Drug Interactions between ifosfamide and LiproZonePak

GENERALLY AVOID: Prilocaine can cause dose-related methemoglobin formation via its ortho-toluidine metabolite. Coadministration with other oxidizing agents that can also induce methemoglobinemia including other local anesthetics (e.g., benzocaine, lidocaine),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, 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 deficiency; hemoglobin M). There have been reports of significant methemoglobinemia (20% to 30%) in infants and children following excessive applications of lidocaine-prilocaine cream. These cases involved the use of large doses, larger than recommended areas of application, or infants under the age of 3 months who did not have fully mature enzyme systems. In addition, a few cases involved the concomitant administration of methemoglobin-inducing agents, including a published case of an infant who was treated with lidocaine-prilocaine cream and sulfamethoxazole-trimethoprim. Most patients recovered spontaneously after removal of the cream. The incidence of systemic adverse reactions including methemoglobinemia following topical use is related to level of systemic absorption and can be expected to be directly proportional to the surface area and duration of exposure. In addition, systemic blood levels may be increased in smaller patients (e.g., children), patients with impaired drug elimination, and application to inflamed/abraded areas or broken skin.

MANAGEMENT: Concomitant use of topical lidocaine-prilocaine formulations with other methemoglobin-inducing agents should be avoided in infants younger than 12 months of age. Caution is advised when used in other 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: 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.

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