warnings and cautions
5 WARNINGS AND PRECAUTIONS Accidental Intravascular Injection: May be associated with convulsions followed by coma and respiratory arrest. Resuscitative equipment, oxygen and other resuscitative drugs should be available. ( 5.1 ) • Systemic Toxicity ( 5.2 ) • Vasoconstrictor Toxicity: Local anesthetic solutions like articaine hydrochloride and epinephrine injection, USP that contain a vasoconstrictor should be used cautiously, especially in patients with impaired cardiovascular function or vascular disease. ( 5.3 ) • Methemoglobinemia ( 5.4 ) • Anaphylaxis and Allergic-Type Reactions ( 5.5 ) 5.1 Accidental Intravascular Injection Accidental intravascular injection of articaine hydrochloride and epinephrine injection, USP may be associated with convulsions, followed by central nervous system or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Dental practitioners who employ local anesthetic agents including articaine hydrochloride and epinephrine injection, USP should be well versed in diagnosis and management of emergencies that may arise from their use. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. To avoid intravascular injection, aspiration should be performed before articaine hydrochloride and epinephrine injection, USP is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided. Small doses of local anesthetics injected in dental blocks may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should be observed constantly. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [ see Dosage and Administration (2.1) ]. 5.2 Systemic Toxicity This includes toxicity arising from accidental intravascular injection of articaine hydrochloride and epinephrine injection, USP discussed in Section 5.1, as well as that related to higher systemic concentrations of local anesthetics or epinephrine [ see Warnings and Precautions (5.3) ]. Systemic absorption of local anesthetics including articaine hydrochloride and epinephrine injection, USP can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses of articaine hydrochloride and epinephrine injection, USP, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations of articaine hydrochloride and epinephrine injection, USP can depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, possibly resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilatation occurs, leading to decreased cardiac output and arterial blood pressure. Articaine hydrochloride and epinephrine injection, USP should also be used with caution in patients with heart block as well as those with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of central nervous system toxicity. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after each local anesthetic injection of articaine hydrochloride and epinephrine injection, USP. Repeated doses of articaine hydrochloride and epinephrine injection, USP may cause significant increases in blood levels because of possible accumulation of the drug or its metabolites. The lowest dosage that results in effective anesthesia should be used to decrease the risk of high plasma levels and serious adverse effects. Tolerance to elevated blood levels varies with the status of the patient. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. Precautions for epinephrine administration, discussed in Section 5.3, should be observed. Debilitated patients, elderly patients, acutely ill patients, and pediatric patients should be given reduced doses commensurate with their age and physical condition [ see Dosage and Administration ( 2.1 , 2.3 ) ]. No studies have been performed in patients with liver dysfunction, and caution should be used in patients with severe hepatic disease. 5.3 Vasoconstrictor Toxicity Articaine hydrochloride and epinephrine injection, USP contains epinephrine, a vasoconstrictor that can cause local or systemic toxicity and should be used cautiously. Local toxicity may include ischemic injury or necrosis, which may be related to vascular spasm. Articaine hydrochloride and epinephrine injection, USP should be used with caution in patients during and following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. The American Heart Association has made the following recommendation regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: “Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used.” (Kaplan, 1986). It is essential to aspirate before any injection to avoid administration of the drug into the blood stream. 5.4 Methemoglobinemia Articaine hydrochloride and epinephrine injection, USP should not be used in patients with congenital or idiopathic methemoglobinemia, or in patients who are receiving treatment with methemoglobin-inducing agents since they are more susceptible to drug-induced methemoglobinemia. Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia include slate grey cyanosis seen in buccal mucous membranes, lips, and nail beds. In severe cases, symptoms may include central cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrythmia, and shock. Methemoglobinemia should be considered if central cyanosis unresponsive to oxygen therapy occurs, especially if methemoglobin-inducing agents have been used. Calculated oxygen saturation and pulse oximetry are inaccurate in the setting of methemoglobinemia. The diagnosis can be confirmed by an elevated methemoglobin level of at least 10% is present. The development of methemoglobinemia is dose-related. Management of methemoglobinemia: If methemoglobinemia does not respond to administration of oxygen, clinically significant symptoms of methemoglobinemia should be treated with administration of a slow intravenous injection (over 5 minutes) of methylene blue at a dosage of 1-2 mg/kg body weight. 5.5 Anaphylaxis and Allergic-Type Reactions Articaine hydrochloride and epinephrine injection, USP contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.