Drug Interactions between dexamethasone / lidocaine and Painaid

MONITOR: Coadministration of local anesthetics with other oxidizing agents that can also induce methemoglobinemia such as antimalarials (e.g., chloroquine, quinine), nitrates and nitrites, sulfonamides, aminosalicylic acid, dimethyl sulfoxide (DMSO), metoclopramide, nitrofurantoin, phenazopyridine, phenobarbital, and phenytoin may increase the risk. Additional risk factors include very young age (e.g., infants less than 6 months), cardiac or pulmonary disease, genetic predisposition, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Data surrounding the incidence of methemoglobinemia are agent-specific and, in many instances, have primarily been reported in case reports and/or in overdose situations.

MANAGEMENT: Monitoring for signs and symptoms of methemoglobinemia is recommended if local anesthetics must be used with other methemoglobin-inducing agents. Signs and symptoms of methemoglobinemia may occur immediately or hours after drug exposure. Patients or their caregivers should be advised to seek medical attention if they notice signs and symptoms of methemoglobinemia (e.g., cyanotic skin discoloration, abnormal blood coloration, 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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MONITOR: Coadministration with corticosteroids may decrease the serum concentrations and therapeutic effects of salicylates. Likewise, serum salicylate levels may increase following withdrawal of corticosteroid therapy, potentially resulting in salicylate toxicity. This interaction has been reported in patients receiving intra-articular as well as oral corticosteroids. One or more mechanisms may be involved, including an increase in the renal clearance and/or an induction of hepatic metabolism of salicylates caused by corticosteroids. Pharmacologically, the potential for increased gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration and perforation, should be considered due to additive ulcerogenic effects of these agents (especially aspirin) on the GI mucosa.

MANAGEMENT: Patients treated concomitantly with a corticosteroid may require higher dosages of salicylates or salicylate-like drugs. Pharmacologic response to these agents should be monitored more closely whenever a corticosteroid is added to or withdrawn from therapy in patients stabilized on their existing salicylate regimen, and the salicylate dosage adjusted as necessary. 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 severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be appropriate, particularly in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients.

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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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MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. 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 severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

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Coadministration with inducers of CYP450 1A2 and/or 3A4 may decrease the plasma concentrations of lidocaine, which is primarily metabolized by these isoenzymes. In four healthy volunteers (2 smokers and 2 nonsmokers), administration of a single 400 mg oral dose of lidocaine following pretreatment with the CYP450 inducer phenobarbital (15 mg/day for 4 weeks, followed by 30 mg/day for 4 weeks) decreased lidocaine systemic exposure (AUC) by 37% and increased its oral clearance by 56% compared to administration of lidocaine alone. In another study, the mean bioavailability of a single 750 mg oral dose of lidocaine in six patients receiving chronic antiepileptic drug therapy (consisting of one or more of the following enzyme-inducing anticonvulsants: phenobarbital, primidone, phenytoin, carbamazepine) was approximately 2.5-fold lower than that reported for six healthy control subjects, while intrinsic clearance was nearly threefold higher. By contrast, the interaction was modest for lidocaine administered intravenously, suggesting induction of primarily hepatic first-pass rather than systemic metabolism of lidocaine. When a single 100 mg dose of lidocaine was given intravenously, mean lidocaine AUC was reduced by less than 10% and serum clearance increased by just 17% in the epileptic patients compared to controls. These changes were not statistically significant. Likewise, mean lidocaine AUC decreased by approximately 11% and plasma clearance increased by 15% when a single 50 mg intravenous dose of lidocaine was administered following pretreatment with the potent CYP450 inducer rifampin (600 mg/day for six days) in ten healthy, nonsmoking male volunteers. Another pharmacokinetic study found that cigarette smoke, an inducer of CYP450 1A2, reduced the bioavailability of lidocaine when administered orally, but had only minor effects on lidocaine administered intravenously. When 4 smokers and 5 non-smokers received 2 doses of lidocaine (100 mg IV followed by 100 mg orally after a 2-day washout period), the smoker's systemic exposure (AUC) of oral lidocaine was 68% lower than non-smokers. The AUC of IV lidocaine was only 9% lower in smokers compared with non-smokers. The clinical impact of smoking on lidocaine has not been studied, however, a loss of efficacy may occur.

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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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