Drug Interactions between amyl nitrite/sodium nitrite/sodium thiosulfate and Silvadene Cream 1%

MONITOR CLOSELY: Sodium nitrite can cause methemoglobin formation, which diminishes oxygen-carrying capacity of the blood. Coadministration with other agents that are also associated with methemoglobinemia including local anesthetics (e.g., benzocaine, lidocaine, prilocaine), antimalarials (e.g., chloroquine, primaquine, quinine, tafenoquine), nitrates and nitrites, sulfonamides, aminosalicylic acid, dapsone, dimethyl sulfoxide, flutamide, metoclopramide (primarily in infants), nitrofurantoin (primarily in infants), phenazopyridine, phenobarbital, phenytoin, and rasburicase may increase the risk. Additional risk factors include very young age, anemia, cardiac/pulmonary disease, peripheral vascular disease, shock, sepsis, acidosis, and genetic predisposition (e.g., NADH cytochrome-b5 reductase deficiency; glucose-6-phosphate dehydrogenase deficiency; hemoglobin M). When sodium nitrite is administered to humans, a wide range of methemoglobin concentrations may occur. Methemoglobin concentrations as high as 58% have been reported after administration of two 300 mg doses to an adult. There have been reports of methemoglobinemia, coma, and death in patients without life-threatening cyanide poisoning but who were treated with injection of sodium nitrite at dosages less than twice those recommended for the treatment of cyanide poisoning.

MANAGEMENT: Sodium nitrite should be used with caution in the presence of other methemoglobin-inducing drugs. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with sodium nitrite. Methemoglobin levels should be monitored and oxygen administered whenever possible. 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; anxiety; and confusion. In severe cases, patients may progress to central nervous system depression, stupor, seizures, acidosis, cardiac arrhythmias, syncope, and shock. 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%. If patient does not respond to administration of oxygen, clinically significant methemoglobinemia should be treated with methylene blue 1 to 2 mg/kg by slow intravenous injection over 5 minutes.

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MONITOR: Topical nitrate and silver (e.g., cerium nitrate, silver nitrate, silver sulfadiazine) preparations can be systemically absorbed and have been associated with rare reports of methemoglobinemia, primarily in burn patients. In addition, bacterial conversion of nitrate to nitrite can contribute to methemoglobinemia. Coadministration with other oxidizing agents that can also induce methemoglobinemia such as ester and amide local anesthetics, antimalarials (e.g., chloroquine, primaquine, quinine, tafenoquine), systemic nitrates and nitrites, sulfonamides, aminosalicylic acid, dapsone, dimethyl sulfoxide, flutamide, metoclopramide, nitrofurantoin, phenazopyridine, phenobarbital, phenytoin, and rasburicase may increase the risk. Additional risk factors may include very young age (e.g., infants less than 6 months); application to large areas of inflamed, abraded, 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).

MANAGEMENT: Depending on the circumstances, caution may be advisable when topical nitrate and silver preparations are used concomitantly with other methemoglobin-inducing agents. Clinicians should be aware of the potential for methemoglobinemia, particularly when treating burn patients. 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. Mild cases often respond to withdrawal of offending agents and symptomatic support. If patient does not respond to administration of oxygen, clinically significant or symptomatic methemoglobinemia can be treated with methylene blue 1 to 2 mg/kg by slow intravenous injection over 5 to 10 minutes, which may be repeated within 30 to 60 minutes if necessary. Higher dosages of methylene blue (usually greater than 7 mg/kg) should be avoided, as it can paradoxically exacerbate methemoglobinemia. Additionally, methylene blue is ineffective and can cause hemolytic anemia in patients with G6PD deficiency. These patients may be treated with exchange transfusion, dialysis, and/or hyperbaric oxygenation in addition to symptomatic support.

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MONITOR: Topical nitrate and silver (e.g., cerium nitrate, silver nitrate, silver sulfadiazine) preparations can be systemically absorbed and have been associated with rare reports of methemoglobinemia, primarily in burn patients. In addition, bacterial conversion of nitrate to nitrite can contribute to methemoglobinemia. Coadministration with other oxidizing agents that can also induce methemoglobinemia such as ester and amide local anesthetics, antimalarials (e.g., chloroquine, primaquine, quinine, tafenoquine), systemic nitrates and nitrites, sulfonamides, aminosalicylic acid, dapsone, dimethyl sulfoxide, flutamide, metoclopramide, nitrofurantoin, phenazopyridine, phenobarbital, phenytoin, and rasburicase may increase the risk. Additional risk factors may include very young age (e.g., infants less than 6 months); application to large areas of inflamed, abraded, 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).

MANAGEMENT: Depending on the circumstances, caution may be advisable when topical nitrate and silver preparations are used concomitantly with other methemoglobin-inducing agents. Clinicians should be aware of the potential for methemoglobinemia, particularly when treating burn patients. 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. Mild cases often respond to withdrawal of offending agents and symptomatic support. If patient does not respond to administration of oxygen, clinically significant or symptomatic methemoglobinemia can be treated with methylene blue 1 to 2 mg/kg by slow intravenous injection over 5 to 10 minutes, which may be repeated within 30 to 60 minutes if necessary. Higher dosages of methylene blue (usually greater than 7 mg/kg) should be avoided, as it can paradoxically exacerbate methemoglobinemia. Additionally, methylene blue is ineffective and can cause hemolytic anemia in patients with G6PD deficiency. These patients may be treated with exchange transfusion, dialysis, and/or hyperbaric oxygenation in addition to symptomatic support.

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