Drug Interactions between chloroquine and codeine / phenylephrine / promethazine

GENERALLY AVOID: Hydroxychloroquine (HCQ) can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such advanced age, congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In a retrospective study of electronic health records analyzing QTc prolongation risk in patients on HCQ alone or with other QT-prolonging drugs, a statistically significant QTc interval increase of 18 ms was observed in the HCQ monotherapy group. No significant QTc increase was found in patients taking HCQ with the evaluated QT-prolonging medications. However, this result may have been influenced by factors such as varying patient sensitivity to QT-prolonging drugs across treatment sites, and differences in HCQ exposure duration prior to QTc measurement in combination therapy cases. QT prolongation has also been reported with chloroquine, with an increased risk reported at higher doses.

MANAGEMENT: Coadministration of hydroxychloroquine or chloroquine with other drugs that can prolong the QT interval should generally be avoided, particularly in patients with baseline QT prolongation (e.g., QTc >=500 msec) or congenital long QT syndrome. Close monitoring of QTc interval, electrolyte levels, and renal and hepatic function is recommended if concomitant use is required, and benefits are anticipated to outweigh the risks. Electrolyte abnormalities should be corrected prior to initiating treatment with hydroxychloroquine. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Because both hydroxychloroquine and chloroquine are eliminated slowly from the body (e.g., terminal half-life of hydroxychloroquine is 40-50 days), potential drug interactions may persist for several weeks to months after their discontinuation.

MONITOR: Drugs that are inhibitors of CYP450 2D6 may interfere with the analgesic effect of codeine. The mechanism is decreased in vivo conversion of codeine to morphine, a metabolic reaction mediated by CYP450 2D6. If an inhibitor is started after a stable dose of codeine is achieved, reduced analgesia and possible opioid withdrawal may result. Conversely, ceasing CYP450 2D6 inhibitor therapy may lead to increased morphine levels, increasing the risk of opioid-related adverse effects.

MANAGEMENT: The possibility of reduced or inadequate pain relief should be considered in patients receiving codeine with drugs that inhibit CYP450 2D6. An increase in the codeine dosage or a different analgesic agent may be necessary in patients requiring therapy with CYP450 2D6 inhibitors. If concurrent therapy is used and the CYP450 2D6 inhibitor is stopped, the dose of codeine may need to be reduced and the patient should be monitored for signs and symptoms of respiratory depression or sedation. In addition, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may interfere with the analgesic effects of codeine for at least 28 days after administration of rolapitant. The manufacturer's prescribing information should be consulted for further information.

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.