Articaine

1 INDICATIONS AND USAGE Articaine HCl and Epinephrine is indicated for local, infiltrative, or conductive anesthesia in both simple and complex dental procedures in adults and pediatric patients 4 years of age and older. Articaine HCl and Epinephrine is a combination of articaine HCl, an amide local anesthetic, and epinephrine, a vasoconstrictor, indicated for local, infiltrative, or conductive anesthesia in both simple and complex dental procedures in adults and pediatric patients 4 years of age and older ( 1 ).

12.1 Mechanism of Action Articaine HCl is an amide local anesthetic. Local anesthetics block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of the affected nerve fibers. Epinephrine is a vasoconstrictor added to articaine HCl to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration.

2 DOSAGE AND ADMINISTRATION For dental procedures by intraoral submucosal infiltration or nerve block ( 2.1 ): For infiltration: 0.5 mL-2.5 mL (20 mg-100 mg articaine HCl) ( 2.1 ) For nerve block: 0.5 mL-3.4 mL (20 mg-136 mg articaine HCl) ( 2.1 ) For oral surgery: 1 ml-5.1 mL (40 mg-204 mg articaine HCl) ( 2.1 ) For most routine dental procedures, Articaine HCl and Epinephrine containing epinephrine 1:200,000 is preferred. However, when more pronounced homeostasis or improved visualization of the surgical field are required, Articaine HCl and Epinephrine containing epinephrine 1:100,000 may be used. ( 2.1 ) Maximum recommended dosages ( 2.2 ): Healthy adults: 7 mg/kg of articaine HCl and 0.0017mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000) Pediatric patients 4-16 years: 7 mg/kg of articaine HCl and 0.0017mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000) 2.1 General Dosing Information Table 1 summarizes the recommended dosages of Articaine HCl and Epinephrine administered by intraoral submucosal infiltration or nerve block for various types of anesthetic dental procedures in healthy adults and pediatric patients. Table 1: Recommended Dosages for Both Strengths Procedure Articaine HCl and Epinephrine Injection Volume (mL) Total dose of articaine HCl (mg) Infiltration 0.5 mL to 2.5 mL 20 mg to 100 mg Nerve block 0.5 mL to 3.4 mL 20 mg to 136 mg Oral surgery 1 mL to 5.1 mL 40 mg to 204 mg The recommended dosages of Articaine HCl and Epinephrine in healthy adults serve only as a guide to the amount of anesthetic required for most routine dental procedures. The dosage to be used in adults depend on several factors such as type and extent of surgical procedure, depth of anesthesia, degree of muscular relaxation, and condition of the patient. In all cases, administer the lowest dosage that will produce the desired result. The dosages of Articaine HCl and Epinephrine to be used in pediatric patients aged 4 to 16 years old are determined by the age and weight of the patient and the type of dental procedure. For most routine dental procedures, Articaine HCl and Epinephrine containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, Articaine HCl and Epinephrine containing epinephrine 1:100,000 may be used. The onset of anesthesia and the duration of anesthesia are proportional to the dosage of the local anesthetic used. Exercise caution when employing large volumes because the incidence of adverse reactions may be dose-related. 2.2 Maximum Recommended Dosages Healthy Adults : The maximum dosage of Articaine HCl and Epinephrine is 7 mg/kg of articaine and 0.0017mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and 1:100,000 or 1:200,000 epinephrine). Pediatric Patients Ages 4 to 16 Years : The maximum dosage of Articaine HCl and Epinephrine is 7 mg/kg of articaine and 0.0017mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and 1:100,000 or 1:200,000 epinephrine) [see Use in Specific Populations ( 8.4 )]. 2.3 Dosing in Special Populations Lower dosages or dosage reduction may be required in debilitated patients, acutely ill patients, elderly patients, and pediatric patients commensurate with their age and physical condition. No studies have been performed in patients with renal or liver impairment. Exercise caution when using Articaine HCl and Epinephrine in patients with severe liver disease. [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.4 , 8.5 , and 8.6 )] 2.4 Important Administration Instructions Visually inspect Articaine HCl and Epinephrine for particulate matter and discoloration prior to administration. Articaine HCl and Epinephrine (articaine HCl and epinephr

6 ADVERSE REACTIONS Reactions to articaine are characteristic of those associated with other amide local anesthetics. Adverse reactions to this group of drugs may also result from excessive plasma levels (which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation), injection technique, volume of injection, or hypersensitivity or they may be idiosyncratic. The most common adverse reactions (incidence >2%) are headache and pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Pierrel S.p.A. at 610-989-4213 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The reported adverse events are derived from clinical trials in the United States and the United Kingdom with a similar product containing articaine and epinephrine. Table 2 displays the adverse events reported in clinical trials where 882 individuals were exposed to articaine containing epinephrine 1:100,000. Table 3 displays the adverse events reported in clinical trials where 182 individuals were exposed to articaine containing epinephrine 1:100,000 and 179 individuals were exposed to articaine containing epinephrine 1:200,000. Adverse reactions observed in at least 1% of patients: Table 2: Adverse Reactions in Controlled Trials with an Incidence of 1% or Greater in Patients Administered articaine containing epinephrine 1:100,000 Body System/Reaction articaine containing epinephrine 1:100,000 (N=882) Incidence Body as a whole Face edema 13 (1%) Headache 31 (4%) Infection 10 (1%) Pain 114 (13%) Digestive system Gingivitis 13 (1%) Nervous system Paresthesia 11 (1%) Table 3: Adverse Reactions in Controlled Trials with an Incidence of 1% or Greater in Patients Administered articaine containing epinephrine 1:200,000 and articaine containing epinephrine 1:100,000 Reaction articaine with epinephrine 1:200,000 (N=179) Incidence articaine with epinephrine 1:100,000 (N=182) Incidence Any adverse event 33 (18%) 35 (19%) Pain 11 (6.1%) 14 (7.6%) Headache 9 (5%) 6 (3.2%) Positive blood aspiration into syringe 3 (1.6%) 6 (3.2%) Swelling 3 (1.6%) 5 (2.7%) Trismus 1 (0.3%) 3 (1.6%) Nausea and emesis 3 (1.6%) 0 (0%) Sleepiness 2 (1.1%) 1 (0.5%) Numbness and tingling 1 (0.5%) 2 (1.%) Palpitation 0 (0%) 2 (1.%) Ear symptoms (earache, otitis media) 1 (0.5%) 2 (1.%) Cough, persistent cough 0 (0%) 2 (1.%) Adverse reactions observed in less than 1% of patients: Table 4: Adverse Reactions in Controlled Trials with an Incidence of Less than 1% but Considered Clinically Relevant Body System Events Body as a Whole Asthenia; back pain; injection site pain; burning sensation above injection site; malaise; neck pain Cardiovascular System Hemorrhage; migraine; syncope; tachycardia; elevated blood pressure Digestive System Dyspepsia; glossitis; gum hemorrhage; mouth ulceration; nausea; stomatitis; tongue edemas; tooth disorder; vomiting Hemic and Lymphatic System Ecchymosis; lymphadenopathy Metabolic and Nutritional System Edema; thirst Musculoskeletal System Arthralgia; myalgia; osteomyelitis Nervous System Dizziness; dry mouth; facial paralysis; hyperesthesia; increased salivation; nervousness; neuropathy; paresthesia; somnolence; exacerbation of Kearns-Sayre Syndrome Respiratory System Pharyngitis; rhinitis; sinus pain; sinus congestion Skin and Appendages Pruritus; skin disorder Special Senses Ear pain; taste perversion 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of articaine hydrochloride with epinephrine. Because these reactions are 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. Persistent paresthesias of the lips, tongue

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: Systemic absorption of Articaine HCl and Epinephrine can produce effects on the central nervous and cardiovascular systems. ( 5.2 ) Vasoconstrictor Toxicity : Local anesthetic solutions like Articaine HCl and Epinephrine that contain a vasoconstrictor should be used cautiously, especially in patients with impaired cardiovascular function or vascular disease. ( 5.3 ) Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. ( 5.4 ) 5.1 Accidental Intravascular Injection Accidental intravascular injection of Articaine HCl and Epinephrine 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 HCl and Epinephrine 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 HCl and Epinephrine 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 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. 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 HCl and Epinephrine 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 HCl and Epinephrine can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses of Articaine HCl and Epinephrine, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations of Articaine HCl and Epinephrine 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 HCl and Epinephrine 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 ane

4 CONTRAINDICATIONS Articaine HCl and Epinephrine is contraindicated in patients who are hypersensitive to products containing sulfites. Products containing sulfites may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people [see Warnings and Precautions ( 5.5 )] . Known hypersensitivity to sulfite ( 4 )

10 OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution [see Warnings and Precautions ( 5.1 , 5.2 )] . The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as hypo-ventilation, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation as needed. The adequacy of the circulation should be assessed. Should convulsions persist despite adequate respiratory support, treatment with appropriate anticonvulsant therapy is indicated. The practitioner should be familiar with the use of anticonvulsant drugs, prior to the use of local anesthetics. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor. If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and/or cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. For additional information about overdose treatment, call a poison control center (1-800-222-1222) .