Lidocaine Hydrochloride and Epinephrine

FLAVALTA solution is indicated for the production of local anesthesia for dental procedures by nerve block or infiltration techniques [see Dosage and Administration (2.2) ]. FLAVALTA solution is a combination of lidocaine, an amide local anesthetic, and epinephrine, an alpha and beta adrenergic agonist indicated for the production of local anesthesia for dental procedures by nerve block or infiltration techniques.

Injection: lidocaine hydrochloride 2% (34 mg/1.7 mL) (20 mg/mL) and epinephrine 1:100,000 (0.017 mg/1.7 mL) (0.01 mg/mL) as a clear, colorless solution in single-dose glass cartridges Injection: lidocaine hydrochloride 2% (34 mg/1.7 mL) (20 mg/mL) and epinephrine 1:100,000 (0.017 mg/1.7 mL) (0.01 mg/mL) as a clear, colorless solution in single-dose glass cartridges

FLAVALTA is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to any components of the injectable formulations. Known history of hypersensitivity to lidocaine or to any local anesthetics of the amide-type or to other components of FLAVALTA ( 4 )

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. […]

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.

Local Anesthetics: The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. ( 7.1 ) Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: Administration of FLAVALTA, which contains epinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. ( 5.3 , 7.2 ) Ergot-Type Oxytocic Drugs: Concurrent administration FLAVALTA, which contains epinephrine, and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. ( 5.3 , 7.3 ) Nonselective Beta-Adrenergic Antagonists: Administration of FLAVALTA (containing a vasoconstrictor, epinephrine), in patients receiving nonselective beta-adrenergic antagonist may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided ( 5.3 , 7.4 ). Drugs Associated with Methemoglobinemia: Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs. ( 7.5 ) 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. ( 5.10 , 7.6)

7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with FLAVALTA cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ].

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The administration of local anesthetic solutions containing epinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential [see Warnings and Precautions (5.3) ].

7.3 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 Warnings and Precautions (5.3) ].

7.4 Nonselective Beta-Adrenergic Antagonists Administration of FLAVALTA solution (containing a vasoconstrictor, epinephrine), in patients receiving a nonselective beta-adrenergic antagonist may result in dose-dependent hypertension and bradycardia with possible heart block. 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 Warnings and Precautions (5.3) ].

7.5 Drugs Associated with Methemoglobinemia Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.2) ]. Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing epinephrine are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.10) ] .

7.7 Phenothiazines and Butyrophenones Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of FLAVALTA and these agents should generally be avoided. In situation when concurrent therapy is necessary, careful patient monitoring is essential.

Pediatric Use: Dosages in pediatric population should be reduced, commensurate with body weight and physical condition. ( 8.4 ) Geriatric Use: Elderly patients should be given reduced doses commensurate with their age and physical condition ( 8.5 ) Hepatic Impairment: Consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment ( 8.6 )

8.1 Pregnancy Risk Summary Available published data and decades of clinical use with lidocaine in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function (see Clinical Considerations ). In published reproduction studies, performed in rats, lower fetal body weights were reported when dosed up to 9.7 times the maximum recommended daily dose during the period of organogenesis and developmental delays in neonates when dosed 0.1 times the maximum recommended daily dose on Gestation Day 11 (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal Adverse Reactions During treatment of systemic toxicity, which may appear as maternal hypotension or fetal bradycardia, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Data Animal Data Reproduction studies with lidocaine have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine. In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 9.7 times the maximum daily dose [MDD] of 500 mg on a mg/m2 basis) in the absence of maternal toxicity. In a published study, lidocaine containing 1:100,000 epinephrine at a dose of 6 mg/kg (approximately 0.1 times the MDD for lidocaine on a mg/m2 basis) injected into the masseter muscle of the jaw or into the gum of the lower jaw of pregnant Long-Evans hooded rats on Gestation Day 11 resulted in developmental delays in the neonates. Developmental delays were observed for negative geotaxis, static righting reflex, visual discrimination response, sensitivity and response to thermal and electrical shock stimuli, and water maze acquisition. The developmental delays of the neonatal animals were transient, with responses becoming comparable to untreated animals later in life. The clinical relevance of these animal data is uncertain.

8.2 Lactation Risk Summary Published data report the presence of lidocaine and its metabolites in human milk in low amounts, along with poor oral bioavailability. There are no data on the effect of lidocaine on the breastfed infant or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLAVALTA and any potential adverse effects on the breastfed child from FLAVALTA or from the underlying maternal condition.

8.4 Pediatric Use Dosages in pediatric population should be reduced, commensurate with body weight and physical condition [see Dosage and Administration (2.2) ] .

8.5 Geriatric Use Elderly patients should be given reduced doses commensurate with their age and physical condition.

8.6 Hepatic Impairment Amide-type local anesthetics such as lidocaine are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with FLAVALTA, especially with repeat doses [see Warnings and Precautions (5.5) ]