Kovanaze (Page 3 of 5)

8.3 Females and Males of Reproductive Potential

Infertility

No information is available on fertility effects in humans.

Females

Based on animal data, KOVANAZE may reduce fertility in females of reproductive potential. In female rats, decreased fertility noted as a decrease in litter size occurred at 0.7 times the oxymetazoline AUC exposure at the MRHD of KOVANAZE. It is not known if the effects on fertility are reversible [ see Nonclinical Toxicology ( 13.1)] .

Males

Based on animal data, KOVANAZE may reduce male fertility. In male rats, decreased sperm motility and sperm concentration occurred at approximately 2 times the oxymetazoline AUC exposure at the MRHD of KOVANAZE [see Nonclinical Toxicology ( 13.1)] .

8.4 Pediatric Use

KOVANAZE has not been studied in pediatric patients under 3 years of age and is not advised for use in pediatric patients weighing less than 40 kg because efficacy has not been demonstrated in these patients [see Clinical Studies ( 14.2)] .

8.5 Geriatric Use

Clinical studies of KOVANAZE did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Monitor geriatric patients for signs of local anesthetic toxicity, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Of note, comparisons of KOVANAZE safety and efficacy results were generally similar among dental patients who were > 50 years old (n=66) and ≤ 50 years old (n=148). However, a trend toward a higher incidence of notable increases in systolic blood pressure was observed in dental patients > 50 years of age compared with patients ≤ 50 years of age (16.6% vs 1.4, respectively) [see Adverse Reactions ( 6.1)]. These increases in blood pressure measurements were generally asymptomatic and transient in nature, and all spontaneously resolved without the need for medical intervention [see Clinical Studies ( 14.1)] .

8.6 Hepatic Disease

Because of an inability to metabolize local anesthetics, those patients with severe hepatic disease may be at a greater risk of developing toxic plasma concentrations of tetracaine. Monitor patients with hepatic disease for signs of local anesthetic toxicity.

8.7 Pseudocholinesterase Deficiency

Because of an inability to metabolize local anesthetics, those patients with pseudocholinesterase deficiency may be at a greater risk of developing toxic plasma concentrations of tetracaine. Monitor patients with pseudocholinesterase deficiency for signs of local anesthetic toxicity.

10 OVERDOSAGE

No addictive properties have been reported in the literature for either tetracaine or oxymetazoline, but there have been numerous case reports of unintended overdose for both compounds. Side effects in adults and children associated with oxymetazoline overdose include dizziness, chest pain, headaches, myocardial infarction, stroke, visual disturbances, arrhythmia, hypertension, or hypotension. Side effects of tetracaine overdose include rapid circulatory collapse, cardiac arrest, and cerebral events.

Possible rebound nasal congestion, irritation of nasal mucosa, and adverse systemic effects (particularly in children), including serious cardiac events, have been associated with overdosage and/or prolonged or too frequent intranasal use of oxymetazoline containing agents.

Accidental ingestion of imidazoline derivatives (i.e., oxymetazoline, naphazoline, tetrahydrozoline) in children has resulted in serious adverse events requiring hospitalization (e.g., coma, bradycardia, decreased respiration, sedation, and somnolence).

Patients should be instructed to avoid using oxymetazoline-containing products (such as Afrin ®) and other α-adrenergic agonists within 24 hours prior to their scheduled dental procedure [see Drug Interactions ( 7.3)] .

Management of an overdose includes close monitoring, supportive care, and symptomatic treatment.

11 DESCRIPTION

KOVANAZE (tetracaine HCl and oxymetazoline HCl) Nasal Spray is a clear aqueous solution in a pre-filled, single-dose intranasal sprayer. The solution pH is 6.0 ± 1.0. The product contains two active ingredients: 30 mg/mL tetracaine HCl (equivalent to 26.4 mg/mL tetracaine) and 0.5 mg/mL oxymetazoline hydrochloride (equivalent to 0.44 mg/mL oxymetazoline). Each spray delivers 0.2 mL of solution containing 6 mg tetracaine hydrochloride (equivalent to 5.27 mg tetracaine) and 0.1 mg of oxymetazoline hydrochloride (equivalent to 0.088 mg oxymetazoline). The product also contains citric acid, sodium citrate, hydroxyethylcellulose, benzyl alcohol, and water. Sodium hydroxide and/or hydrochloric acid are added for pH adjustment as needed.

Tetracaine hydrochloride is an ester local anesthetic. Chemically it is 2-(dimethylamino)ethyl 4-(butylamino)benzoate hydrochloride. Its molecular weight is 300.8 for the hydrochloride salt and 264.4 for the free base. It is freely soluble in water and soluble in ethanol. Its structural formula is:

Tetracaine Hydrochloride Structural Formula

Oxymetazoline hydrochloride is a vasoconstrictor. Chemically it is 3-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-6-(1,1,-dimethylethyl)-2,4-dimethylphenol mono-hydrochloride. Its molecular weight is 296.8 for the hydrochloride salt and 260.4 for the free base. It is freely soluble in water and ethanol and has a partition coefficient of 0.1 in octanol/water. Its structural formula is:

Oxymetazoline Hydrochloride Structural Formula
Tetracaine Hydrochloride Structural Formula Oxymetazoline Hydrochloride Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tetracaine is a local anesthetic of the ester type and exerts its activity by blocking sodium ion channels required for the initiation and conduction of neuronal impulses. Oxymetazoline is an imidazoline derivative with sympathomimetic activity. It is believed to be a mixed α 12 -adrenoceptor agonist and, by stimulating adrenergic receptors, it elicits vasoconstriction of dilated arterioles and reduces nasal blood flow.

12.3 Pharmacokinetics

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.

Metabolism

Oxymetazoline is converted to a glucuronide conjugate in vitro by UGT1A9.

Tetracaine is rapidly and thoroughly cleaved by esterases in plasma and other tissues to PBBA and dimethylaminoethanol. These metabolites have an unspecified activity.

Excretion

The apparent clearance of oxymetazoline after nasal administration of KOVANAZE has not been determined. It is thought that the primary route of oxymetazoline elimination at clinically relevant concentrations is by renal excretion.

PBBA clearance cannot be determined after administration of tetracaine.

Special Populations

Pediatrics:

In subjects 4-15 years of age (n=18) that received KOVANAZE doses of 0.1 mL (10 to < 20 kg body weight), 0.2 mL (20 to < 40 kg), or 0.4 mL (≥ 40 kg), oxymetazoline attained maximum concentrations within approximately 10 minutes to 30 minutes (median time) following the end of dosing. The observed oxymetazoline mean C max values were 0.37 ± 0.43, 0.85 ± 0.45, and 1.2 ± 0.39 ng/mL in the 0.1 mL, 0.2 mL, and 0.4 mL dose groups, respectively. The observed oxymetazoline mean AUC 0-inf values were 0.99 (AUC can be calculated only in one subject), 2.53 ± 1.08, and 2.64 ± 0.41 ng.h/mL in the 0.1 mL, 0.2 mL, and 0.4 mL dose groups, respectively. Mean elimination half-life values for oxymetazoline were approximately 1.6 to 4.3 hours across pediatric dose groups.

Plasma concentrations of tetracaine were below the limit of assay quantification (0.05 ng/mL) in all subjects.

PBBA attained maximum concentrations within approximately 20 minutes to 30 minutes (median time) following the end of dosing. The observed PBBA mean C max values were 166 ± 71, 345 ± 172, and 365 ± 30 ng/mL in the 0.1 mL, 0.2 mL, and 0.4 mL dose groups, respectively. The observed PBBA mean AUC 0-inf values were 529 ± 222, 826 ± 606, and 665 ± 86 ng.h/mL in the 0.1 mL, 0.2 mL, and 0.4 mL dose groups, respectively. Mean elimination half-life values for PBBA were approximately 1.6 to 2.8 hours across pediatric dose groups.

Elderly: The pharmacokinetics of KOVANAZE were not evaluated in subjects greater than 50 years of age.

Renal or Hepatic Impairment: The pharmacokinetics of oxymetazoline, tetracaine, and PBBA were not evaluated after nasal administration of KOVANAZE in subjects with renal or hepatic impairment.

Race: There were insufficient data to evaluate the effect of race on oxymetazoline, tetracaine, and PBBA pharmacokinetics after nasal administration of KOVANAZE.

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