RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

WARNINGS AND PRECAUTIONS, Methemoglobinemia (5.4)

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CLINICAL PHARMACOLOGY SECTION

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 ZORCAINE. Complete anesthesia lasts approximately 1 hour for infiltrations and up to approximately 2 hours for nerve block.

Administration of ZORCAINE 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 γ-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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INDICATIONS & USAGE SECTION

Highlight: Zorcaine® 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)

1 INDICATIONS AND USAGE

Zorcaine® 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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Injection provided in: (3)

• Glass cartridges (single-dose) containing:

- Articaine hydrochloride 4% (40 mg/mL) and epineprhine 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)

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)

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DRUG INTERACTIONS SECTION

Highlight: 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)

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:

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CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

Three randomized, double-blind, active-controlled studies were designed to evaluate effectiveness of ZORCAINE containing epinephrine 1:100,000 as a dental anesthetic. Patients ranging in age from 4 years to over 65 years old underwent simple dental procedures such as single uncomplicated extractions, routine operative procedures, single apical resections, and single crown procedures, or complex dental procedures such as multiple extractions, multiple crowns and/or bridge procedures, multiple apical resections, alveolectomies, muco-gingival operations, and other surgical procedures on the bone. ZORCAINE containing epinephrine 1:100,000 was administered by intraoral submucosal infiltration and/or nerve block for these dental procedures.

Efficacy was measured immediately following the procedure by having the patient and investigator rate the patient’s procedural pain using a 10 cm visual analog scale (VAS), in which a score of zero represented no pain and a score of 10 represented the worst pain imaginable. Mean patient and investigator VAS pain scores were 0.3-0.4 cm for simple procedures and 0.5-0.6 cm for complex procedures.

Four randomized, double-blind, active-controlled studies were performed comparing ZORCAINE containing epinephrine 1:100,000 versus Articaine HCl and Epinephrine containing epinephrine 1:200,000. The first two studies used electric pulp testers (EPT) to evaluate the success rate (maximum EPT value within 10 minutes), onset, and duration of ZORCAINE containing epinephrine 1:100,000 versus Articaine HCl and Epinephrine containing epinephrine 1:200,000 and articaine solution without epinephrine in healthy adults between 18 and 65 years old. Results indicated that the anesthetic characteristics of the 1:100,000 and 1:200,000 formulations are not significantly different.

A third study compared the difference in visualization of the surgical field after administration of ZORCAINE containing epinephrine 1:100,000 versus Articaine HCl and Epinephrine containing epinephrine 1:200,000 during bilateral maxillary periodontal surgeries in patients ranging from 21 to 65 years old. ZORCAINE containing epinephrine 1:100,000 provided better visualization of the surgical field and less blood loss during the procedures. In a fourth study, designed to assess and compare cardiovascular safety, when the maximum dose of each formulation was administered, no clinically relevant differences in blood pressure or heart rate between formulations were observed.

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OVERDOSAGE SECTION

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).

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SPL UNCLASSIFIED SECTION

Manufactured by Novocol Pharmaceutical of Canada, Inc.
Cambridge, Ontario, Canada N1R 6X3

Rev. 08/2019 (2306-3)

Cook-Waite and Zorcaine are trademarks of Septodont Holdings SAS

REFERENCES SECTION

15 REFERENCES

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

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