Oraqix

1 INDICATIONS AND USAGE Oraqix is an amide local anesthetic indicated for adults who require localized anesthesia in periodontal pockets during scaling and/or root planing. Oraqix is an amide local anesthetic indicated for adults who require localized anesthesia in periodontal pockets during scaling and/or root planing. ( 1 )

2 DOSAGE AND ADMINISTRATION Use the included blunt-tipped applicator and the dispenser, which is sold separately, to apply gel to gingival margins and periodontal pockets. ( 2 ) May be reapplied as needed up to a maximum of 5 cartridges per treatment session.( 2 ) 2.1 General Dosing Information DO NOT INJECT [see Warnings and Precautions (5.2) ] Apply Oraqix on the gingival margin around the selected teeth using the blunt-tipped applicator included in the package and the dispenser, which is sold separately. Wait 30 seconds, and then fill the periodontal pockets with Oraqix using the blunt-tipped applicator until the gel becomes visible at the gingival margin. Wait another 30 seconds before starting treatment. A longer waiting time does not enhance the anesthesia. Anesthetic effect, as assessed by probing of pocket depths, has a duration of approximately 20 minutes (individual overall range 14–31 minutes). If the anesthesia starts to wear off, Oraqix may be re-applied if needed. Typically, one cartridge (1.7g) or less of Oraqix will be sufficient for one quadrant of the dentition. When administered, Oraqix should be a liquid. If it has formed a gel, it should be placed in a refrigerator (do not freeze) until it becomes a liquid again. When in the liquid state, the air bubble visible in the cartridge will move if the cartridge is tilted. 2.2 Maximum Recommended Dosage The maximum recommended dose of Oraqix at one treatment session is 5 cartridges, i.e., 8.5g gel.

5 WARNINGS AND PRECAUTIONS Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. ( 5.1 ) DO NOT INJECT ( 5.2 ) Allergic and anaphylactic reactions can occur ( 5.3 ) Avoid contact with eyes ( 5.4 ) Use with caution in patients with severe hepatic disease ( 5.6 ) 5.1 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 ORAQIX 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. 5.2 DO NOT INJECT Oraqix should not be used with standard dental syringes. Only use this product with the Oraqix blunt-tipped applicator and the dispenser which is available from DENTSPLY Pharmaceutical. 5.3 Allergic/anaphylactic reactions Allergic and anaphylactic reactions associated with lidocaine or prilocaine in Oraqix can occur. These reactions may be characterized by urticaria, angioedema, bronchospasm, and shock. If these reactions occur they should be managed by conventional means. 5.4 Avoid Contact with Eyes Oraqix coming in contact with the eye should be avoided because animal studies have demonstrated severe eye irritation. A loss of protective reflexes may allow corneal irritation and potential abrasion. If eye contact occurs, immediately rinse the eye with water or saline and protect it until normal sensation returns. In addition, the patient should be evaluated by an ophthalmologist, as indicated. 5.5 History of Drug Sensitivity Patients allergic to paraminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine and/or prilocaine. However, Oraqix should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain. 5.6 Severe Hepatic Disease Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations of lidocaine and prilocaine.

4 CONTRAINDICATIONS Oraqix is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to any other component of the product. A history of hypersensitivity to local anesthetics of the amide type ( 4 ) A history of hypersensitivity to any component of the product ( 4 )

7 DRUG INTERACTIONS Other local anesthetics or agents structurally related to local anesthetics ( 7.1 ) Drugs That May Cause Methemoglobinemia When Used With ORAQIX ( 7.2 ) 7.1 Other Local Anesthetics or Agents Structurally Related to Local Anesthetics Oraqix should be used with caution in combination with dental injection anesthesia, other local anesthetics, or agents structurally related to local anesthetics, e.g., Class 1 antiarrhythmics such as tocainide and mexiletine, as the toxic effects of these drugs are likely to be additive and potentially synergistic. 7.2 Drugs That May Cause Methemoglobinemia When Used With ORAQIX 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: 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, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sufonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

8.1 Pregnancy Pregnancy Category B .Reproduction studies have been performed in rats with lidocaine, prilocaine and a 1:1 (weight:weight) mixture of the two compounds. There was no evidence of harm to the fetus at subcutaneous doses of up to 30 mg/kg lidocaine (estimated exposure was approximately equivalent to the expected lidocaine exposure at the maximum recommended human dose of Oraqix (lidocaine and prilocaine periodontal gel) 2.5% / 2.5% on a mg/m 2 basis). Following intramuscular prilocaine doses of up to 300 mg/kg (estimated exposure was approximately 11 times the expected prilocaine exposure at the maximum recommended human dose of Oraqix gel on a mg/m 2 basis), there was no evidence of impaired fertility or harm to the fetus. Similarly, subcutaneous administration of a lidocaine and prilocaine mixture of 40 mg/kg of each compound (estimated exposures were approximately 1.5 times the expected lidocaine and prilocaine exposures at the maximum recommended human dose of Oraqix gel on a mg/m 2 basis) produced no teratogenic, embryotoxic, or fetotoxic effects. Reproductive toxicology studies of lidocaine were also conducted in rabbits. There was no evidence of harm to the fetus at a dose of 5 mg/kg, s.c. (60 mg/m 2 ). Treatment of rabbits with 15 mg/kg (180 mg/m 2 ) produced evidence of maternal toxicity and evidence of delayed fetal development, including a non-significant decrease in fetal weight (7%) and an increase in minor skeletal anomalies (skull and sternebral defects, reduced ossification of the phalanges). The effects of lidocaine and prilocaine on post-natal development was examined in rats treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine or prilocaine (60 mg/m 2 and 180 mg/m 2 on a body surface area basis, respectively up to 1.4-fold the maximum recommended exposure for a single procedure). This time period encompassed 3 mating periods. There was no evidence of altered post-natal development in any offspring; however, both doses of either drug reduced the average number of pups per litter surviving until weaning of offspring from the first 2 mating periods. In a separate study, the effect of prilocaine on pre- and postnatal development was examined in rats treated with up to 60 mg/kg, s.c. (up to 2.8 times the maximum recommended human dose of prilocaine in Oraqix gel on a mg/m 2 basis) from Day 6 of gestation to weaning. There was no evidence of altered post-natal development, viability, or reproductive capacity in any offspring. All the above calculations of exposure are assuming 100% bioavailability of lidocaine and prilocaine after Oraqix administration. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Oraqix should be used during pregnancy only if the benefits outweigh the risks. Reproduction studies on the Oraqix drug product, including the inactive ingredients, have not been conducted.

8.3 Nursing Mothers Lidocaine and, possibly, prilocaine are excreted in breast milk. Caution should be exercised when Oraqix is administered to nursing women.

6 ADVERSE REACTIONS Most common adverse reactions (incidence >15%) are application site reactions including pain, soreness, irritation, numbness, ulcerations, vesicles, edema, abscess and/or redness. ( 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 can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice . Although no major differences in adverse events between Oraqix and placebo-treated subjects were observed, all patients in the placebo-controlled studies received either Oraqix or a placebo gel (consisting of the vehicle in Oraqix without lidocaine or prilocaine). Therefore, it is not possible to determine if adverse events in each treatment group were attributable to the inactive ingredients comprising the Oraqix or vehicle or if adverse event rates were higher than expected background rates. Therefore, a causal relationship between the reported adverse reactions and Oraqix could neither be established nor ruled out. Following SRP treatment with Oraqix in 391 patients, the most frequent adverse events were local reactions in the oral cavity (see following table ). These events, which occurred in approximately 15% of patients, included pain, soreness, irritation, numbness, vesicles, ulcerations, edema and/or redness in the treated area. Of the 391 patients treated with Oraqix, five developed ulcerative lesions and two developed vesicles of mild to moderate severity near the site of SRP. In addition, ulcerative lesions in or near the treated area were also reported for three out of 168 patients who received placebo. Other symptoms reported in more than one patient were headache, taste perversion, nausea, fatigue, flu, respiratory infection, musculoskeletal pain and accident/injury. Table 1. Number (percent) of patients with adverse events occurring in more than one patient in any of the treatment groups. Each patient is counted only once per adverse event. The occurrence in a single patient is included in this table if the same symptom has been seen in at least one patient in another group. System Organ Class PreferredTerm Oraqix gel in a cross-over study, 170 subjects received either Oraqix or lidocaine injection 2% in each test period (N=391)n (%) Placebo gel (N=168)n (%) Lidocaine injection (N=170)n (%) Muscular-Skeletal System Disorders Myalgia 1(0) 2(1) Arthralgia and/or Arthropathy 1(0) 1(1) Central & Peripheral Nervous System Disorders Headache 8(2) 3(2) 5(3) Dizziness 1(0) 1(1) 1(1) Special Senses Other, Disorders Taste Perversion includes complaints of bad or bitter taste lasting for up to 4 hours after administration of Oraqix 8(2) 1(1) Gastro-Intestinal System Disorders Nausea 3(1) 1(1) Respiratory System Disorders Respiratory Infection 2(1) 1(1) Rhinitis 2(1) Body as a whole-General Disorders Accident and/or Injury 2(1) 2(1) Fatigue 3(1) 2(1) Flu-Like Disorder 2(1) Pain (remote from application site) 1(0) 1(1) 1(1) Application Site Disorders i.e. symptoms in the oral cavity Anesthesia Local 2(1) Application Site Reaction includes pain, soreness, irritation, numbness, ulcerations, vesicles, edema, abscess and/or redness in the treated area 52(13) 20(12)