Flavalta

5 WARNINGS AND PRECAUTIONS Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after injection of FLAVALTA. ( 5.1 ) Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. See full prescribing information for more detail on managing these risks. ( 5.2 ) Allergic-Type Reactions to Sulfites in FLAVALTA and Anaphylactic Reactions: FLAVALTA contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people ( 5.4 ) Risk of Systemic Toxicities with Unintended Intravascular Injection: Unintended intravascular injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Aspirate for blood prior to each dose ( 5.9 ) 5.1 Dose-Related Toxicity The safety and effectiveness of FLAVALTA depends on proper dosage, correct technique, adequate precautions and readiness for emergencies. 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. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Signs and symptoms of depressed cardiovascular function may commonly result from a vasovagal reaction, particularly if the patient is in an upright position: placing the patient in the recumbent position is recommended when an adverse response is noted after injection of a local anesthetic. Vasovagal reactions may elicit a range of clinical manifestations, from prodrome signs of pre-syncope (e.g. lightheadedness, pallor, nausea, sweating, visual disturbances, weakness) to brief loss of consciousness (i.e. syncope). Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use [see Adverse Reactions (6) ] . The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Use the lowest dosage of FLAVALTA that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of FLAVALTA solution and administer fractional (incremental) doses when feasible. Injection of repeated doses of lidocaine may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical status. 5.2 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue FLAVALTA and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.3 Risk of Adverse Reactions Due to Drug Interactions with FLAVALTA Risk of Severe, Persistent Hypertension Due to Drug Interactions Between FLAVALTA and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Administration of FLAVALTA (containing a vasoconstrictor, epinephrine) in patients receiving monoamine oxidase inhibitors (MAOI), or tricyclic antidepressants may result in severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient’s hemodynamic status is essential [see Drug Interactions (7.2) ]. Risk of Severe, Persistent Hypertension or Cerebrovascular Accidents Due to Drug Interactions Between FLAVALTA and Ergot-Type Oxytocic Drugs Concurrent administration of FLAVALTA and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of FLAVALTA concomitantly with ergot-type oxytocic drugs [see Drug Interactions (7.3) ]. Risk of Hypertension and Bradycardia Due to Drug Interactions Between FLAVALTA and Nonselective Beta-Adrenergic Antagonists Administration of FLAVALTA (containing a vasoconstrictor, epinephrine) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient’s blood pressure and heart rate is essential [see Drug Interactions (7.4) ]. 5.4 Allergic-Type Reactions to Sulfites in FLAVALTA FLAVALTA solution contains potassium 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 and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non asthmatic people. 5.5 Risk of Toxicity in Patients with Hepatic Impairment Because amide-type local anesthetics such as lidocaine are metabolized by the liver, consider using reduced dosing and increased monitoring in patients with moderate and severe hepatic impairment who are treated with FLAVALTA, especially with repeat doses [see Uses in Specific Populations (8.6) ]. 5.6 Risk of Use in Patients with Impaired Cardiovascular Function FLAVALTA should also be given in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, heart block) because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by FLAVATA. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.7 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply Use FLAVALTA in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease or hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury (such as exfoliating or ulcerating lesions) or necrosis may result. 5.8 Risk of Adverse Reactions with Use in Head and Neck Area Small doses of local anesthetics injected into the head and neck area for dental treatment may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injection of larger doses. Confusion, convulsions, respiratory depression and/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. Monitor circulation and respiration and constantly observe patients receiving FLAVALTA. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2) ]. 5.9 Risk of Systemic Toxicities with Unintended Intravascular Injection Unintended intravascular injection of FLAVALTA may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Aspirate for blood before all injections of FLAVALTA to avoid intravascular injection. However, a negative aspiration for blood does not ensure against an intravascular injection. 5.10 Risk of Cardiac Arrythmias with Concomitant Use of Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics [see Drug Interactions (7.6) ]. In deciding whether to concurrently use FLAVALTA with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. 5.11 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa Because of the long duration of anesthesia when FLAVALTA is administered, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see Patient Counseling Information (17) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling: Dose-Related Toxicity [see Warnings and Precautions (5.1) ] Methemoglobinemia [see Warnings and Precautions (5.2) ] Severe, Persistent Hypertension, Cerebrovascular Accidents, and Bradycardia Due to Drug Interactions [see Warnings and Precautions (5.3) ] Allergic-Type Reactions [see Warnings and Precautions (5.4) ] Systemic Toxicities with Unintended Intravascular Injection [see Warnings and Precautions (5.9) ] The following adverse reactions from voluntary reports or clinical studies have been reported with lidocaine or lidocaine and epinephrine. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions to FLAVALTA are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. The most commonly encountered acute adverse reactions that demand immediate counter measures were related to the CNS and the cardiovascular system. These adverse reactions were generally dose-related and due to high plasma levels which may have resulted from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of lidocaine, with slow, incomplete, or no recovery. These adverse events have been reported primarily following nerve blocks in the mandible involving the trigeminal nerve and its branches. Nervous System Disorders Adverse reactions were characterized by excitation and/or depression of the central nervous system and included lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. Neurologic effects following administration have included persistent anesthesia, paresthesia, weakness, paralysis, all with slow, incomplete, or no recovery. Convulsions: Incidence varied with the procedure used and the total dose administered. The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Cardiac Disorders: High doses or unintentional intravascular injection have led to high plasma levels of lidocaine and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest [see Warnings and Precautions (5.9) ]. In addition, the beta-adrenergic receptor stimulating action of epinephrine may lead to excitatory cardiovascular responses, such as tachycardia, palpitations, and hypertension. Vasovagal Reactions: dizziness, loss of consciousness, nausea, diaphoresis, syncope, and hypotension. Immune System Disorders Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to sulfites in epinephrine-containing solutions. [see Warnings and Precautions (5.4) ]. There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine. Hematologic Methemoglobinemia [see Warnings and Precautions (5.2) ]. Most common adverse reactions are related to the central nervous system and the cardiovascular system. To report SUSPECTED ADVERSE REACTIONS, contact Septodont at 1-888-888-1441 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.