Drug Interactions between Prikaan and Saleto

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: The combined use of low-dose or high-dose aspirin with other nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. Aspirin at anti-inflammatory dosages or higher may also decrease the plasma concentrations of many NSAIDs. The decreases have ranged from none or small (piroxicam, meloxicam, naproxen, tolmetin) to substantial (flurbiprofen, ibuprofen). However, the therapeutic response does not appear to be affected. Investigators theorize that aspirin may displace NSAIDs from plasma protein binding sites, resulting in increased concentration of unbound, or free, drug available for clearance. The increase in NSAID free fraction, and possibly some contributory anti-inflammatory effect from aspirin, may account for the lack of overall effect on therapeutic response.

MANAGEMENT: Caution is advised if aspirin, particularly at anti-inflammatory dosages, is used with other NSAIDs. Concomitant administration of NSAIDs is considered contraindicated or not recommended with aspirin at analgesic/anti-inflammatory dosages by many NSAID manufacturers. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as abdominal pain, bloating, sudden dizziness or lightheadedness, nausea, vomiting, hematemesis, anorexia, and melena.

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One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

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