginkgo biloba in 1992 stated that no known drug interactions exist, spontaneous hyphema has been reported in an elderly male who began taking ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
Aspirin, and valproic acid are all highly protein bound. Displacement of valproic acid from binding sites can lead to an increase in the serum valproic acid concentration. The displacement of valproic acid can cause an increase in valproic acid free drug concentrations. In such cases, a patient may experience valproic acid toxicity even if the total drug concentration is within the therapeutic range. Careful drug concentration assessment is needed when concomitant aspirin; butalbital; caffeine and valproic acid or divalproex sodium is used.
Aspirin, ASA; butalbital; caffeine may interact with hydantoin anticonvulsants (e.g., ethotoin, phenytoin or fosphenytoin) via several mechanisms. Aspirin, and phenytoin are all highly protein bound. Large doses of salicylates (i.e., > 2000 mg/day) can displace phenytoin from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug. Displacement of phenytoin from binding sites can lead to a decrease in the total phenytoin serum concentration. Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4 and may reduce the efficacy of concomitantly administered medications with a narrow therapeutic range if butalbital is administered chronically, such as ethotoin, phenytoin or fosphenytoin. Careful drug concentration assessment may be needed when concomitant aspirin; butalbital; caffeine; codeine and ethotoin, phenytoin (or fosphenytoin) is used.
Aspirin, ASA; butalbital; caffeine; codeine may interact with carbamazepine. Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4 and may reduce the efficacy of concomitantly administered medications with a narrow therapeutic range if butalbital is administered chronically, such as carbamazepine.
Use of aspirin; butalbital; caffeine with acetazolamide may lead to increased serum acetazolamide concentrations. Both acetazolamide and aspirin undergo renal tubular secretion. Consideration of acetazolamide dose reduction and observance for any adverse effects from acetazolamide is warranted.
Clinicians should be aware that grapefruit juice contains an unknown compound that can inhibit cytochrome P450 isozymes in the gut wall. Data are limited and conflicting, as to whether grapefruit juice alters the serum concentrations and/or AUC of caffeine. This food-drug interaction might potentiate the clinical effects and duration of action of caffeine. Also, caffeine can reduce the hypnotic effects of butalbital, which may be considered a beneficial effect in aspirin; butalbital; caffeine combinations. Certain foods that contain high amounts of caffeine or theobromine, a related methylxanthine, should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects, like nausea or tremors. Such foods include coffee, teas, caffeinated colas, and chocolate.
Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar. This mechanism may explain how salicylates can potentiate the clinical effects of antidiabetic agents, however, displacement of sulfonylureas from protein binding sites has also been reported. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose or use of greater than maximum recommended daily dosages, salicylates can cause either hypoglycemia or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
The analgesic activity of aspirin; butalbital; caffeine may be reduced when used with rifampin or rifapentine, as both drugs are cytochrome P450 isoenzyme inducers. Caffeine is metabolized by CYP1A2 and butalbital undergoes oxidative metabolism. Due to the induction of the metabolism of butalbital and/or caffeine, the clinical response to aspirin; butalbital; caffeine may be inadequate. Consideration of another analgesic choice may be warranted.
When an inducer and/or inhibitor of the cytochrome P450 isoenzyme system, such as anti-retroviral protease inhibitors and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) is used with barbiturates, a complex interaction occurs. Decreased efficacy of the antiretroviral agent due to metabolism induction by the barbiturate may be noted. Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4. However, clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use. The extended use of aspirin; butalbital; caffeine is not recommended, as butalbital is habit-forming and potentially abusable. However, if aspirin; butalbital; caffeine is used on a chronic basis, monitor for reduced efficacy of drugs for HIV infection. The manufacturer recommends that delavirdine, a NNRTI, not be given with barbiturates due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant mutations of HIV. Also, the antiretroviral agent may cause changes in barbiturate or caffeine efficacy or increased adverse reactions due to enzyme induction or inhibition. For example, ritonavir may increase adverse effects of caffeine due to inhibition of hepatic cytochrome P450 1A2 isoenzymes. As enzyme inducers, efavirenz and nevirapine could induce the metabolism of caffeine and/or butalbital, altering the clinical response. The efficacy of aspirin; butalbital; caffeine may be reduced.
Additive CNS depression may occur if aspirin; butalbital; caffeine combination products are used concomitantly with opiate agonists, mixed opiate agonists/antagonists, dronabinol, THC, sedating H1-blockers, tramadol, phenothiazines, general anesthetics, amoxapine, carisoprodol, droperidol, entacapone, haloperidol, maprotiline, methocarbamol, mirtazapine, molindone, nefazodone, olanzapine, pramipexole, pregabalin, quetiapine, pimozide, risperidone, ropinirole, tolcapone, trazodone, skeletal muscle relaxants, or anxiolytics, sedatives, and hypnotics. Although both butalbital and benzodiazepines bind to the GABA A receptor, their facilitative effects on GABA transmission are additive. Caution should be exercised during concomitant use of any CNS-depressant drugs and aspirin; butalbital; caffeine. Dosage reduction of aspirin; butalbital; caffeine may be necessary. Additionally, barbiturates are known hepatic enzyme inducers and may increase metabolism of ramelteon (primarily metabolized by CYP1A2) over a longer period of time. Ramelteon efficacy may be reduced, although additive CNS depressant effects might overrule.
Additive CNS depression may occur if aspirin; butalbital; caffeine combination products are used concomitantly with tricyclic antidepressants. Dosage reduction of aspirin; butalbital; caffeine may be necessary. Barbiturates, such as butalbital, are inducers of many cytochrome P450 isoenzymes such as 1A2, 2C9, 2C19, and 3A4. Thus, barbiturates may significantly increase the clearance of selected TCAs; a clinical interaction with butalbital and imipramine has been documented. Although imipramine is primarily a substrate for CYP2D6, the 1A2, 3A4, and 2C19 isoenzymes are also involved. After 2 weeks of beginning a butalbital combination medicine for a chronic headache disorder, a patient’s serum imipramine concentration fell 50% and an exacerbation of her depressive disorder occurred. Monitoring patients for loss of therapeutic effect is recommended if aspirin; butalbital; caffeine is added to therapy; serum imipramine concentration monitoring may be helpful.
Clozapine and butalbital have CNS depressant effects and thus, additive effects, especially sedation may occur. Furthermore, 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, aspirin; butalbital; caffeine should be used cautiously during clozapine treatment.
Ethanol can cause an increased risk of gastric irritation and GI mucosal bleeding when given with aspirin; butalbital; caffeine, as both ethanol and aspirin are mucosal irritants and aspirin decreases platelet aggregation. Patients that consume 3 or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Additive CNS depression can also be seen when combining ethanol and barbiturates, such as butalbital. The lethal dose of butalbital is smaller if alcohol is also consumed. Both ethanol and butalbital can cause drowsiness, confusion, coma, respiratory depression, hypotension, and hypovolemic shock. Administration of aspirin should be limited or avoided altogether in patients with alcoholism or who consume ethanol regularly. Chronic alcoholism is often associated with hypoprothrombinemia, which increases the risk of aspirin-induced bleeding.
If aspirin; butalbital; caffeine is used on a chronic basis, monitor for reduced efficacy of concomitantly used drugs that undergo oxidative metabolism, especially drugs with a narrow therapeutic range (e.g., theophylline). Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4. However, clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use. The extended use of aspirin; butalbital; caffeine is not recommended, as butalbital is habit-forming and potentially abusable.
The risk of bleeding is increased when aspirin; butalbital; caffeine is administered to patients already receiving anticoagulants, such as heparin and warfarin. Aspirin can potentiate the anticoagulant effects and can increase the risk of bleeding because of its effect on platelet aggregation and interaction with heparin and warfarin. Significant drug interactions may occur between aspirin; butalbital; caffeine and warfarin. Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4. However, clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use. Butalbital may decrease the therapeutic effect of warfarin and necessitate upward warfarin dosage adjustment. Conversely, when aspirin; butalbital; caffeine is discontinued, the warfarin dose may need to be decreased, as the enzyme-inducing effects of butalbital are no longer present. Also, aspirin may displace warfarin from protein binding sites leading to increased prothrombin time and bleeding time. Aspirin; butalbital; caffeine should be used cautiously in patients receiving warfarin therapy; clinicians should note that dosage adjustment of warfarin therapy may be required.
Aspirin; butalbital; caffeine should, in general, not be used with monoamine oxidase inhibitors (MAOIs). Additive CNS depression may occur if aspirin; butalbital; caffeine is used concomitantly with MAOIs or drugs with MAOI activity (e.g., furazolidone, linezolid and procarbazine). Also, dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine’s sympathomimetic effects due to inhibition of monoamine oxidase. 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.
Due to the thrombocytopenic effects of imatinib, STI-571 an additive risk of bleeding may be seen in patients receiving aspirin; butalbital; caffeine. Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4. However, clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use. The extended use of aspirin; butalbital; caffeine is not recommended, as butalbital is habit-forming and potentially abusable. Use of aspirin; butalbital; caffeine on a chronic basis for patients taking imatinib may not be advisable, as imatinib is metabolized by cytochrome CYP3A4 and thus, imatinib plasma concentrations may be lowered.
Caution should be exercised when aspirin; butalbital; caffeine is given in combination with methotrexate. Concomitant administration of salicylates with high-dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any salicylate be used cautiously with methotrexate even when lower doses of methotrexate are given for the treatment of rheumatoid arthritis or psoriasis. Elderly patients and patients with renal impairment may be at particular risk. Since both methotrexate and salicylates are weak acids, aspirin can impair the renal excretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites.
Aspirin; butalbital; caffeine combination products may interact with antineoplastic agents and immunosuppressives. Aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. In general, because certain antineoplastic agents can cause clinically significant thrombocytopenia, they may increase the risk of aspirin-associated bleeding (i.e. GI bleeding, inhibited platelet aggregation, and prolonged bleeding time). Although usually seen with large salicylate doses, aspirin may displace mercaptopurine, 6-MP from secondary binding sites, resulting in bone marrow toxicities and blood dyscrasias. 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.
Because aspirin can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, an increased risk of bleeding may be seen in patients receiving agents that cause clinically significant thrombocytopenia. Notable interactions may occur with antithymocyte globulin or strontium-89 chloride.
The CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants. Therefore, aspirin; butalbital; caffeine should be avoided or used cautiously with amphetamine, dextroamphetamine, methylphenidate, pemoline, pseudoephedrine, beta2-agonists, nicotine, or other sympathomimetics. When combined with any of these medications, caffeine can cause nervousness, irritability, insomnia, and/or cardiac arrhythmias.
Caffeine appears to reduce serum lithium concentrations. In 11 coffee-drinking patients stabilized on lithium, serum lithium concentrations increased during 2 weeks when coffee was withheld and fell when coffee was resumed. Lithium ADRs have also been noted to increase simultaneously with a reduction in caffeine intake. Clinicians should note, however, that coffee, not pure caffeine, was the variable in this study. Patients taking lithium should be counseled regarding their intake of caffeine and caffeine containing products, such as aspirin; butalbital; caffeine.
Corticosteroids enhance the renal clearance of salicylates. Thus, cessation of corticosteroid use may lead to salicylism. Dose adjustments may be necessary in patients receiving both corticosteroids and an aspirin; butalbital; caffeine product. While there is controversy regarding the ulcerogenic potential of corticosteroids alone, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin.
Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4. Thus, butalbital, especially with regular use, may accelerate the hepatic clearance of estrogens or progestins. As a result, the effectiveness of oral contraceptives, or other hormonal contraceptives can be lost. Aspirin; butalbital; caffeine should be avoided in patients receiving hormonal contraceptives, or, if necessary, these patients should be instructed to use an additional or different form of birth control. For patients taking estrogens for other indications, a higher dose of estrogen may be required if aspirin; butalbital; caffeine is used on a chronic basis.
Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4. Quinidine is primarily metabolized by the CYP3A4 enzyme and drugs that affect this enzyme may theoretically alter the metabolism of quinidine. Thus, butalbital, especially with regular use, may accelerate the hepatic clearance of quinidine. Monitor quinidine serum concentrations closely if aspirin; butalbital; caffeine is added or stopped. Dose adjustments for quinidine may be necessary if aspirin; butalbital; caffeine is either added to or discontinued from concurrent quinidine treatment.
Due to the inhibition of renal prostaglandins by salicylates, concurrent use of aspirin; butalbital; caffeine and other nephrotoxic agents may lead to additive nephrotoxicity. Aspirin; butalbital; caffeine should be given with caution to patients taking aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, foscarnet, or parenteral vancomycin. Monitor renal function carefully during concurrent therapy.
The concomitant administration of cidofovir and NSAIDs, such as aspirin is contraindicated due to the potential for increased nephrotoxicity. Aspirin; butalbital; caffeine should be discontinued 7 days prior to beginning cidofovir.
Concurrent use of probenecid and salicylates is contraindicated. Although the plasma concentration of salicylates is not influenced by probenecid, the uricosuric actions of probenecid are inhibited by salicylates. Aspirin; butalbital; caffeine should also not be used concurrently with sulfinpyrazone when used to treat hyperuricemia or gout, because aspirin can decrease the uricosuric effects. In addition, sulfinpyrazone can decrease salicylic acid excretion leading to increased plasma concentration.
No adverse events associated with the use of salicylates after varicella vaccination have been reported. However, the manufacturer of varicella virus vaccine live recommends the avoidance of salicylates or aspirin, ASA use for 6 weeks after vaccination. Reye’s syndrome, which exclusively affects children under 15 years old, has been associated with aspirin use following active varicella infection. Vaccination with close clinical monitoring is recommended for children who require therapeutic aspirin, ASA therapy. According to the CDC, the use of attenuated, live varicella virus vaccine is thought to present less risk than natural varicella disease to children.
Aspirin; butalbital; caffeine should be used with caution in patients who are taking alendronate. In clinical trials, the incidence of upper gastrointestinal adverse events was increased in patients that received aspirin-containing medicines with alendronate 10 mg daily or higher. One patient with a history of peptic ulcer disease and gastrectomy that received alendronate 10 mg daily and aspirin got an anastomotic ulcer with mild hemorrhage. The patient recovered upon alendronate and aspirin discontinuation.
During antihypertensive therapy with beta-blockers, high concentrations of vasodilatory prostaglandins are produced in response to reflex-mediated pressor mechanisms (e.g., sympathetic tone). Concurrent use of beta-blockers with aspirin may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
Aspirin can increase the risk of renal insufficiency in patients receiving diuretics, secondary to the effects of salicylates on renal blood flow. Aspirin inhibits renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Thus, the effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin; butalbital; caffeine. Aspirin may decrease the hyperuricemic effect of hydrochlorothiazide, HCTZ and furosemide. Concomitant use of aspirin and potassium-sparing diuretics, such as triamterene or spironolactone, may cause hyperkalemia.
Psyllium can interfere with the absorption of certain oral drugs if administered concomitantly. For example, psyllium fiber can adsorb salicylates. Per the psyllium manufacturers, administration of other prescribed oral drugs should be separated from the administration of psyllium by at least 2 hours.
Flaxseed fiber can impair the absorption of oral drugs when administered concomitantly. However, no drug interaction studies have been performed to assess the degree to which the absorption of oral drugs may be altered. Based on interactions of other plant seed fiber (e.g., psyllium) used as a bulk-forming laxative, flaxseed fiber may adsorb salicylates. Administration of prescribed oral agents should be separated from the administration of flaxseed fiber by at least 2 hours.
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. Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4 and thus, may increase the metabolism and reduce the effective serum concentrations of voriconazole. However, clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use. Barbiturates are also substrates for the CYP2C9 isoenzyme, and voriconazole (known to inhibit CYP2C9) may theoretically increase the barbiturate serum concentration.
There are potential interactions between aspirin, ASA; butalbital; caffeine products and the selective serotonin reuptake inhibitors (SSRIs). The combined use of a SSRI and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Clomipramine, a tricyclic antidepressant with serotonergic activity may produce similar results when combined with aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in >26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. Clomipramine was included in the SSRI category in this study. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate. Barbiturates, such as butalbital are inducers of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, and 3A4. However, clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use. The extended use of aspirin; butalbital; caffeine is not recommended, as butalbital is habit-forming and potentially abusable. However, if aspirin; butalbital; caffeine is used on a chronic basis, monitor for reduced efficacy of a SSRI.
Caffeine is metabolized by CYP1A2. Atazanavir, fluvoxamine, mexiletine, enoxacin, ciprofloxacin, tacrine, zileuton, and cimetidine are inhibitors of the cytochrome P450 isoenzyme 1A2 (the list may not be inclusive of all agents that inhibit CYP1A2). Due to the decreased metabolism of caffeine via CYP1A2, exaggerated effects of caffeine would be expected.
Excessive sedation and other central nervous system depressant effects may occur with concomitant valerian and aspirin; butalbital; caffeine use. The valerian derivative, dihydrovaltrate binds at barbiturate binding sites. Also, valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain, and the non-volatile monoterpenes (valepotriates) have sedative activity.
Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. In a case-controlled study of patients with early renal failure, the regular use of aspirin and acetaminophen was associated with an odds ratio of 2.2 (95% confidence interval 1.4 to 3.5) when regular aspirin users were the reference group. The trend toward greater risk with an increasing cumulative life-time dose of acetaminophen was statistically significant with a risk that was 2.4-times as high for subjects who had consumed a total > 500 g of acetaminophen in combination with aspirin than for those who had used aspirin alone. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
The hyponatremic and hypotensive effects of angiotensin II receptor antagonists and angiotensin converting enzyme (ACE) inhibitors may be diminished by concurrent use of aspirin. Furthermore, reduced renal blood flow is expected with a decreased pressure gradient through the glomeruli, which can occur when aspirin is used with an ACE inhibitor or an angiotensin II receptor antagonist. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin prevent the production of vasodilatory prostaglandins in the afferent arteriole of the kidney. Vasodilation of the efferent arteriole of the kidney from prevention of angiotensin 2 production can occur with ACE inhibitors or angiotensin II receptor antagonists. As a result, efferent arteriolar resistance is diminished. Of 144 patients that took an ACE inhibitor and had at least 3 prescriptions filled for a newly started NSAID in the previous 90 days, 5 were admitted to a hospital for renal dysfunction. In contrast, only 5 of 1189 that did not meet the NSAID criteria were hospitalized for renal dysfunction.
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.
Ranolazine is primarily metabolized by CYP3A isoenzymes. Although not studied, barbiturates may induce the metabolism of ranolazine and potentially result in reduced antianginal effects. Monitor the antianginal response to ranolazine therapy closely during coadministration with barbiturates.
In vivo data indicate echinacea may inhibit the metabolism of caffeine. Echinacea reduces the oral clearance of caffeine by 27% and increases the mean AUC by 129% (90% CI 106 - 152%). Monitor patients for signs of increased caffeine serum concentrations if these drugs are coadministered until more data are available.
Aspirin, ASA; butalbital; caffeine combination products contain the antiplatelet agent aspirin. Additive platelet effects may occur if Aspirin, ASA; butalbital; caffeine is given in combination with other platelet inhibitors. In addition, anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of these drugs and, thus, adverse effects. Monitor patients for an increase in adverse effects of caffeine and for an increase in the risk of bleeding if these drugs are coadministered.
[ Last revised: 4/28/2006 10:04:00 AM ]
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