Drug Interactions between Fortabs and MLK F2

GENERALLY AVOID: Additive toxicities may occur when bupivacaine is coadministered with other local anesthetics. The potential for increased risk of systemic toxicities such as methemoglobinemia and central nervous system and cardiovascular adverse reactions should be recognized.

MANAGEMENT: Additional use of local anesthetics should generally be avoided within 96 hours following administration of bupivacaine. If coadministration cannot be avoided, overall local anesthetic exposure through 72 hours must be considered in addition to monitoring for the development of methemoglobinemia as well as central nervous system and cardiovascular adverse reactions. 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. Early warning signs of central nervous system toxicity may include restlessness, anxiety, incoherent speech, dizziness, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, blurred vision, tremors, twitching, depression, and drowsiness. Cardiovascular toxicity may include atrioventricular block, ventricular arrhythmias, cardiac arrest, and decreased cardiac output and arterial blood pressure due to depressed cardiac conductivity, excitability, and myocardial contractility. Patients should have cardiovascular and respiratory vital signs and state of consciousness constantly monitored while under treatment.

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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: Barbiturates may decrease the plasma concentrations and systemic effects of both endogenous and exogenous corticosteroids. The mechanism is accelerated corticosteroid metabolism due to induction of the CYP450 3A4 enzymatic pathway by barbiturates.

MANAGEMENT: Patients treated concomitantly with a barbiturate may require higher dosages of corticosteroids or adrenocorticotropic agents. Pharmacologic response to these agents should be monitored more closely whenever a barbiturate is added to or withdrawn from therapy in patients stabilized on their existing corticosteroid or adrenocorticotropic regimen, and the dosage(s) adjusted as necessary.

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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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Coadministration with barbiturates may decrease the plasma concentrations of lidocaine. The proposed mechanism is induction of lidocaine metabolism via CYP450 3A4. In four healthy volunteers (2 smokers and 2 nonsmokers), administration of a single 400 mg oral dose of lidocaine following pretreatment with 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. Because lidocaine is not available commercially for oral administration, the interaction may be of limited clinical relevance. Both lidocaine and barbiturates are CNS depressants which may lead to additive effects. However, barbiturates may be used together with lidocaine in emergency cases, such as treating convulsions caused by lidocaine overdosage, while considering the depressive effects barbiturates have on respiration and circulation.

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