Drug Interactions between ranolazine and tramadol

MONITOR: Ranolazine can cause dose-related prolongation of the QT interval. Tramadol may also prolong the QT interval, and theoretically, coadministration of multiple 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 apparent linear relationship is much steeper in cirrhotic subjects with mild or moderate hepatic impairment. In contrast, there have also been no reported cases of torsade de pointes in clinical studies of ranolazine comprising 3,669 patient-years of treatment. In Study CVT3036 (MERLIN-TIMI36), no proarrhythmic effects were observed on 7-day Holter recordings in 3,162 acute coronary syndrome (ACS) patients treated with ranolazine. In addition, 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 of 3 or more beats (52% versus 61%). The effect of tramadol on the QT interval was evaluated in a randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple-dose ECG study of 62 healthy subjects. The maximum placebo-adjusted mean change from baseline in the Fridericia-corrected QT interval (QTcF) was 5.5 msec in the 400 mg/day treatment arm (100 mg every 6 hours on days 1 through 3 with a single 100 mg dose on day 4) and 6.5 msec in the 600 mg/day treatment arm (150 mg every 6 hours on days 1 through 3 with a single 150 mg dose on day 4), both occurring at the 8-hour time point. 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).

MONITOR: Coadministration with ranolazine may decrease the opioid-like effects of tramadol, a substrate of the CYP450 2D6 isoenzyme. The mechanism is decreased conversion of tramadol to its active metabolite, M1, due to inhibition of CYP450 2D6 activity by ranolazine. Ranolazine has been shown in vitro to be an inhibitor of CYP450 2D6. In animal studies, M1 was up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in binding to mu-opioid receptors.

MANAGEMENT: Concomitant use of ranolazine and tramadol should generally be avoided. If coadministration is required, careful consideration of the effects on tramadol and M1 is required. Patients should be monitored for opioid withdrawal, seizures, and serotonin syndrome, and care should be exercised in patients suspected to be at an increased risk of torsade de pointes. 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. Particular care should be exercised in patients suspected to be at an increased risk of torsade de pointes. 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.

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