Aspirininteractions

Table 1 includes clinically significant drug interactions with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP.

Table 1: Clinically Significant Drug Interactions with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with CYP3A4 inhibitors may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine.

Intervention: If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Intervention: If concomitant use of a CYP3A4 inducer is necessary, evaluate patients at frequent intervals for reduced efficacy and signs of opioid withdrawal and consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage as needed. If a CYP3A4 inducer is discontinued, consider Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage reduction, and evaluate patients at frequent intervals for signs of respiratory depression and sedation.

Examples: Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 Clinical Impact: Codeine in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is metabolized by CYP2D6 to form morphine. The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentrations of active metabolite morphine which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is achieved. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate patients at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, evaluate patients for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate patients at frequent intervals for signs and symptoms of respiratory depression or sedation.

Examples: paroxetine, fluoxetine, bupropion, quinidine Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP immediately if serotonin syndrome is suspected.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT 3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Intervention: Do not use Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and/or precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine, Muscle Relaxants Clinical Impact: Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention: Evaluate patients for signs of respiratory depression that may be greater than otherwise expected, decrease the dosage of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing an opioid overdose reversal agent.

Examples: Cyclobenzaprine, metaxalone.

Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.

Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is used concomitantly with anticholinergic drugs.

Anticoagulants Clinical Impact: Aspirin may enhance the effects of anticoagulants. Concurrent use may increase the risk of bleeding. Aspirin can also displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time.

Intervention: Evaluate patients for signs of bleeding.

Examples: Warfarin, heparin, enoxaparin, clopidogrel, prasugrel, rivaroxaban, apixaban Uricosuric Agents Clinical Impact: Aspirin inhibits the uricosuric effects of uricosuric agents.

Intervention: Avoid concomitant use.

Examples: Probenecid Carbonic Anhydrase Inhibitors Clinical Impact: Concurrent use with aspirin can lead to high serum concentrations of the carbonic anhydrase inhibitor and cause toxicity due to competition at the renal tubule for secretion.

Intervention: Consider reducing the dose of the carbonic anhydrase inhibitor. Evaluate the patients for any adverse effects from the carbonic anhydrase inhibitor.

Examples: Acetazolamide, methazolamide Methotrexate Clinical Impact: Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance.

Intervention: Use caution if using concomitantly, especially in elderly patients or patients with renal impairment. Evaluate patients for methotrexate toxicity.

Nephrotoxic Agents Clinical Impact: Concomitant use with aspirin may lead to additive nephrotoxicity due to the inhibition of renal prostaglandins by aspirin. Also, the plasma concentration of aspirin is increased by conditions that reduce the glomerular filtration rate or tubular secretion.

Intervention: Use Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with caution if used concomitantly with nephrotoxic agents. Evaluate the renal function of patients.

Examples: Aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin Angiotensin Converting Enzyme (ACE) Inhibitors Clinical Impact: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin- angiotensin conversion pathway.

Intervention: Use caution if using concomitantly. Evaluate the blood pressure and renal function of patients.

Examples: Ramipril, captopril Beta Blockers Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention.

Intervention: Use caution if using concomitantly. Evaluate the blood pressure and renal function of patients.

Examples: Metoprolol, propranolol Hypoglycemic Agents Clinical Impact: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia.

Intervention: Patients should be advised to consult a physician if any signs or symptoms of hypoglycemia occur.

Examples: Insulin, glimepiride, glipizide Anticonvulsants Clinical Impact: Aspirin can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.

Intervention: Use caution if using concomitantly.

Examples: Phenytoin, valproic acid Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Clinical Impact: Concurrent use with aspirin may increase the risk of bleeding or lead to decreased renal function. Aspirin may enhance serious side effects and toxicity of ketorolac by displacing it from its plasma protein binding sites and/or reducing its renal clearance.

Intervention: Avoid concomitant use.

Examples: Ketorolac, ibuprofen, naproxen, diclofenac Corticosteroids Clinical Impact: In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance.

Intervention: Avoid concomitant use.

Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP if serotonin syndrome is suspected. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP because they may reduce analgesic effect of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP or precipitate withdrawal symptoms.