Drug Interactions between difelikefalin and Synalgos-DC

MONITOR: The central nervous system (CNS) adverse effects of difelikefalin (e.g., dizziness, somnolence, mental status changes, gait disturbances) may be potentiated by the concomitant use of opioids. In two clinical trials, 17% of hemodialysis patients receiving difelikefalin reported at least one CNS side effect, compared to 12% of patients who received placebo. When patients were analyzed by age, the incidence of somnolence was found to be higher in difelikefalin-treated patients 65 years of age or older (7%) than in those less than 65 years old (2.8%).

MONITOR: Concomitant use of difelikefalin with opioids may increase the risk of hyperkalemia. In clinical trials, the incidence of hyperkalemia was 4.7% in patients who received difelikefalin versus 3.5% in placebo-treated patients. Additionally, 2.8% of difelikefalin-treated subjects had potassium levels greater than 7 mmol/L, compared to 1.0% in the placebo group. In subjects also receiving opioids, the incidence of hyperkalemia was almost doubled in the difelikefalin group (11.7%) compared to the placebo group (6.2%). The clinical relevance of these findings is unknown, as a causal relationship has not been established.

MANAGEMENT: Caution is advised during coadministration of difelikefalin with opioids. Patients should be monitored for increased adverse CNS effects, particularly in patients 65 years of age and older. Patients should not drive, operate machinery, or engage in hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them. In addition, more frequent monitoring of serum potassium levels may be required. Patients should be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, convulsion, weak pulse, and a slow or irregular heartbeat.

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.