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

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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CONTRAINDICATED: Phosphodiesterase-5 (PDE5) inhibitors may potentiate the hypotensive effect of organic nitrates. Severe hypotension, syncope, or myocardial ischemia may result from use of the combination. The mechanism involves peripheral vasodilation secondary to enhanced levels of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells, as PDE5 inhibitors prevent degradation of cGMP while nitrates promote its synthesis. Single oral doses of the PDE5 inhibitors sildenafil (100 mg) and vardenafil (20 mg) have produced mean maximum decreases in supine blood pressure (systolic/diastolic) of approximately 8.4/5.5 and 7.0/8.0 mmHg, respectively, compared to placebo. The decrease in blood pressure was most notable approximately 1 to 2 hours after sildenafil dosing and 1 to 4 hours after vardenafil dosing and was additive with that produced by nitrates. A single 200 mg dose of avanafil produced transient decreases in sitting blood pressure of 8.0/3.3 mmHg in healthy volunteers, with maximum decrease observed at 1 hour after dosing. When given with sublingual nitroglycerin 0.4 mg to healthy males, avanafil 200 mg produced decreases from baseline in sitting and standing blood pressure of 8.2/6.4 and 6.9/7.0 mmHg, respectively, relative to placebo. Tadalafil 20 mg administered to healthy male subjects produced no significant difference in supine or standing blood pressure compared to placebo, although the drug did potentiate the hypotensive effect of nitrates at a dosage of 5 to 20 mg.

MANAGEMENT: The use of PDE5 inhibitors in patients receiving organic nitrates or other nitric oxide donors, either regularly or intermittently, is considered contraindicated. A suitable time interval following sildenafil or vardenafil use for the safe administration of nitrates has not been determined. For patients treated with avanafil or tadalafil, at least 12 hours after the last dose of avanafil and 48 hours after the last dose of tadalafil are recommended before nitrate administration, should it be deemed medically necessary in a life-threatening situation. Even then, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring. Patients should be advised to seek immediate medical attention if they experience anginal chest pain after taking a PDE5 inhibitor.

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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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