Drug Interactions between amyl nitrite/sodium nitrite/sodium thiosulfate and lofexidine

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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GENERALLY AVOID: The hypotensive and bradycardic effects of lofexidine may be increased if it is used concurrently with other medications capable of these effects. Clinical trials reported orthostatic hypotension (29% and 42%), bradycardia (24% and 32%), and hypotension (30% and 30%) more frequently in patients on lofexidine 2.16 mg and 2.88 mg, respectively, compared to placebo (5%, 5%, and 1%, respectively).

MANAGEMENT: Concomitant use of lofexidine with medications that can decrease pulse rate or blood pressure should generally be avoided. If patients are using lofexidine in an outpatient setting, they should be capable of and counseled on self-monitoring for hypotension, orthostasis, and bradycardia. Patients should also be instructed to remain hydrated, rise carefully from a sitting or lying down position, and to contact their healthcare provider for guidance on dosing if hypotension or bradycardia occur.

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MONITOR: Coadministration with antihypertensive agents, diuretics, vasodilators, or phosphodiesterase-5 (PDE5) inhibitors may potentiate the hypotensive effect of sodium nitrite. Since sodium nitrite can cause serious hypotension and methemoglobin formation, patients may be at increased risk for complications related to inadequate perfusion and oxygenation. In healthy volunteers, oral doses of 120 to 180 mg caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, subjects exhibited tachycardia and hypotension with syncope within minutes after being placed in the upright position. A wide range of methemoglobin concentrations may occur following sodium nitrite administration. Methemoglobin concentrations as high as 58% have been reported after administration of two 300 mg doses to an adult. There have been reports of severe hypotension, methemoglobinemia, cardiac dysrhythmias, 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 concomitant antihypertensive agents, diuretics, vasodilators, or PDE5 inhibitors. Hemodynamics should be monitored during and after administration of sodium nitrite, and the infusion rate decreased if significant hypotension occurs. In addition, methemoglobin levels should be monitored and oxygen administered during treatment whenever possible.

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