Oraqix

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

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot 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.

Read the entire FDA prescribing information for Oraqix (Lidocaine and Prilocaine Periodontal Gel)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of lidocaine and prilocaine periodontal gel in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of lidocaine and prilocaine periodontal gel in the elderly. However, elderly patients are more likely to have age-related kidney or liver problems, which may require caution and an adjustment in the dose for patients receiving lidocaine and prilocaine periodontal gel.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acecainide
• Amiodarone
• Bretylium
• Dofetilide
• Ibutilide
• Sotalol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency, history of or
• Heart disease or
• Heart rhythm problems—May cause side effects to become worse.

• Methemoglobinemia (blood disorder), history of—Should not use in patients with this condition.

• Liver disease, severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

It is very important that your dentist check you closely for any problems or unwanted effects that may be caused by this medicine.

This medicine may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your dentist right away if you have a rash; itching; hoarseness; trouble with breathing; trouble with swallowing; or any swelling of your hands, face, or mouth after you receive the medicine.

This medicine may cause a rare, but serious blood problem called methemoglobinemia. Call your dentist right away if you develop a blue or bluish purple color on the lips, fingernails, or skin, or have headaches, dizziness, fainting, sleepiness, or trouble with breathing after you receive this medicine.

During the time that the gum feels numb, serious injury can occur. Be especially careful to avoid injury until the numbness wears off and you have normal feeling in the area. Avoid foods or liquids that are very hot or very cold. Do not chew gum or food while your mouth feels numb. You may accidentally bite your tongue or the inside of your cheeks.

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. 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, 1 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.

Maximum Recommended Dosage

The maximum recommended dose of Oraqix at one treatment session is 5 cartridges, i.e., 8.5g gel.

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/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 (60mg/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.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Very young children are more susceptible to methemoglobinemia. There have been reports of clinically significant methemoglobinemia in infants and children following excessive applications of lidocaine 2.5% topical cream [See Warnings and Precautions (5.1)].

Geriatric Use

Of the total number of subjects in clinical studies of Oraqix, 7% were aged 65 and over, while 1% were aged 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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.

Pharmacodynamics

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).

Pharmacokinetics

Absorption: 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.

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.

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.

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.

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.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [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)

Applies to lidocaine / prilocaine topical: topical cream, topical film, topical kit

Local

Local side effects have included erythema, edema, and abnormal sensation. Local effects observed in the trials of the cream on intact skin have included paleness (37%), erythema (30%), alterations in temperature sensations (7%), edema (6%), itching (2%), and rash (