Drug Interactions between Eryzole and ropivacaine / sufentanil

MONITOR: Coadministration of local anesthetics with other oxidizing agents that can also induce methemoglobinemia such as antimalarials (e.g., chloroquine, quinine), nitrates and nitrites, sulfonamides, aminosalicylic acid, dimethyl sulfoxide (DMSO), metoclopramide, nitrofurantoin, phenazopyridine, phenobarbital, and phenytoin may increase the risk. Additional risk factors include very young age (e.g., infants less than 6 months), cardiac or pulmonary disease, genetic predisposition, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Data surrounding the incidence of methemoglobinemia are agent-specific and, in many instances, have primarily been reported in case reports and/or in overdose situations.

MANAGEMENT: Monitoring for signs and symptoms of methemoglobinemia is recommended if local anesthetics must be used with other methemoglobin-inducing agents. Signs and symptoms of methemoglobinemia may occur immediately or hours after drug exposure. Patients or their caregivers should be advised to seek medical attention if they notice signs and symptoms of methemoglobinemia (e.g., cyanotic skin discoloration, abnormal blood coloration, nausea, headache, dizziness, lightheadedness, lethargy, fatigue, dyspnea, tachypnea, tachycardia, palpitation, anxiety, and confusion). In severe cases, patients may progress to central nervous system depression, stupor, seizures, acidosis, cardiac arrhythmias, syncope, shock, coma, and death. Methemoglobinemia should be considered if central cyanosis is unresponsive to oxygen. Calculated oxygen saturation and pulse oximetry are generally not accurate in the setting of methemoglobinemia. The diagnosis can be confirmed by an elevated methemoglobin level of at least 10% using co-oximetry. Methemoglobin concentrations greater than 10% of total hemoglobin will typically cause cyanosis, and levels over 70% are frequently fatal. However, symptom severity is not always related to methemoglobin levels. Experts suggest that treatment of methemoglobinemia varies from supplemental oxygen and symptom support to the administration of methylene blue, depending on severity of symptoms and/or the presence of G6PD deficiency. Institutional guidelines and/or individual product labeling should be consulted for further guidance.

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Coadministration with inhibitors of CYP450 3A4 may modestly increase the plasma concentrations of ropivacaine. Although ropivacaine is primarily metabolized by CYP450 1A2, it has been shown to undergo some metabolism via CYP450 3A4. In eight healthy volunteers, pretreatment with the 3A4 inhibitor erythromycin (500 mg three times a day for 6 days) was found to have only minor effects on the pharmacokinetics of a single dose of ropivacaine (0.6 mg/kg IV over 30 minutes) compared to placebo. However, in combination with the potent 1A2 inhibitor fluvoxamine (100 mg daily), erythromycin further increased the area under the plasma concentration-time curve (AUC) of ropivacaine by 50% compared to fluvoxamine alone, which increased the ropivacaine AUC by 3.7-fold. Fluvoxamine alone prolonged the elimination half-life of ropivacaine from 2.3 to 7.4 hours, while the addition of erythromycin further increased the half-life to 11.9 hours. In another study, pretreatment with the potent 3A4 inhibitor ketoconazole (100 mg twice daily for 2 days) decreased the mean total plasma clearance of ropivacaine (40 mg IV over 20 minutes) by just 15% in 12 healthy volunteers. Thus, it appears that CYP450 3A4 inhibitors may only have a significant effect on the pharmacokinetics of ropivacaine in the presence of a CYP450 1A2 inhibitor such as fluvoxamine, ciprofloxacin, or mexiletine.

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