Articaine Hydrochloride and Epinephrine

WARNINGS AND PRECAUTIONS, Methemoglobinemia ( 5.4 )

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

2 DOSAGE AND ADMINISTRATION • For dental procedures by intraoral submucosal infltration or nerve block ( 2.1 ): - For infltration: 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 Important Dosage 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 Articaine HCl and Epinephrine Injection Procedure 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 dosages 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. 2.2 Maximum Recommended Dosages Healthy Adults: The maximum recommended 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 recommended 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 Dosage in Specific 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 Injection is available in glass cartridges. Prior to using the glass cartridges, disinfect by wiping the cap thoroughly with USP isopropyl alcohol (70%). Avoid use of isopropyl alcohol, as well as solutions of …

3 DOSAGE FORMS AND STRENGTHS Injection (clear, colorless solution), provided in: Glass cartridges (single-dose) containing (less than a full cartridge or more than one cartridge may be used for an individual patient): - Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) - Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) Injection provided in: Glass cartridges (single-dose) containing: - Articaine hydrochloride 4% (40 mg/mL) and epineprhine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) - Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL)

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 )

6 ADVERSE REACTIONS Reactions to articaine are characteristic of those associated with other amide-type 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 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 in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The reported adverse reactions are derived from clinical trials in the United States and the United Kingdom. Table 2 displays the adverse reactions reported in clinical trials where 882 individuals were exposed to Articaine HCl and Epinephrine containing epinephrine 1:100,000. Table 3 displays the adverse reactions reported in clinical trials where 182 individuals were exposed to Articaine HCl and Epinephrine containing epinephrine 1:100,000 and 179 individuals were exposed to Articaine HCl and Epinephrine 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 HCl and Epinephrine containing Epinephrine 1:100,000 Body System/Reaction Articaine HCl and Epinephrine 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 HCl and Epinephrine containing Epinephrine 1:200,000 and Articaine HCl and Epinephrine 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 reaction 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 (0.5%) 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 in Patients Administered Articaine HCl and Epinephrine 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 identifed during post-approval use of articaine hydrochloride with epinephrine. Because these reactions a …

7 DRUG INTERACTIONS The administration of local anesthetic solutions containing epinephrine to patients receiving monoamine oxidase inhibitors, nonselective beta-adrenergic antagonists or tricyclic antidepressants may produce severe, prolonged hypertension. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. 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 ( 5.1 )]. 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: Table 5. Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, procaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Monoamine Oxidase Inhibitors, Nonselective Beta-Adrenergic Antagonists, or Tricyclic Antidepressants: May produce severe, prolonged hypertension ( 7 ) Phenothiazines and Butyrophenones: May reduce or reverse the pressor effect of epinephrine ( 7 )

8 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal studies, may cause fetal harm. ( 8.1 ) Nursing Mothers : Exercise caution when administering to a nursing woman. ( 8.3 ) Pediatric Use : Safety and effectiveness in pediatric patients below the age of 4 years have not been established. ( 8.4 ) 8.1 Pregnancy Teratogenic Effects-Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women with articaine with epinephrine. Articaine hydrochloride and epinephrine (1:100,000) has been shown to increase fetal deaths and skeletal variations in rabbits when given in doses approximately 4 times the maximum recommended human dose (MRHD). Articaine HCl and Epinephrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In embryo-fetal toxicity studies in rabbits, 80 mg/kg, subcutaneously (approximately 4 times the MRHD based on body surface area) caused fetal death and increased fetal skeletal variations, but these effects may be attributable to severe maternal toxicity, including seizures, observed at this dose. In contrast, no embryo-fetal toxicities were observed when articaine and epinephrine (1:100,000) was administered subcutaneously throughout organogenesis at doses up to 40 mg/kg in rabbits and 80 mg/kg in rats (approximately 2 times the MRHD based on body surface area). In pre- and postnatal developmental studies subcutaneous administration of articaine hydrochloride to pregnant rats throughout gestation and lactation, at a dose of 80 mg/kg (approximately 2 times the MRHD based on body surface area) increased the number of stillbirths and adversely affected passive avoidance, a measure of learning, in pups. This dose also produced severe maternal toxicity in some animals. A dose of 40 mg/kg (approximately equal to the MRHD on a mg/m2 basis) did not produce these effects. A similar study using articaine and epinephrine (1:100,000) rather than articaine hydrochloride alone produced maternal toxicity, but no effects on offspring. 8.3 Nursing Mothers It is not known whether Articaine HCl and Epinephrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Articaine HCl and Epinephrine is administered to a nursing woman. When using Articaine HCl and Epinephrine, nursing mothers may choose to pump and discard breast milk for approximately 4 hours (based on plasma half-life) following an injection of Articaine HCl and Epinephrine (to minimize infant ingestion) and then resume breastfeeding. 8.4 Pediatric Use Safety and effectiveness of Articaine HCl and Epinephrine in pediatric patients below the age of 4 years have not been established. Safety of doses greater than 7 mg/kg (0.175 mL/kg) in pediatric patients has not been established. The safety and effectiveness of Articaine HCl and Epinephrine for local, infiltrative, or conductive anesthesia in both simple and complex dental procedures have been established in pediatric patients ages 4 to 16 years old. Safety and effectiveness was established in clinical trials with 61 pediatric patients between the ages of 4 and 16 years administered another product containing articaine hydrochloride 4% and epinephrine 1:100,000 injections. Fifty-one of these patients received doses from 0.76 mg/kg to 5.65 mg/kg (0.9 mL to 5.1 mL) of articaine HCl for simple dental procedures and 10 patients received doses between 0.37 mg/kg and 7.48 mg/kg (0.7 mL to 3.9 mL) of articaine HCl for complex dental procedures. Approximately 13% of these pediatric patients required additional injections of anesthetic for complete anesthesia. Safety of doses greater than 7 mg/kg (0.175 mL/kg) of articaine HCl in pediatric patients has not been established. Dosages in pediatric patients should be reduced, commensurate with age, body weight, and physical condition [ see Dosage and Administration ( 2.2 ) ]. 8.5 Geriatric Use In clinical trials, 54 patients between the ages of 65 and 75 …

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.

11 DESCRIPTION Articaine HCl and Epinephrine Injection, for intraoral submucosal infiltration use, is a sterile, aqueous solution that contains articaine HCl 4% (40mg/mL) and epinephrine bitartrate in an epinephrine 1:200,000 or epinephrine 1:100,000 strength. Articaine HCl is an amino amide local anesthetic, chemically designated as 4-methyl-3-[2-(propylamino)- propionamido]-2-thiophene-carboxylic acid, methyl ester hydrochloride and is a racemic mixture. Articaine HCl has a molecular weight of 320.84 and the following structural formula: Articaine HCl has a partition coefficient in n-octanol/Soerensen buffer (pH 7.35) of 17 and a pKa of 7.8. Epinephrine bitartrate, (-)-1-(3,4-dihydroxyphenyl)-2-methylamino-ethanol (+) tartrate (1:1) salt, is a vasoconstrictor with a concentration of 1:200,000 or 1:100,000 (expressed as free base). It has a molecular weight of 333.3 and the following structural formula: Articaine HCl and Epinephrine contains the following inactive ingredients: sodium chloride (1.0 mg/mL), sodium metabisulfite (0.5 mg/mL), and water for injection. The product is formulated with a 10% overage of epinephrine. The pH is adjusted to 3.6 with hydrochloric acid. Structure Structure2

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 ).

16 HOW SUPPLIED/STORAGE AND HANDLING Articaine HCl and Epinephrine Injection is a clear, colorless solution available in 1.8 mL single-dose glass cartridges, packaged in boxes of 50 and 100 cartridges in the following two strengths (less than a full cartridge or more than one cartridge may be used for an individual patient): • Articaine HCl 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.09 mg/mL): - NDC 43498-993-01 (50 cartridges/box), • Articaine HCl 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL): - NDC 43498-816-01 (50 cartridges/box), Products is formulated with a 10% overage of epinephrine. Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light. Do not freeze.