Drug Interactions between aspirin / butalbital / caffeine / codeine and Di-Phen

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, phenothiazines).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

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MONITOR: Coadministration of codeine with potent or moderate CYP450 3A4 inducers may result in lower codeine plasma concentrations, higher levels of the inactive metabolite norcodeine, and less metabolism via CYP450 2D6, resulting in lower morphine levels. This interaction may lead to reduced codeine efficacy and potentially initiate the onset of withdrawal symptoms in patients who are physically dependent. In addition, patients may be at an increased risk of CNS and/or respiratory-depressant effects from increased levels of codeine once concomitant therapy with the CYP450 3A4 inducer is ceased. This is particularly worrisome if the CYP450 3A4 inducer also possesses CNS- and/or respiratory-depressant effects. This interaction has also been reported with dihydrocodeine.

MANAGEMENT: The potential loss of efficacy of codeine or dihydrocodeine and onset of opioid withdrawal symptoms should be considered when used in combination with a potent or moderate CYP450 3A4 inducer. Alternative agents with no or minimal CYP450 3A4 induction potential are recommended whenever possible. Some manufacturers of products containing codeine advise against the concomitant use of codeine with CYP450 3A4 inducers. If concomitant use is considered necessary, caution and close clinical and laboratory monitoring are recommended. Dosage adjustments may also be required whenever a CYP450 3A4 inducer is added to or withdrawn from therapy. Following discontinuation of a CYP450 3A4 inducer, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression.

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MONITOR: Barbiturates may induce or inhibit the metabolism of phenytoin. Plasma phenytoin concentrations may be decreased or increased. The mechanism are induction of hepatic CYP450 phenytoin metabolism by therapeutic doses of barbiturates, and competitive inhibition of metabolism by large doses. Also, when phenytoin is added to a regimen, the plasma levels of barbiturates may significantly increase via an unknown mechanism.

MANAGEMENT: Close laboratory and clinical observation for altered effects of both agents is recommended when doses of either agent are started, changed, or discontinued. Patients should be advised to notify their physician if they experience loss of seizure control or excessive or prolonged sedative effects. It may be necessary to alter the dosage of one or both of the drugs.

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In vitro studies suggest that salicylates may displace phenytoin from plasma protein-binding sites. The potential for phenytoin toxicity exists. The clinical significance is unknown. One case of phenytoin toxicity has been reported in a patient taking aspirin. However, clinical studies in healthy subjects and epileptic patients (taking phenytoin and 1500 mg aspirin/day) have not reported significant pharmacokinetic changes, adverse effects, or loss of seizure control.

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One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

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