Oraqix (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either lidocaine or prilocaine. Chronic oral toxicity studies of o-toluidine, a metabolite of prilocaine, have shown that this compound is a carcinogen in both mice and rats. The tumors associated with o-toluidine included hepatocarcinomas/adenomas in female mice, multiple occurrences of hemangiosarcomas/hemangiomas in both sexes of mice, sarcomas of multiple organs, transitional-cell carcinomas/papillomas of urinary bladder in both sexes of rats, subcutaneous fibromas/fibrosarcomas and mesotheliomas in male rats, and mammary gland fibroadenomas/adenomas in female rats. These findings were observed at the lowest tested dose of 150 mg/kg/day or greater over two years (estimated daily exposures in mice and rats were approximately 6 and 12 times, respectively, the estimated exposure to o-toluidine at the maximum recommended human dose of 8.5g of Oraqix gel on a mg/m2 basis). Thus, the no effect dose is less than 6 to 12 times the estimated exposure to o-toluidine at the maximum recommended human dose, assuming 100% bioavailability of prilocaine from the Oraqix gel. Complete conversion of prilocaine to its metabolite o-toluidine on a molar basis is assumed. This gives a conversion on a weight basis of about 50% for prilocaine base (dependent on the molecular weights, i.e. 220 for prilocaine base and 107 for o-toluidine).

Mutagenesis — The mutagenic potentials of lidocaine and prilocaine have been tested in the Ames Salmonella reverse mutation assay, an in vitro chromosome aberrations assay in human lymphocytes and in an in vivo mouse micronucleus assay. There was no indication of any mutagenic effects for either compound in these studies. o-Toluidine, metabolite of prilocaine, was positive in Escherichia coli DNA repair and phage-induction assays. Urine concentrates from rats treated orally with 300 mg/kg o-toluidine were mutagenic to Salmonella typhimurium in the presence of metabolic activation. Several other tests on o-toluidine, including reverse mutations in five different Salmonella typhimurium strains with or without metabolic activation, and single strand breaks in DNA of V79 Chinese hamster cells, were negative.

Impairment of Fertility: The effect of lidocaine on fertility was examined in the rat model. Administration of 30 mg/kg, s.c. (180 mg/m2 or 1.4-fold the maximum recommended human oral dose for one treatment session assuming 100% bioavailability of lidocaine) to the mating pair did not produce alterations in fertility or general reproductive performance of rats. There are no studies that examine the effect of lidocaine or prilocaine on sperm parameters. The effects of prilocaine on fertility was examined in rats treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine or prilocaine (60 mg/m2 and 180 mg/m2 on a body surface area basis, respectively up to 1.4-fold the maximum recommended exposure for a single procedure assuming 100% bioavailability of lidocaine and prilocaine). This time period encompassed 3 mating periods. There was no evidence of altered fertility.

14 CLINICAL STUDIES

A total of 337 patients (146 men and 191 women; 169 Oraqix and 168 placebo) were studied in three randomized, double-blind, placebo-controlled trials. Patients received a median dose of approximately 1 cartridge (1.7g gel), ranging from ¼ to 2½ cartridges per quadrant treated. The analgesic effect of Oraqix was assessed by asking patients to rate their pain on a continuous visual analog scale (VAS) from 0 (no pain) to 100 mm (worst pain imaginable). Patients were asked to report overall procedural pain 5 minutes following manual scaling and/or root planing (SRP) in a single quadrant that had been pre-treated with Oraqix or placebo (vehicle only, without lidocaine or prilocaine). In all three studies, patients were given Oraqix or placebo (vehicle only, without lidocaine or prilocaine). In all three studies, patients who were given Oraqix reported lower VAS scores during the procedure than those given placebo. Study B3 recruited patients with a known sensitivity to mechanical probing of dental pockets, whereas in studies B1 and B2, this was not a requirement. Results of B1, B2 and B3 are summarized below.

Table 2. Visual Analog Pain Scale (100 mm scale)
Visual Analog Pain Scale
Study(No. of patients) OraqixMedian VAS PlaceboMedian VAS
*
p<0.05
B1 (n=122)* 7 17
B2 (n=130)* 5 13
B3 (n=85)* 11 27

The trial also compared individual patient estimates of pain on a 5-step categorical Verbal Rating Scale (VRS) which included the following categories: no pain, mild pain, moderate pain, severe pain, and very severe pain. The results of those who reported no pain or mild pain are shown in the test table.

Table 3. Verbal Rating Scale
Number of Patients Reporting “no pain” or “mild pain” during SRP
Study(No. of patients) OraqixMedian VAS PlaceboMedian VAS
*
p<0.05 in the statistical test of the full five categorical scale
B1 (n=122)* 57 (90%) 38 (64%)
B2 (n=130)* 49 (78%) 51 (76%)
B3 (n=85)* 30 (70%) 20 (48%)

16 HOW SUPPLIED/STORAGE AND HANDLING

Oraqix (lidocaine and prilocaine periodontal gel), 2.5%/2.5%, is supplied in dental cartridges that provide 1.7g gel. Individually blister-packaged cartridges of Oraqix are distributed in a carton of 20 (NDC 66312-110-20). Each individual blister package also contains a sterile blunt-tipped applicator. Each blunt-tipped applicator is for single use only. Oraqix is intended for use with the Oraqix Dispenser.

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]. [See USP Controlled Room Temperature.] At temperatures below +5°C Oraqix may become opaque. This opacity will disappear when the cartridge is warmed to room temperature.

DO NOT FREEZE. Some components of Oraqix may precipitate if cartridges are frozen. Cartridges should not be used if they contain a precipitate.

Do not use dental cartridge warmers with Oraqix. The heat will cause the product to gel.

See FDA-approved patient labeling (Patient Information)

17 PATIENT COUNSELING INFORMATION

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.

Patients should be cautioned to avoid injury to the treated area, or exposure to extreme hot or cold temperatures, until complete sensation has returned.

Manufactured for:
Dentsply PharmaceuticalYork, PA 17404

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