Drug Interactions between Promethazine with DM and ranolazine

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.

MONITOR: Coadministration with CYP450 2D6 inhibitors may increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. Coadministration of dextromethorphan (60 mg orally, once) with the CYP450 2D6 inhibitor panobinostat (20 mg orally once a day on days 3, 5, and 8) in 14 patients with advanced cancer had a highly variable effect on dextromethorphan levels, increasing the peak plasma concentration (Cmax) of dextromethorphan by 20% to 200%, and total systemic exposure (AUC 0 to infinity) by 20% to 130%, compared to dextromethorphan given alone. The moderate CYP450 2D6 inhibitor asunaprevir, given at 200 mg twice daily, also increased Cmax and AUC of a single 30 mg dose of dextromethorphan by 2.7- and 3.9-fold, respectively, in 17 study subjects.

MANAGEMENT: Caution should be exercised if these drugs must be used together. Patients should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

MONITOR: Ranolazine 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, although there is little experience in this setting. At Tmax following repeat dosing of 1000 mg twice daily, the mean effect of ranolazine on QTc is approximately 6 msec. However, in 5% of the population with the highest plasma concentrations, the prolongation of QTc is 15 msec or more. The relationship between ranolazine plasma level and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by a dosage of 1000 mg twice a day, and this relationship is not significantly affected by age, weight, gender, race, heart rate, congestive heart failure, diabetes, or renal impairment. However, the apparent linear relationship is much steeper in cirrhotic subjects with mild or moderate hepatic impairment. Ranolazine did not induce torsade de pointes or other arrhythmias in several in vitro and animal models. There have also been no reported cases of torsade de pointes in clinical studies of ranolazine comprising 3,669 patient-years of treatment. In fact, ranolazine was found to be antiarrhythmic in Study CVT 3036 (MERLIN-TIMI 36), which was a Phase 3, randomized, double-blind, parallel-group, placebo-controlled clinical trial designed to evaluate the efficacy and safety of ranolazine as chronic therapy in patients with non-ST elevation acute coronary syndromes (ACS) treated with other standard therapy. No proarrhythmic effects were observed on 7-day Holter recordings in 3,162 ACS patients treated with ranolazine. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with ranolazine (80%) versus placebo (87%), including ventricular tachycardia >= 3 beats (52% versus 61%). 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 as 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).

MANAGEMENT: Caution is recommended if ranolazine is used in combination with other drugs that can prolong the QT interval. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of ranolazine, the maximum recommended dosage of 1000 mg twice daily should not be exceeded. 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. Ranolazine is contraindicated in patients with liver cirrhosis because of the profound effect on QT prolongation in this population.