Drug Interactions between aluminum hydroxide / diphenhydramine / lidocaine / magnesium hydroxide / simethicone topical and chloroquine

MONITOR: Some topical anesthetics can be systemically absorbed and cause methemoglobinemia, particularly when applied to mucous membranes. Coadministration with other oxidizing agents that can also induce methemoglobinemia such as injectable local anesthetics, antimalarials (e.g., chloroquine, primaquine, quinine, tafenoquine), nitrates and nitrites, sulfonamides, aminosalicylic acid, dapsone, dimethyl sulfoxide, flutamide, metoclopramide, nitrofurantoin, phenazopyridine, phenobarbital, phenytoin, and rasburicase may increase the risk. Additional risk factors include very young age (e.g., infants less than 6 months); application to inflamed/abraded areas or broken skin; anemia; cardiac or pulmonary disease; peripheral vascular disease; liver cirrhosis; shock; sepsis; acidosis; and genetic predisposition (e.g., NADH cytochrome-b5 reductase deficiency; glucose-6-phosphate dehydrogenase (G6PD) deficiency; hemoglobin M). There have been rare reports of significant methemoglobinemia associated with administration of topical anesthetics, primarily following application to mucous membranes prior to dental procedures or via the oropharyngeal route prior to procedures such as intubation, laryngoscopy, bronchoscopy, and endoscopy. Very rarely, methemoglobinemia has also been reported with use of anesthetic throat lozenges.

MANAGEMENT: Caution is advised when topical anesthetics are used concomitantly with other methemoglobin-inducing agents. Clinicians should be aware of the potential for methemoglobinemia, particularly when topical anesthetics are applied to mucous membranes or given via the oropharyngeal route. Signs and symptoms of methemoglobinemia may be delayed some hours after drug exposure. Patients or their caregivers should be advised to seek medical attention if they notice signs and symptoms of methemoglobinemia such as slate-grey cyanosis in buccal mucous membranes, lips, and nail beds; 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.

ADJUST DOSING INTERVAL: Concomitant administration of antacids or kaolin may reduce the oral bioavailability of chloroquine. The proposed mechanism is adsorption of chloroquine by polyvalent cations present in these agents. Delayed dissolution of chloroquine tablets in the presence of antacids may also be a contributing factor. In six healthy study subjects, administration of a single 1 gram dose of chloroquine phosphate in combination with a 1 gram dose of magnesium trisilicate or kaolin decreased chloroquine systemic exposure (AUC) by approximately 18% and 29%, respectively, compared to administration alone. In vitro evidence of the interaction has also been reported for other antacids including calcium carbonate and gerdiga. The clinical significance has not been established.

MANAGEMENT: Chloroquine product labeling suggests separating the doses by at least 4 hours if concomitant therapy with antacids or kaolin is required. The same precaution may be applicable to hydroxychloroquine, although no data are available to support this recommendation. Some authorities recommend separating the dose of hydroxychloroquine from antacids and kaolin by at least 2 hours (AU).

ADJUST DOSING INTERVAL: Concomitant administration of antacids or kaolin may reduce the oral bioavailability of chloroquine. The proposed mechanism is adsorption of chloroquine by polyvalent cations present in these agents. Delayed dissolution of chloroquine tablets in the presence of antacids may also be a contributing factor. In six healthy study subjects, administration of a single 1 gram dose of chloroquine phosphate in combination with a 1 gram dose of magnesium trisilicate or kaolin decreased chloroquine systemic exposure (AUC) by approximately 18% and 29%, respectively, compared to administration alone. In vitro evidence of the interaction has also been reported for other antacids including calcium carbonate and gerdiga. The clinical significance has not been established.

MANAGEMENT: Chloroquine product labeling suggests separating the doses by at least 4 hours if concomitant therapy with antacids or kaolin is required. The same precaution may be applicable to hydroxychloroquine, although no data are available to support this recommendation. Some authorities recommend separating the dose of hydroxychloroquine from antacids and kaolin by at least 2 hours (AU).