Common Adverse Reactions in Adult Dental Patients and Pediatric Patients Weighing 40 kg or More

The most common adverse reactions to occur in Phase 3 trials with KOVANAZE in adult dental patients and pediatric dental patients weighing 40 kg or more were rhinorrhea, nasal congestion, nasal discomfort, oropharyngeal pain, and lacrimation increased [ Table 1] .

No serious adverse events with KOVANAZE have occurred [see Clinical Studies ( 14.1)] .

Intranasal ulcerations, some of which were transient, were noted to have occurred following treatment with KOVANAZE. In Phase 3 trials, 6 (3%) patients who received KOVANAZE, but no patients who received placebo, developed nasal ulcers that were present on exam the same day as KOVANAZE dosing. Three (2%) KOVANAZE and 2 (2%) placebo-treated patients without nasal ulcerations on the day of KOVANAZE or placebo dosing were observed to have nasal ulcerations at the next day follow-up visit.

Less Common Adverse Reactions in Phase 3 Clinical Trials Adult Dental Patients and Pediatric Dental Patients Weighing 40 kg or More

Dysphagia (i.e., the sensation of difficult swallowing) is a notable adverse reaction reported in Phase 3 trials, occurring in 1.15% of patients.

For medical advice about adverse reactions, contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact St. Renatus, LLC at 800-865-4925 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch/.

Risk Summary

Limited published data on tetracaine use in pregnant women are not sufficient to inform any risks. Published epidemiologic studies of nasal oxymetazoline used as a decongestant during pregnancy do not identify a consistent association with any specific malformation or pattern of malformations [see Data] . In animal reproduction and development studies, oxymetazoline given subcutaneously to rats during the period of organogenesis caused structural abnormalities at a dose approximately 7.6 times the exposure of oxymetazoline HCl at the 0.3 mg maximum recommended human dose (MRHD) of KOVANAZE. In a pre- and post-natal development study, oxymetazoline given subcutaneously to rats caused embryo-fetal toxicity manifested by reduced implantation sites and live litter sizes at approximately 1.5 times the MRHD and increased pup mortality at 6 times the MRHD. No adverse developmental effects were observed following subcutaneous administration of tetracaine HCl only to rats and rabbits during organogenesis at 32 and 6 times, respectively, the estimated exposure of tetracaine HCl at the 18 mg MRHD of KOVANAZE [see Data] .

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 and to 20%, respectively.

Data

Risk Summary

There are no data on the presence of tetracaine, oxymetazoline, or their metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Detectable levels of oxymetazoline, tetracaine and the major metabolite of tetracaine, p-butylaminobenzoic acid (PBBA), were found in the milk of lactating rats following subcutaneous administration of oxymetazoline HCl in combination with tetracaine HCl during the period of organogenesis through parturition and subsequent pup weaning [see Data] . Due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KOVANAZE and any potential adverse effects on the breastfed infant from KOVANAZE or from the underlying maternal condition.

Data

In a pre- and post-natal development study, rats were given oxymetazoline HCl subcutaneously at doses of 0.01, 0.03, and 0.1 mg/kg/day (0.6, 1.5, and 7.6 times, respectively, the oxymetazoline AUC exposure at the MRHD) in combination with 7.5 mg/kg tetracaine HCl (12 times the AUC exposure as measured by PBBA at the MRHD) from Gestational Day [GD] 7 to Lactation Day [LD] 20. Concentrations of oxymetazoline, tetracaine, and PBBA were measured in the milk of lactating rats at approximately 2 hours postdose on LD 15. The concentrations of oxymetazoline were generally dose dependent (2.5, 7.0, and 33.8 ng/mL at 0.01, 0.03, and 0.1 mg/kg/day, respectively). The concentrations of tetracaine and PBBA were generally similar across all 7.5 mg/kg/day tetracaine HCl dosing groups regardless of the presence of oxymetazoline (54.2 – 72.9 ng/mL for tetracaine, and 100.5 – 131.2 ng/mL for PBBA).

Infertility

No information is available on fertility effects in humans.

Absorption

Following nasal administration of 0.6 mL KOVANAZE in adult subjects (n=24), oxymetazoline attained maximum concentrations within approximately 10 minutes following the end of dosing. The observed mean oxymetazoline C max and AUC 0-inf value were 1.78 ng/mL and 4.24 ng.h/mL, respectively. The observed median T max was 5 minutes.

Plasma concentrations of tetracaine in all subjects were at or below the limit of assay quantification (0.05 ng/mL). Of all plasma samples analyzed, only one quantifiable tetracaine concentration was observed in a single sample from one subject, which was at the limit of assay quantification. The primary metabolite of tetracaine, p-butylaminobenzoic acid (PBBA) achieved peak concentrations within approximately 25 minutes following the end of KOVANAZE dosing. The observed mean PBBA C max and AUC 0-inf value were 465 ng/mL and 973 ng.h/mL, respectively. The observed median T max was 20 minutes.

Distribution

Protein binding and distribution of oxymetazoline and PBBA have not been determined. Plasma protein binding of tetracaine has been reported to be 75% to 85%.

Elimination

The terminal half-life of oxymetazoline in plasma following nasal administration of KOVANAZE to adult subjects is approximately 5.2 hours.

The elimination half-life and apparent clearance of tetracaine could not be determined after KOVANAZE administration because it is rapidly and thoroughly hydrolyzed in plasma. The plasma half-life of PBBA is approximately 2.6 hours in adult subjects.

Special Populations

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of tetracaine or oxymetazoline.

Mutagenesis

Tetracaine base was negative in the in vitro Ames bacterial reverse mutation assay and the in vivo mouse micronucleus assay. In the in vitro chromosome aberration assay using Chinese hamster ovary cells, tetracaine base was negative in the absence of metabolic activation, and equivocal in the presence of metabolic activation. No studies have been conducted to evaluate the mutagenic potential of oxymetazoline.

Impairment of Fertility

Male and female rats were given subcutaneous doses of oxymetazoline HCl alone at 0.1 mg/kg/day, tetracaine HCl alone at 7.5 mg/kg/day, or the combination of oxymetazoline HCl at 0.01, 0.03, or 0.1 mg/kg/day oxymetazoline with 7.5 mg/kg/day tetracaine HCl prior to and during mating. Oxymetazoline HCl at ≥ 0.03 mg/kg/day reduced the percentage of motile sperm and sperm counts at 2 times the oxymetazoline AUC exposure at the MRHD of KOVANAZE. There were no effects on male mating behavior at any dose tested. The no-effect level for sperm effects was 0.01 mg/kg/day (0.7 times the oxymetazoline AUC exposure at the MRHD of KOVANAZE).

In female rats, a reduction in the number of viable embryos was observed at oxymetazoline AUC exposures equivalent to 0.7 times the MRHD and higher, given alone or in combination with tetracaine HCl. Reduced numbers of corpora lutea and implantation sites were observed at 7.5 times the oxymetazoline AUC exposure at the MRHD in animals given oxymetazoline HCl alone or in combination with tetracaine HCl. These effects were attributed to oxymetazoline HCl because similar effects were not observed in rats given tetracaine HCl alone. A no-effect level for fertility in female rats was not established in this study.

No effects on male or female fertility were attributed to tetracaine HCl at 7.5 mg/kg/day (28 and 33 times the AUC exposure for males and females, respectively, as measured by PBBA [major tetracaine metabolite] at the MRHD of KOVANAZE).

Study 1

Study 1 was a Phase 3, multicenter, randomized, double-blind, placebo and active-controlled, parallel-groups study designed to compare the efficacy and safety of intranasally administered KOVANAZE to both tetracaine HCl alone and placebo, for providing dental anesthesia sufficient to allow completion of the standard dental procedure on a single maxillary tooth (#4-13) in adults.

A total of 110 patients were enrolled in two clinical centers and randomized to receive three 0.2 mL intranasal sprays of either KOVANAZE (n=44), tetracaine alone (n=44), or placebo (n=22). All randomized patients completed the study dental procedure.

Fifty-three percent (53%) of randomized patients were female and 76% were White, with a mean age of 35 years (range 18 to 73 years).

Eighty-four percent (95% CI: 70%, 93%) of KOVANAZE patients were able to complete the dental procedure without the need for rescue medication compared to 27% (95% CI: 15%, 43%) who received tetracaine alone and 27% (95% CI: 11%, 50%) who received placebo.

KOVANAZE had a lower success rate for dental procedures on the 2 nd pre-molar (teeth #4 and #13) compared with more anterior teeth (#5 through #12): 63% for the 2 nd pre-molars vs 96% for more anterior teeth.

In this trial, the median duration of a dental procedure successfully completed with KOVANAZE was 11 minutes, although one successfully completed dental procedure was as long as 43 minutes. Of the people that needed rescue medication in the KOVANAZE arm, they required it within the first 6 minutes following the start of the dental procedure.

Study 2

Study 2 was a Phase 3, multicenter, randomized, double-blind, parallel-groups study designed to compare the efficacy and safety of intranasally administered KOVANAZE to placebo, for providing dental anesthesia sufficient to allow completion of the standard dental procedure on a single maxillary tooth (#4-13) in adults.

A total of 150 adult patients were enrolled at three study centers and received either KOVANAZE (n=100) or placebo (n=50) as a dose of two or three 0.2 mL intranasal sprays. All except two randomized patients (one each in the KOVANAZE and placebo groups) completed the study dental procedure.

Fifty-five percent (55%) of randomized patients were female and 63% were White, with a mean age of 41 years (range 18 to 78 years).

Eighty-eight percent (95% CI: 80%, 94%) of KOVANAZE patients were able to complete the dental procedure without the need for rescue medication compared to 28% (95% CI: 16%, 43%) of patients who received placebo.

KOVANAZE had a lower success rate for dental procedures on the 2 nd pre-molar (teeth #4 and #13) compared with more anterior teeth (#5 through #12): 64% for the 2 nd pre-molars vs 96% for more anterior teeth.

Study 3

Study 3 was a Phase 3, multicenter, randomized, double-blind, parallel-groups study designed to compare the efficacy and safety of intranasally administered KOVANAZE to placebo for providing dental anesthesia sufficient to allow completion of the standard dental procedure on a single maxillary tooth (permanent teeth 4-13 or primary teeth A-J) for pediatric patients aged 3 through 17.

A total of 90 patients, 3 through 17 years of age inclusive, were enrolled at two study centers. Patients received one or two intranasal sprays of either KOVANAZE (n=60) or placebo (n=30) based on body weight: one 0.1 mL spray for patients weighing 10 kg to less than 20 kg; two 0.1 mL sprays for 20 kg to less than 40 kg; or two 0.2 mL sprays for patients weighing 40 kg or more. All except one randomized patient in the KOVANAZE group completed the study dental procedure.

Fifty-one percent (51%) of randomized patients were male and 89% were White, with a mean age of 8 years (range 3 to 17 years).

Even though a greater percentage of patients were able to complete the dental procedure without the need for rescue anesthesia for KOVANAZE: 77% for KOVANAZE (95% CI: 64%, 87%) compared to 53% for placebo (95% CI: 34%, 72%) an analysis by weight indicated that efficacy was only established for patients weighing 40 kg or more [see Table 3] .