ORABLOC- articaine hydrochloride and epinephrine bitartrate injection

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ARTICAINE HYDROCHLORIDE (UNII: QS9014Q792) (ARTICAINE - UNII:D3SQ406G9X), EPINEPHRINE BITARTRATE (UNII: 30Q7KI53AK) (EPINEPHRINE - UNII:YKH834O4BH)
Available from:
Pierrel S.p.A.
INN (International Name):
ARTICAINE HYDROCHLORIDE
Composition:
ARTICAINE HYDROCHLORIDE 40 mg in 1 mL
Administration route:
SUBMUCOSAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
ORABLOC 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. ORABLOC 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)] . 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). ORABLOC should be used during pregnancy only if the potential benefit justifies the potentia
Product summary:
ORABLOC® (articaine hydrochloride 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): Both products are 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.
Authorization status:
New Drug Application
Authorization number:
45146-110-01, 45146-110-02, 45146-120-01, 45146-120-02

ORABLOC- articaine hydrochloride and epinephrine bitartrate injection

Pierrel S.p.A.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ORABLOC® safely and effectively. See full

prescribing information for ORABLOC®.

ORABLOC® (articaine HCl and epinephrine) injection, for intraoral submucosal infiltration use

Initial U.S. Approval: 2000

RECENT MAJOR CHANGES

Warnings and Precautions, Methemoglobinemia (5.4) 11/2018

INDICATIONS AND USAGE

ORABLOC 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).

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, ORABLOC containing epinephrine 1:200,000 is preferred. However, when more

pronounced homeostasis or improved visualization of the surgical field are required, ORABLOC 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)

DOSAGE FORMS AND STRENGTHS

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)

CONTRAINDICATIONS

Known hypersensitivity to sulfite (4)

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 ORABLOC can produce effects on the central nervous and cardiovascular

systems. (5.2)

Vasoconstrictor Toxicity: Local anesthetic solutions like ORABLOC 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)

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

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)

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)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 11/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

2.2 Maximum Recommended Dosages

2.3 Dosing in Special Populations

2.4 Important Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Accidental Intravascular Injection

5.2 Systemic Toxicity

5.3 Vasoconstrictor Toxicity

5.4 Methemoglobinemia

5.5 Anaphylaxis and Allergic-Type Reactions

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal and Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

ORABLOC 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.

Sections or subsections omitted from the full prescribing information are not listed.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

Table 1 summarizes the recommended dosages of ORABLOC 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

Orabloc

Injection

Volume

(mL)

Total dose of

articaine HCl

(mg)

Infiltration

0.5 mL to 2.5

20 mg to 100

Nerve

block

0.5 mL to 3.4

20 mg to 136

Oral

surgery

1 mL to 5.1

40 mg to 204

The recommended dosages of ORABLOC 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 ORABLOC 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, ORABLOC containing epinephrine 1:200,000 is preferred.

However, when more pronounced hemostasis or improved visualization of the surgical field are

required, ORABLOC 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 ORABLOC 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 ORABLOC 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 ORABLOC 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 ORABLOC for particulate matter and discoloration prior to administration.

ORABLOC (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 ethyl alcohol that are not of USP grade because they may

contain denaturants that are injurious to rubber. Immersion is not recommended.

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 can 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)

4 CONTRAINDICATIONS

ORABLOC 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)].

5 WARNINGS AND PRECAUTIONS

5.1 Accidental Intravascular Injection

Accidental intravascular injection of ORABLOC 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 ORABLOC 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 ORABLOC 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 ORABLOC 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 ORABLOC can

produce effects on the central nervous and cardiovascular systems.

At blood concentrations achieved with therapeutic doses of ORABLOC, changes in cardiac conduction,

excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However,

toxic blood concentrations of ORABLOC 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. ORABLOC 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

ORABLOC. Repeated doses of ORABLOC 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 dysfunction, and caution should be used in patients

with severe hepatic disease.

5.3 Vasoconstrictor Toxicity

ORABLOC 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. ORABLOC should be used with caution in patients during or 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 ORABLOC 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

ORABLOC 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.

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.

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

Sys tem/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, 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 has been described following use of articaine with epinephrine and has

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.

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:

Clas s

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

8 USE IN SPECIFIC POPULATIONS

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). ORABLOC 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 ORABLOC is excreted in human milk. Because many drugs are excreted in

human milk, caution should be exercised when ORABLOC is administered to a nursing woman. When

using ORABLOC, nursing mothers may choose to pump and discard breast milk for approximately 4

hours (based on plasma half-life) following an injection of ORABLOC (to minimize infant ingestion)

and then resume breastfeeding.

8.4 Pediatric Use

Safety and effectiveness of ORABLOC 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 ORABLOC 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 years, and 11 patients 75 years and over

received another product containing articaine and 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 mL to 11.9 mL) of articaine HCl were

administered safely to 35 patients for simple procedures and doses from 1.05 mg/kg to 4.27 mg/kg (1.3

mL to 6.8 mL) of articaine HCl were administered safely 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 mL to 11.9 mL) of articaine

HCl were administered safely to 7 patients for simple procedures and doses of 1.12 mg/kg to 2.17

mg/kg (1.3 mL to 5.1 mL) of articaine HCl were safely 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

dysfunction [see Warnings and Precautions (5.2)].

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).

11 DESCRIPTION

ORABLOC® (articaine hydrochloride 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:

ORABLOC® 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.

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 ORABLOC. Complete anesthesia lasts approximately 1 hour for infiltrations and

up to approximately 2 hours for nerve block.

Administration of ORABLOC 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 mg and 204 mg doses

are 385 ng/mL and 900 ng/mL, respectively. Following intraoral administration of a near maximum dose

of 476 mg, articaine reaches peak blood concentrations of 2037 ng/mL 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% to 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to evaluate the carcinogenic potential of articaine HCI 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).

14 CLINICAL STUDIES

Another product containing articaine with epinephrine 1:100,000 was studied in three randomized,

double-blind, active-controlled trials to evaluate the effectiveness of articaine 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. Articaine containing epinephrine

1:100,000 was administered by intraoral submucosal infiltration 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 cm-0.4 cm for simple procedures and 0.5 cm-0.6 cm for

complex procedures.

Articaine with epinephrine 1:100,000 was also studied compared to articaine with epinephrine

1:200,000 in four randomized, double-blind, active controlled trials. The first two studies used electric

pulp testers (EPT) to evaluate the success rate (maximum EPT value within 10 minutes), onset, and

duration of articaine containing epinephrine 1:100,000 versus articaine 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 were

not significantly different.

A third study compared the difference in visualization of the surgical field after administration of

articaine containing 1:100,000 epinephrine versus articaine containing 1:200,000 epinephrine during

bilateral maxillary periodontal surgeries in patients ranging from 21 to 65 years old. Articaine

containing 1:100,000 epinephrine 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.

15 REFERENCES

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

1986.

16 HOW SUPPLIED/STORAGE AND HANDLING

ORABLOC® (articaine hydrochloride 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 45146-120-02 (50 cartridges/box)

NDC 45146-120-01 (100 cartridges/box)

Articaine HCl 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL):

NDC 45146-110-02 (50 cartridges/box),

NDC 45146-110-01 (100 cartridges/box)

Both products are 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.

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.

Manufactured in Italy by:

Pierrel S.p.A. - Strada Statale Appia 46/48 - 81043

Capua (CE), Italy

Revised: 11/2018

00710723-02

Package Label - Principal Display Panel – Orabloc® (Articaine Hydrochloride 4% and

Epinephrine 1:100,000) Injection Cartridge Label

Package Label - Principal Display Panel – Orabloc® (Articaine Hydrochloride 4% and

Epinephrine 1:100,000) Injection Carton Label

Package Label - Principal Display Panel – Orabloc® (Articaine Hydrochloride 4% and

Epinephrine 1:200,000) Injection Cartridge Label

Package Label - Principal Display Panel – Orabloc® (Articaine Hydrochloride 4% and

Epinephrine 1:200,000) Injection Carton Label

ORABLOC

articaine hydrochloride and epinephrine bitartrate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:45146 -110

Route of Administration

SUBMUCOSAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ARTICAINE HYDRO CHLO RIDE (UNII: QS9 0 14Q79 2) (ARTICAINE -

UNII:D3SQ40 6 G9 X)

ARTICAINE

HYDROCHLORIDE

40 mg

in 1 mL

EPINEPHRINE BITARTRATE (UNII: 30 Q7KI53AK) (EPINEPHRINE -

UNII:YKH8 34O4BH)

EPINEPHRINE

10 ug in 1 mL

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:45146 -110 -

50 in 1 BOX

0 3/0 1/20 11

1

1.8 mL in 1 CARTRIDGE; Type 0 : No t a Co mbinatio n

Pro duc t

2

NDC:45146 -110 -0 1 10 0 in 1 BOX

0 3/0 1/20 11

2

1.8 mL in 1 CARTRIDGE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 2246 6

0 3/0 1/20 11

ORABLOC

articaine hydrochloride and epinephrine bitartrate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:45146 -120

Route of Administration

SUBMUCOSAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ARTICAINE HYDRO CHLO RIDE (UNII: QS9 0 14Q79 2) (ARTICAINE -

UNII:D3SQ40 6 G9 X)

ARTICAINE

HYDROCHLORIDE

40 mg

in 1 mL

EPINEPHRINE BITARTRATE (UNII: 30 Q7KI53AK) (EPINEPHRINE -

UNII:YKH8 34O4BH)

EPINEPHRINE

5 ug in 1 mL

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:45146 -120 -

50 in 1 BOX

0 3/0 1/20 11

1

1.8 mL in 1 CARTRIDGE; Type 0 : No t a Co mbinatio n

Pro duc t

2

NDC:45146 -120 -0 1 10 0 in 1 BOX

0 3/0 1/20 11

2

1.8 mL in 1 CARTRIDGE; Type 0 : No t a Co mbinatio n

Pro duc t

Pierrel S.p.A.

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 2246 6

0 3/0 1/20 11

Labeler -

Pierrel S.p.A. (458463044)

Revised: 11/2018

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