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warnings and cautions
5 WARNINGS AND PRECAUTIONS Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetic use ( 5.1 ) Hypertension and Thyroid Disease : Shown to increase blood pressure in some clinical trial patients. Monitor blood pressure. Use in patients with inadequately controlled hypertension or active thyroid disease is not advised ( 5.2 ). Epistaxis : Use is not recommended in patients with a history of frequent nose bleeds (≥5 per month). If a decision to use is made, monitor these patients carefully ( 5.3 ). Dysphagia : Carefully monitor patients for dysphagia ( 5.4 ). Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.5 ). 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 )] The most common adverse reactions occurring in >10% of patients include rhinorrhea, nasal congestion, nasal discomfort, oropharyngeal pain, and lacrimation increased ( 6 ). Transient, asymptomatic elevations in systolic blood pressure (≥ 25 mm Hg from baseline) and diastolic blood pressures (≥ 15 mm Hg from baseline) have been reported ( 6 ). 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. 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/ .