Kovanaze

KOVANAZE- tetracaine hydrochloride and oxymetazoline hydrochloride spray
St. Renatus

1 INDICATIONS AND USAGE

KOVANAZE ^TM is indicated for regional anesthesia when performing a restorative procedure on Teeth 4-13 and A-J in adults and children who weigh 40 kg or more.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

• KOVANAZE is for intranasal use only.
• Administer ipsilateral (same side) to the maxillary tooth on which the dental procedure will be performed.
• Wait 10 minutes after administration of KOVANAZE to perform a test drill to confirm that the tooth involved is anesthetized. A patient may not experience the same sensations of numbness or tingling of the lips and cheeks associated with injectable dental anesthetics.

2.2 Dosing in Adults (≥ 18 years old)

• 2 sprays (0.2 mL each) administered 4 to 5 minutes apart in the nostril ipsilateral to the maxillary tooth on which the dental procedure will be performed. Initiate the dental procedure 10 minutes after the second spray.
• 1 additional spray (0.2 mL) if adequate anesthesia to initiate the dental procedure has not been achieved 10 minutes after the second spray.

2.3 Dosing in Children (who weigh 40 kg or more)

• 2 sprays (0.2 mL each) administered 4 to 5 minutes apart in the nostril ipsilateral to the maxillary tooth on which the dental procedure will be performed. Initiate the dental procedure 10 minutes after the second spray.

Age Group	Dose
Adults (≥ 18 years old)	2 sprays (0.2 mL per spray), 4 to 5 minutes apart 1 additional spray (0.2 mL) if adequate anesthesia has not been achieved 10 minutes after the second spray
Children who weigh 40 kg or more	2 sprays (0.2 mL per spray), 4 to 5 minutes apart

3 DOSAGE FORMS AND STRENGTHS

Nasal spray in pre-filled, single-dose sprayer: 6 mg tetracaine HCl and 0.1 mg oxymetazoline HCl (equivalent to 5.27 mg tetracaine and 0.088 mg oxymetazoline) in each 0.2 mL spray.

4 CONTRAINDICATIONS

KOVANAZE is contraindicated in patients with a history of allergy to or intolerance of tetracaine, benzyl alcohol, other ester local anesthetics, p -aminobenzoic acid (PABA), oxymetazoline, or any other component of the product [see Warnings and Precautions ( 5.5)] .

5 WARNINGS AND PRECAUTIONS

5.1 Methemoglobinemia

​ Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

​ Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue KOVANAZE and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

5.2 Risk of Hypertension

KOVANAZE has not been studied in Phase 3 trials in adult dental patients with blood pressure greater than 150/100 or in those with inadequately controlled active thyroid disease. KOVANAZE has been shown to increase blood pressure in some patients in clinical trials. Monitor patients for increased blood pressure. Use in patients with uncontrolled hypertension or inadequately controlled active thyroid disease of any type is not advised [see Adverse Reactions ( 6.1)] .

5.3 Epistaxis

In clinical trials, epistaxis occurred more frequently with KOVANAZE than placebo. Either do not use KOVANAZE in patients with a history of frequent nose bleeds (≥ 5 per month) or monitor patients with frequent nose bleeds more carefully if KOVANAZE is used. [see Adverse Reactions ( 6.1)].

5.4 Dysphagia

In clinical trials, dysphagia occurred more frequently with KOVANAZE than placebo. Carefully monitor patients for this adverse reaction.

5.5 Anaphylactic Reactions

Allergic or anaphylactic reactions have been associated with tetracaine, and may occur with other components of KOVANAZE. They are characterized by urticaria, angioedema, bronchospasm, and shock. If an allergic reaction occurs, seek emergency help immediately.

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

• Methemoglobinemia [see Warnings and Precautions ( 5.1)]
• Hypertension [see Warnings and Precautions ( 5.2)]
• Epistaxis [see Warnings and Precautions ( 5.3)]
• Dysphagia [see Warnings and Precautions ( 5.4)]
• Anaphylatic Reactions [see Warnings and Precautions ( 5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The adverse reactions information described below is from Phase 3 randomized, controlled clinical trials [see Clinical Studies ( 14)] . These data reflect exposure to KOVANAZE in 154 adult dental patients and 20 pediatric dental patients (aged 7 to 17 years) with a need for an operative restorative dental procedure requiring local anesthesia for a single vital maxillary tooth (other than a maxillary first, second, or third molar) with no evidence of pulpal pathology. [see Clinical Studies ( 14)].

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)] .

Table 1: Common Adverse Reactions in ≥ 2% of Phase 3 Adult Dental Patients and Pediatric Patients Weighing 40 kg or More

SOC / Preferred Term	KOVANAZE (N=174)	Active Comparator* (N=54)	Placebo (N=88)
Respiratory System Disorders	141 (81%)	50 (93%)	18 (21%)
Rhinorrhea (runny nose)	91 (52%)	20 (37%)	3 (3%)
Nasal congestion	56 (32%)	34 (63%)	6 (7%)
Nasal discomfort	45 (26%)	7 (13%)	5 (6%)
Oropharyngeal pain (sore throat)	25 (14%)	5 (9%)	0 (0%)
Intranasal hypoesthesia	18 (10%)	8 (15%)	5 (6%)
Pharyngeal hypoesthesia (numb throat)	17 (10%)	10 (19%)	0 (0%)
Throat Irritation	15 (9%)	1 (2%)	0 (0%)
Rhinalgia	10 (6%)	3 (6%)	2 (2%)
Sneezing	7 (4%)	2 (4%)	1 (1%)
Epistaxis	4 (2%)	2 (4%)	0 (0%)
Nasal Dryness	4 (2%)	0 (0%)	1 (1%)
Nervous System Disorders	39 (22%)	5 (9%)	6 (7%)
Headache	18 (10%)	3 (6%)	4 (5%)
Dysgeusia	14 (8%)	1 (2%)	1 (1%)
Sinus headache	5 (3%)	0 (0%)	0 (0%)
Dizziness	5 (3%)	0 (0%)	1 (1%)
Sensory Disturbance	4 (2%)	0 (0%)	0 (0%)
Eye Disorders	29 (17%)	8 (15%)	4 (5%)
Lacrimation increased (watery eye)	23 (13%)	6 (11%)	4 (5%)
Gastrointestinal Disorders	16 (9%)	5 (9%)	3 (3%)
Oral Discomfort	4 (2%)	0 (0%)	0 (0%)
Investigations	12 (7%)	0 (0%)	4 (5%)
BP systolic increased	8 (5%)	0 (0%)	2 (2%)
BP diastolic increased	6 (3%)	0 (0%)	1 (1%)
Cardiac Disorders	8 (5%)	5 (9%)	1 (1%)
Bradycardia	5 (3%)	3 (6%)	1 (1%)
Vascular Disorders	6 (3%)	2 (4%)	1 (1%)
Hypertension	5 (3%)	1 (2%)	1 (1%)
* Active Comparator was tetracaine only spray used in two clinical studies in adults.

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/.