Drug Interactions between Ascomp with Codeine and clopidogrel

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.

MONITOR: Coadministration with opioid agonists may delay and reduce the absorption of orally administered P2Y12 inhibitors (e.g., clopidogrel, prasugrel, ticagrelor). The proposed mechanism may involve opioid-mediated slowed gastric emptying. In one study, IV morphine (5 mg) given immediately prior to a loading dose of clopidogrel (600 mg) decreased the systemic exposure (AUC) and maximum concentration (Cmax) of the active metabolite of clopidogrel by 34% and increased the time to peak concentration (Tmax) of clopidogrel when compared with placebo (105 minutes vs 83 minutes, respectively). In addition, morphine reduced the pharmacodynamic (antiplatelet) effects of clopidogrel. In another study, IV morphine (5 mg) given immediately prior to a loading dose of ticagrelor (180 mg) decreased the AUC of ticagrelor and its active metabolite by approximately 36%, doubled the Tmax of ticagrelor, and reduced the antiplatelet effects of ticagrelor. The clinical relevance of this interaction is unknown. The risks associated with other opioid agonists are also unknown.

MANAGEMENT: Although data are limited, caution is recommended when orally administered P2Y12 inhibitors are given concomitantly with opioid agonists. In acute coronary syndrome patients who require an opioid agonist, the use of a parenteral antiplatelet agent, such as cangrelor, should be considered.

MONITOR: Clopidogrel has been shown to potentiate the inhibition of platelet aggregation due to aspirin. Single-dose studies have not shown a prolongation of bleeding time when aspirin was added to clopidogrel; however, the risk of gastrointestinal (GI) bleeding may be increased. A large clinical trial reported that clopidogrel 75 mg/day plus aspirin 75 to 325 mg/day for up to 1 year was associated with a higher incidence of major GI bleeding (1.3% vs 0.7% with aspirin alone). These two medications are routinely used together for their additive antiplatelet, antistroke effect. The safety of chronic administration of aspirin or other salicylates with clopidogrel has not been established.

MANAGEMENT: Until further data are available, caution is recommended, especially in patients at risk of bleeding (i.e., GI ulceration), if clopidogrel is coadministered on a long-term basis with drugs that may cause GI lesions. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, red or black stools, or bloody or coffee-ground emesis. Patients should also be counseled to avoid any other over-the-counter salicylate products.

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.