Articadent

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 DENTSPLY Pharmaceutical at 1-800-989-8826 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 ARTICADENT containing epinephrine 1:100,000. Table 3 displays the adverse reactions reported in clinical trials where 182 individuals were exposed to ARTICADENT containing epinephrine 1:100,000 and 179 individuals were exposed to ARTICADENT 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 ARTICADENT containing Epinephrine 1:100,000 Body System/Reaction ARTICADENT 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 ARTICADENT containing Epinephrine 1:200,000 and ARTICADENT containing Epinephrine 1:100,000 Reaction ARTICADENT with epinephrine 1:200,000 (N=179) Incidence ARTICADENT 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 ARTICADENT Body System Reactions 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 postapproval use of ARTICADENT. 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, and oral tissues have been reported with use of articaine hydrochloride, with slow, incomplete, or no recovery. These postmarketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches. Hypoesthesia has been reported with use of articaine, especially in pediatric age groups, which is usually reversible. Prolonged numbness can result in soft tissue injuries such as that of the lips and tongue in these age groups. Ischemic injury and necrosis have been described following use of articaine with epinephrine and have been postulated to be due to vascular spasm of terminal arterial branches. Paralysis of ocular muscles has been reported, especially after posterior, superior alveolar injections of articaine during dental anesthesia. Symptoms include diplopia, mydriasis, ptosis, and difficulty in abduction of the affected eye. These symptoms have been described as developing immediately after injection of the anesthetic solution and persisting one minute to several hours, with generally complete recovery.

4 CONTRAINDICATIONS ARTICADENT 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 )

11 DESCRIPTION ARTICADENT (articaine hydrochloride and epinephrine injection), for intraoral submucosal infiltration use, is a sterile, aqueous solution that contains articaine HCl 4% (40 mg/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: ARTICADENT contains the following inactive ingredients: sodium chloride (1.6 mg/mL), and sodium metabisulfite (0.5 mg/mL). The product is formulated with a 15% overage of epinephrine. The pH is adjusted with sodium hydroxide. Chemical Structure Chemical Structure

2 DOSAGE AND ADMINISTRATION For dental procedures by intraoral submucosal infiltration or nerve block. ( 2.1 ) - For infiltration: 0.5-2.5 mL (20-100 mg articaine HCl) - For nerve block: 0.5-3.4 mL (20-136 mg articaine HCl) - For oral surgery: 1.0-5.1 mL (40-204 mg articaine HCl) For most routine dental procedures, ARTICADENT containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, ARTICADENT containing epinephrine 1:100,000 may be used. ( 2.1 ) Maximum recommended dosages ( 2.2 ): - Healthy adults : 7 mg/kg of articaine HCl and 0.0017 mg/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 0.0017 mg/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 ARTICADENT 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 ARTICADENT 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 ARTICADENT 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 ARTICADENT 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, ARTICADENT containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, ARTICADENT 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 recommended dosage of ARTICADENT is 7 mg/kg of articaine and 0.0017 mg/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 ARTICADENT is 7 mg/kg of articaine and 0.0017 mg/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 ARTICADENT 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 ARTICADENT for particulate matter and discoloration prior to administration. Prior to using the glass cartridges, disinfect by wiping the cap thoroughly with USP grade isopropyl alcohol (70%). Avoid use of isopropyl alcohol, as well as solutions of ethyl alcohol that are not of USP grade because they may contain denaturants that are injurious to rubber. Immersion is not recommended. Discard unused portion.

1 INDICATIONS AND USAGE ARTICADENT 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. ARTICADENT 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.

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).

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 be avoided; however, in situations when concurrent therapy is necessary, careful patient monitoring is essential [see Warnings and Precautions (5.2) ]. 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, procaine, ropivacaine, 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 )

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Clinically, the order of loss of nerve function is as follows: (1) pain; (2) temperature; (3) touch; (4) proprioception; and (5) skeletal muscle tone. The onset of anesthesia has been shown to be within 1 to 9 minutes of injection of ARTICADENT. Complete anesthesia lasts approximately 1 hour for infiltrations and up to approximately 2 hours for nerve block. Administration of ARTICADENT results in a 3- to 5-fold increase in plasma epinephrine concentrations compared to baseline; however, in healthy adults it does not appear to be associated with marked increases in blood pressure or heart rate, except in the case of accidental intravascular injection [see Warnings and Precautions (5.1) ]. 12.3 Pharmacokinetics Absorption: Following dental injection by the submucosal route of an articaine solution containing epinephrine 1:200,000, articaine reaches peak blood concentration about 25 minutes after a single dose injection and 48 minutes after three doses. Peak plasma levels of articaine achieved after 68 and 204 mg doses are 385 and 900 ng/mL, respectively. Following intraoral administration of a near maximum dose of 476 mg, articaine reaches peak blood concentrations of 2037 and 2145 ng/mL for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively, approximately 22 minutes post-dose. Distribution: Approximately 60 to 80% of articaine HCl is bound to human serum albumin and y-globulins at 37°C in vitro. Elimination: Metabolism: Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid. Excretion: At the dose of 476 mg of articaine, the elimination half-life was 43.8 minutes and 44.4 minutes for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively. Articaine is excreted primarily through urine with 53-57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. A minor metabolite, articainic acid glucuronide, is also excreted in urine. Articaine constitutes only 2% of the total dose excreted in urine.

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.

12.2 Pharmacodynamics Clinically, the order of loss of nerve function is as follows: (1) pain; (2) temperature; (3) touch; (4) proprioception; and (5) skeletal muscle tone. The onset of anesthesia has been shown to be within 1 to 9 minutes of injection of ARTICADENT. Complete anesthesia lasts approximately 1 hour for infiltrations and up to approximately 2 hours for nerve block. Administration of ARTICADENT results in a 3- to 5-fold increase in plasma epinephrine concentrations compared to baseline; however, in healthy adults it does not appear to be associated with marked increases in blood pressure or heart rate, except in the case of accidental intravascular injection [see Warnings and Precautions (5.1) ].

12.3 Pharmacokinetics Absorption: Following dental injection by the submucosal route of an articaine solution containing epinephrine 1:200,000, articaine reaches peak blood concentration about 25 minutes after a single dose injection and 48 minutes after three doses. Peak plasma levels of articaine achieved after 68 and 204 mg doses are 385 and 900 ng/mL, respectively. Following intraoral administration of a near maximum dose of 476 mg, articaine reaches peak blood concentrations of 2037 and 2145 ng/mL for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively, approximately 22 minutes post-dose. Distribution: Approximately 60 to 80% of articaine HCl is bound to human serum albumin and y-globulins at 37°C in vitro. Elimination: Metabolism: Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid. Excretion: At the dose of 476 mg of articaine, the elimination half-life was 43.8 minutes and 44.4 minutes for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively. Articaine is excreted primarily through urine with 53-57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. A minor metabolite, articainic acid glucuronide, is also excreted in urine. Articaine constitutes only 2% of the total dose excreted in urine.

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8

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 epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) ( 3 ) - Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) ( 3 )

Articadent Articaine hydrochloride and Epinephrine Bitartrate ARTICAINE HYDROCHLORIDE ARTICAINE EPINEPHRINE BITARTRATE EPINEPHRINE SODIUM CHLORIDE SODIUM METABISULFITE WATER SODIUM HYDROXIDE Articadent Articaine hydrochloride and Epinephrine Bitartrate ARTICAINE HYDROCHLORIDE ARTICAINE EPINEPHRINE BITARTRATE EPINEPHRINE SODIUM CHLORIDE SODIUM METABISULFITE WATER SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies to evaluate the carcinogenic potential of articaine HCl in animals have not been conducted. Five standard mutagenicity tests, including three in vitro tests (the nonmammalian Ames test, the mammalian Chinese hamster ovary chromosomal aberration test, and a mammalian gene mutation test with articaine HCl) and two in vivo mouse micronucleus tests (one with articaine and epinephrine 1:100,000 and one with articaine HCl alone) showed no mutagenic effects. No effects on male or female fertility were observed in rats for articaine and epinephrine 1:100,000 administered subcutaneously in doses up to 80 mg/kg/day (approximately 2 times the MRHD based on body surface area).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies to evaluate the carcinogenic potential of articaine HCl in animals have not been conducted. Five standard mutagenicity tests, including three in vitro tests (the nonmammalian Ames test, the mammalian Chinese hamster ovary chromosomal aberration test, and a mammalian gene mutation test with articaine HCl) and two in vivo mouse micronucleus tests (one with articaine and epinephrine 1:100,000 and one with articaine HCl alone) showed no mutagenic effects. No effects on male or female fertility were observed in rats for articaine and epinephrine 1:100,000 administered subcutaneously in doses up to 80 mg/kg/day (approximately 2 times the MRHD based on body surface area).

NDA020971

Articadent

Articaine hydrochloride and Epinephrine Bitartrate

66312-601

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL - 1.7 mL Cartridge Carton - epinephrine 1:100,000 Dentsply Sirona NDC 66312-601-16 Reorder #: 51116 Articadent ® DENTAL (articaine HCl and epinephrine) Injection Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 Intraoral Submucosal Injection Contains sodium metabisulfite 50 Single-Dose Cartridges, 1.7 mL each Sterile aqueous Solution for Injection Rx only PRINCIPAL DISPLAY PANEL - 1.7 mL Cartridge Carton - epinephrine 1:100,000

WARNINGS AND PRECAUTIONS, Methemoglobinemia ( 5.4 )

Manufactured for Dentsply Pharmaceutical York, PA 17404 By Novocol Pharmaceutical of Canada, Inc. Cambridge, Ontario, Canada N1R 6X3 Rev 07/2019 (2639-7)

17 PATIENT COUNSELING INFORMATION Loss of Sensation and Muscle Function : Inform patients in advance of the possibility of temporary loss of sensation and muscle function following infiltration and nerve block injections [see Adverse Reactions (6.2) ] . Instruct patients not to eat or drink until normal sensation returns. Methemoglobinemia : Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

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 ARTICADENT containing epinephrine 1:100,000. Table 3 displays the adverse reactions reported in clinical trials where 182 individuals were exposed to ARTICADENT containing epinephrine 1:100,000 and 179 individuals were exposed to ARTICADENT 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 ARTICADENT containing Epinephrine 1:100,000 Body System/Reaction ARTICADENT 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 ARTICADENT containing Epinephrine 1:200,000 and ARTICADENT containing Epinephrine 1:100,000 Reaction ARTICADENT with epinephrine 1:200,000 (N=179) Incidence ARTICADENT 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 ARTICADENT Body System Reactions 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

15 REFERENCES Kaplan, EL, editor. Cardiovascular disease in dental practice. Dallas; American Heart Association; 1986.

8.5 Geriatric Use In clinical trials, 54 patients between the ages of 65 and 75 years, and 11 patients 75 years and over received ARTICADENT containing epinephrine 1:100,000. Among all patients between 65 and 75 years, doses from 0.43 mg/kg to 4.76 mg/kg (0.9 to 11.9 mL) were administered to 35 patients for simple procedures and doses from 1.05 mg/kg to 4.27 mg/kg (1.3 to 6.8 mL) were administered to 19 patients for complex procedures. Among the 11 patients ≥ 75 years old, doses from 0.78 mg/kg to 4.76 mg/kg (1.3 to 11.9 mL) were administered to 7 patients for simple procedures and doses of 1.12 mg/kg to 2.17 mg/kg (1.3 to 5.1 mL) were administered to 4 patients for complex procedures. Approximately 6% of patients between the ages of 65 and 75 years and none of the 11 patients 75 years of age or older required additional injections of anesthetic for complete anesthesia compared with 11% of patients between 17 and 65 years old who required additional injections. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.3 Nursing Mothers It is not known whether ARTICADENT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARTICADENT is administered to a nursing woman. When using ARTICADENT, nursing mothers may choose to pump and discard breast milk for approximately 4 hours (based on plasma half-life) following an injection of ARTICADENT (to minimize infant ingestion) and then resume breastfeeding.

8.4 Pediatric Use Safety and effectiveness of ARTICADENT 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 ARTICADENT 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 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 to 5.1 mL) for simple dental procedures and 10 patients received doses between 0.37 mg/kg and 7.48 mg/kg (0.7 to 3.9 mL) for complex dental procedures. Approximately 13% of these pediatric patients required additional injections of anesthetic for complete anesthesia. Dosages in pediatric patients should be reduced, commensurate with age, body weight, and physical condition [see Dosage and Administration (2.2) ].

8.1 Pregnancy Teratogenic Effects - Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women with ARTICADENT. 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). ARTICADENT 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/m 2 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.

Teratogenic Effects - Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women with ARTICADENT. 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). ARTICADENT 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/m 2 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 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 ARTICADENT. 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). ARTICADENT 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/m 2 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 ARTICADENT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARTICADENT is administered to a nursing woman. When using ARTICADENT, nursing mothers may choose to pump and discard breast milk for approximately 4 hours (based on plasma half-life) following an injection of ARTICADENT (to minimize infant ingestion) and then resume breastfeeding. 8.4 Pediatric Use Safety and effectiveness of ARTICADENT 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 ARTICADENT 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 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 to 5.1 mL) for simple dental procedures and 10 patients received doses between 0.37 mg/kg and 7.48 mg/kg (0.7 to 3.9 mL) for complex dental procedures. Approximately 13% of these pediatric patients required additional injections of anesthetic for complete anesthesia. 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 years, and 11 patients 75 years and over received ARTICADENT containing epinephrine 1:100,000. Among all patients between 65 and 75 years, doses from 0.43 mg/kg to 4.76 mg/kg (0.9 to 11.9 mL) were administered to 35 patients for simple procedures and doses from 1.05 mg/kg to 4.27 mg/kg (1.3 to 6.8 mL) were administered to 19 patients for complex procedures. Among the 11 patients ≥ 75 years old, doses from 0.78 mg/kg to 4.76 mg/kg (1.3 to 11.9 mL) were administered to 7 patients for simple procedures and doses of 1.12 mg/kg to 2.17 mg/kg (1.3 to 5.1 mL) were administered to 4 patients for complex procedures. Approximately 6% of patients between the ages of 65 and 75 years and none of the 11 patients 75 years of age or older required additional injections of anesthetic for complete anesthesia compared with 11% of patients between 17 and 65 years old who required additional injections. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal and Hepatic Impairment No studies have been performed with articaine hydrochloride 4% and epinephrine 1:200,000 injection or articaine hydrochloride 4% and epinephrine 1:100,000 injection in patients with renal or hepatic impairment [see Warnings and Precautions (5.2) ].

16 HOW SUPPLIED/STORAGE AND HANDLING ARTICADENT (articaine hydrochloride and epinephrine) injection is a clear, colorless solution available in 1.7 mL single-dose glass cartridges, packaged in boxes of 50 cartridges in the following two strengths (less than a full cartridge or more than one cartridge may be used for an individual patient): ARTICADENT containing articaine HCl 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) (NDC 66312-602-16) ARTICADENT containing articaine HCl 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) (NDC 66312-601-16) Storage and Handling Store at controlled room temperature 25°C (77°F) with brief excursions permitted between 15° and 30°C (59°F-86°F) [see USP Controlled Room Temperature]. Protect from light. Do Not Freeze.

Storage and Handling Store at controlled room temperature 25°C (77°F) with brief excursions permitted between 15° and 30°C (59°F-86°F) [see USP Controlled Room Temperature]. Protect from light. Do Not Freeze.