Mechanism of Action
Lidocaine and prilocaine belong to the amide class of local anesthetics. Both lidocaine and prilocaine block sodium ion channels required for the initiation and conduction of neuronal impulses, resulting in local anesthesia.
After application of Oraqix on the gingival margin and a waiting period of 30 seconds, additional Oraqix is applied directly into periodontal pockets to provide localized anesthesia. The onset of local anesthetic effect after application of Oraqix into the periodontal pocket occurs by 30 seconds and a longer waiting time does not enhance the anesthetic affect. Anesthetic effect, as assessed by probing of pocket depths, lasted for about 20 minutes (individual overall range 14 to 31 minutes).
Lidocaine and prilocaine are absorbed from Oraqix via the oral mucous membranes. After a single application of 0.9to 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 8.5g 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.
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.
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-hydroxy2,6-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]. 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].
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.
The pharmacokinetics of lidocaine and prilocaine after Oraqix administration have not been studied in pediatric patients.
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.
No pharmacokinetic studies were conducted to specifically address special populations.
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.
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.
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)||Oraqix Median VAS||Placebo Median VAS|
|*p < 0.05 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”
|Study (No. of Patients)||Oraqix||Placebo|
|B1 (n=122)*||57 (90%)||38 (64%)|
|B2 (n=130)*||49 (78%)||51 (76%)|
|B3 (n=85)*||30 (70%)||20 (48%)|
|*p < 0.05 in the statistical test of the full five categorical scale|
Last reviewed on RxList: 8/17/2012
This monograph has been modified to include the generic and brand name in many instances.
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