Articaine Hydrochloride and Epinephrine Bitartrate

SEPTOCAINE 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. SEPTOCAINE 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 or older.

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% (68 mg/1.7mL) (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) – Articaine hydrochloride 4% (68 mg/1.7mL) (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% (68 mg/1.7mL) (40 mg/mL) and epineprhine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) ( 3 ) – Articaine hydrochloride 4% (68 mg/1.7mL) (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) ( 3 )

SEPTOCAINE 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 )

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 SEPTOCAINE can produce effects on the central nervous and cardiovascular systems. ( 5.2 ) Vasoconstrictor Toxicity: Local anesthetic solutions like SEPTOCAINE 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 SEPTOCAINE 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 SEPTOCAINE 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 SEPTOCAINE 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 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 SEPTOCAINE 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 SEPTOCAINE can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses of SEPTOCAINE, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations of SEPTOCAINE 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. SEPTOCAINE 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 anesthetic injection of SEPTOCAINE. Repeated doses of SEPTOCAINE may cause significant increases in blood levels because of possible accumulation of the drug or its metabolites. The lowest dosage that results in effective anesthesia should be used to decrease the risk of high plasma levels and serious adverse effects. Tolerance to elevated blood levels varies with the status of the patient. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. Precautions for epinephrine administration, discussed in Section 5.3, should be observed. Debilitated patients, elderly patients, acutely ill patients, and pediatric patients should be given reduced doses commensurate with their age and physical condition [see Dosage and Administration (2.1 , 2.3) ]. No studies have been performed in patients with liver impairment, and caution should be used in patients with severe hepatic disease.

5.3 Vasoconstrictor Toxicity SEPTOCAINE contains epinephrine, a vasoconstrictor that can cause local or systemic toxicity and should be used cautiously. Local toxicity may include ischemic injury or necrosis, which may be related to vascular spasm. SEPTOCAINE should be used with caution in patients during and following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. The American Heart Association has made the following recommendation regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: "Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used." (Kaplan, 1986). It is essential to aspirate before any injection to avoid administration of the drug into the blood stream.

5.4 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 SEPTOCAINE 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.

5.5 Anaphylaxis and Allergic-Type Reactions SEPTOCAINE contains sodium 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. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

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 Septodont at 1-800-872-8305 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 SEPTOCAINE containing epinephrine 1:100,000. Table 3 displays the adverse reactions reported in clinical trials where 182 individuals were exposed to SEPTOCAINE containing epinephrine 1:100,000 and 179 individuals were exposed to SEPTOCAINE 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 SEPTOCAINE containing Epinephrine 1:100,000 Body System/Reaction SEPTOCAINE 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 Septocaine containing Epinephrine 1:200,000 and Septocaine containing Epinephrine 1:100,000 Reaction SEPTOCAINE with epinephrine 1:200,000 (N=179) Incidence SEPTOCAINE 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 SEPTOCAINE 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 SEPTOCAINE. 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 casual 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.

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 )

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 SEPTOCAINE. 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). SEPTOCAINE 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 SEPTOCAINE is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SEPTOCAINE is administered to a nursing woman. When using SEPTOCAINE, nursing mothers may choose to pump and discard breast milk for approximately 4 hours (based on plasma half life) following an injection of SEPTOCAINE (to minimize infant ingestion) and then resume breastfeeding.

8.4 Pediatric Use Safety and effectiveness of SEPTOCAINE 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 SEPTOCAINE 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 SEPTOCAINE 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/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) ].

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.