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/m2 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/m2 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/m2 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/m2). Treatment of rabbits with 15 mg/kg (180 mg/m2) 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/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). 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/m2 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.

Absorption: Lidocaine and prilocaine are absorbed from Oraqix via the oral mucous membranes. After a single application of 0.9 to 3.5 g Oraqix, the mean (±SD) lidocaine and prilocaine Cmax values were 182 (±53) and 77 (±27) ng/mL, respectively. After a total of 8 to 8.5 g Oraqix administered as repeated applications over 3 hours, the mean (±SD) lidocaine Cmax was 284 (±122) ng/mL, ranging between 157 and 552 ng/mL. The mean lidocaine AUC∞ was 84,000 ng/min/mL. The mean (±SD) prilocaine Cmax was 106 (±45) ng/mL, ranging between 53 and 181 ng/mL. The mean prilocaine AUC∞ was 26,000 ng/min/mL.

The increase in Cmax of both lidocaine and prilocaine is proportional (or less than proportional) to the dose after single application of Oraqix. The Cmax after a cumulative dose of 8.5 g Oraqix administered as repeated applications over 3 hours, (i.e. the highest recommended dose, corresponding to 212.5 mg each of lidocaine and prilocaine base), is lower than that extrapolated from the proportional increase in plasma concentrations at lower doses.

The median Tmax of lidocaine and prilocaine was 30 minutes, ranging between 20 and 40 min., after the start of a single application of 0.9 to 3.5 g Oraqix, and 200 minutes, ranging between 120 and 200 min., after a cumulative dose of 8.5 g Oraqix administered as repeated applications over 3 hours.

The toxicities of lidocaine and prilocaine are thought to be additive. Systemic CNS toxicity may occur over a range of plasma concentrations of local anesthetics. CNS toxicity may typically be found around 5000 ng/mL of lidocaine, however a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL. Pharmacological thresholds for prilocaine are poorly defined.

Distribution: Lidocaine and prilocaine have an intermediate degree of plasma protein binding, mainly to 1-acid glycoprotein, with a protein binding of 70% and 40%, respectively. When administered intravenously, the mean volume of distribution (for 60 kg person) at steady state for lidocaine and prilocaine were 90 L and 156 L, respectively. Oraqix is not intended for intravenous administration. Both lidocaine and prilocaine cross the placental and blood brain barriers, presumably by passive diffusion.

Metabolism: Lidocaine and prilocaine are mainly metabolized in the liver. Prilocaine and lidocaine are not metabolized by plasma esterases. The main metabolism of lidocaine is through N-dealkylation to monoethylglycinexylidide (MEGX) and glycinexylidide (GX), which is mainly mediated by CYP3A4. These metabolites are hydrolyzed to 2,6-xylidine, which is converted to 4-hydroxy- 2,6-xylidine (mediated by CYP2A6), the major urinary metabolite in man. After a total of 8 to 8.5g Oraqix administered as repeated applications over 3 hours, the mean (+SD) 2,6-xylidine Cmax was 18 (+8.4) ng/mL ranging between 8 and 32 ng/mL. The mean 2,6-xylidine AUC∞ was 9800 ng/min/mL (±6370), ranging between 3480 to 24,580 ng/min/mL). MEGX has an antiarrhythmic and convulsant activity similar to that of lidocaine and a somewhat longer half-life. GX has a weak antiarrhythmic effect but lacks convulsant activity and has a half-life of about 10 h.

Prilocaine is split at the amide linkage to o-toluidine, which is converted further to 4- and 6- hydroxytoluidine. The prilocaine metabolite o-toluidine and the hydroxylated metabolites of o-toluidine are excreted mainly in the urine. o-Toluidine has been shown to be carcinogenic in several animal models. After a total of 8 to 8.5g Oraqix was administered as repeated applications over 3 hours, the mean (±SD) o-toluidine Cmax was 25 (±11) ng/mL ranging between 13 and 44 ng/mL. The mean o-toluidine AUC∞ was 9200 ng/min/mL. The median Tmax was 220 minutes, ranging between 90 and 240 min. In addition, o-Toluidine can cause the formation of methemoglobin (metHb) following treatment with prilocaine. Individual maximum blood concentrations of metHb increased from 0 to 1.1% up to 0.8 to 1.7% following administration of the maximum recommended dose of 8.5g Oraqix administrated as repeated applications over 3 hours. The Tmax of metHb ranged from 1 to 4 hours. Normally, <1 % of the total hemoglobin is in the form of metHb. [See OVERDOSAGE (10)]. Patients with glucose-6-phosphate dehydrogenase deficiencies, and patients taking oxidizing drugs such as antimalarials and sulfonamides are more susceptible to drug-induced methemoglobinemia. [See Warnings and Precautions (5.1)].

Elimination: Lidocaine and prilocaine have systemic clearances of 0.95 and 2.37 L/min, respectively, after intravenous administration as single agents. The terminal half-life of both drugs after intravenous administration as single agents is 1.6 h. Oraqix is not intended for intravenous administration.

However, after application of Oraqix to the periodontal pockets the mean (±SD) terminal lidocaine half-life was 3.6 (±1.3)hours, ranging between 2.2 and 6.5 h. The mean (±SD) terminal prilocaine half-life was 2.8 (±1.0) hours, ranging between 2.0 to 5.7 h. For the metabolite o-toluidine the mean terminal half-life was 4.0 (±1.1) hours, ranging between 2.0 and 5.7 hours. For the metabolite 2,6-xylidine the mean terminal half-life was 8.0 (±4.0) hours, ranging between 3.7 and 18.3 hours.

Pediatrics: The pharmacokinetics of lidocaine and prilocaine after Oraqix administration have not been studied in pediatric patients.

Geriatrics: The pharmacokinetics of lidocaine and prilocaine after Oraqix administration have not been studied in geriatric patients. However, intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). No studies in the intravenous pharmacokinetics of prilocaine in elderly patients have been performed.

Special populations: No pharmacokinetic studies were conducted to specifically address special populations.

Renal Impairment: Lidocaine and prilocaine and their metabolites are known to be excreted by the kidney, and the metabolites may accumulate in patients with impaired renal function.

Hepatic Impairment: The half-life of lidocaine may be prolonged two-fold or more in patients with liver dysfunction. Liver dysfunction may also alter prilocaine pharmacokinetics. Because of their inability to metabolize local anesthetics normally, patients with severe hepatic disease, are at a greater risk of developing toxic plasma concentrations of lidocaine and prilocaine.

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.