Kovanaze

Before taking Kovanaze, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Kovanaze or to any of its ingredients
• have high blood pressure
• have thyroid disease
• have used any nasal products recently
• have a history of congenital or idiopathic methemoglobinemia
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Your doctor will check your or your child's progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

Call your dentist or doctor right away if you or your child have stuffy or runny nose, mild nose bleeds, dizziness, or trouble swallowing after receiving this medicine.

Tetracaine may cause methemoglobinemia. Tell your doctor right away if you or your child have bluish-colored lips, fingernails, palms, dark urine, difficulty breathing, dizziness or lightheadedness, fever, headache, pale skin, rapid heart rate, sore throat, unusual bleeding or bruising, or unusual tiredness or weakness.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your dentist or doctor right away if you or your child have a rash, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Avoid using other products containing oxymetazoline (eg, Afrin®) within 24 hours before the scheduled dental procedure. Do not use other inhaled medicines while using Kovanaze™.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Bloody nose
• blurred vision
• chest pain or discomfort
• difficulty swallowing
• dizziness
• headache
• lightheadedness, dizziness, or fainting
• nervousness
• pounding in the ears
• shortness of breath
• slow or fast, irregular heartbeat
• ulcers in the nose
• unusual tiredness

• Bluish-colored lips, fingernails, or palms
• cough
• dark urine
• difficulty breathing
• dizziness or lightheadedness
• fever
• hives or welts, itching, or skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• noisy breathing
• pale skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid heart rate
• redness of the skin
• sore throat
• tightness in the chest
• unusual bleeding or bruising

Get emergency help immediately if any of the following symptoms of overdose occur:

• Blurred or loss of vision
• chest pain or discomfort
• confusion
• difficulty in speaking
• disturbed color perception
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• double vision
• fainting
• fast, slow, or irregular heartbeat
• halos around lights
• headache
• inability to move the arms, legs, or facial muscles
• inability to speak
• lightheadedness
• nausea
• nervousness
• night blindness
• no blood pressure or pulse
• overbright appearance of lights
• pain or discomfort in the arms, jaw, back, or neck
• pounding in the ears
• slow speech
• stopping of heart
• stuffy nose
• sweating
• tunnel vision
• unconsciousness
• unusual tiredness or weakness
• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings in the nose
• change in taste
• loss of taste
• sore throat
• stuffy or runny nose
• watering of the eyes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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.

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)] .

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)].

Dysphagia

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

Methemoglobinemia

Tetracaine may cause methemoglobinemia, particularly in conjunction with methemoglobin-inducing agents. Based on the literature, patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Use of Kovanaze in patients with a history of congenital or idiopathic methemoglobinemia is not advised.

Patients taking concomitant drugs associated with drug-induced methemoglobinemia, such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, p-aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine, may be at greater risk for developing methemoglobinemia.

Initial signs and symptoms of methemoglobinemia (which may be delayed for up to several hours following exposure) are characterized by a slate grey cyanosis seen in, e.g., buccal mucous membranes, lips and nail beds. In severe cases, symptoms may include central cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrythmia and shock. Methemoglobinemia should be considered if central cyanosis unresponsive to oxygen therapy occurs, especially if methemoglobinemia-inducing agents have been used. Calculated oxygen saturation and pulse oximetry are inaccurate in the identification of methemoglobinemia. Confirm diagnosis by measuring methemoglobin level with co-oximetry. Normally, methemoglobinemia levels are <1%, and cyanosis may not be evident until a level of at least 10% is present.

Treat clinically significant symptoms of methemoglobinemia with a standard clinical regimen such as a slow intravenous infusion of methylene blue at a dosage of 1-2 mg/kg given over a 5 minute period.

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.

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 ( 7.2)] .

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

Kovanaze (tetracaine HCl and oxymetazoline HCl) Nasal Spray is a clear aqueous solution in a pre-filled, single-use 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:

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:

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 1/α 2-adrenoceptor agonist and, by stimulating adrenergic receptors, it elicits vasoconstriction of dilated arterioles and reduces nasal blood flow.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

• Inform patients of the likelihood of expected side effects (including runny nose, nasal congestion, mild nose bleeds, dizziness, and/or a sensation of difficulty in swallowing) that should resolve within the same day. Instruct patients to contact their dentist or health care professional if these symptoms persist [see Adverse Reactions ( 6)] .
• Advise patients to inform the dental practitioner if they are taking monoamine oxidase inhibitors (MAOIs), nonselective beta adrenergic antagonists, or tricyclic antidepressants [see Drug Interactions ( 7.1)] .
• Instruct patients 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 ( 7.2)] .
• Advise patients of the signs and symptoms of hypersensitivity reactions and to seek immediate medical attention should they occur [see Warnings and Precautions ( 5.5)] .

St. Renatus, LLC
        Manufactured for:
        St. Renatus, LLC
        Fort Collins, CO 80526

Kovanaze is a trademark of St. Renatus, LLC.

Principal Display Panel - Box Label

NDC 69803-100-10

Kovanaze

(tetracaine HCl and oxymetazoline HCl)

NASAL SPRAY

0.2 mL per sprayer

Containing 6 mg tetracaine HCl and 0.1 mg oxymetazoline HCl

(equivalent to 5.27 mg tetracaine and 0.088 mg oxymetazoline)

Contents: 30 sprayers

Rx only

NOT FOR INJECTION

Store refrigerated at 2 to 8°C (36 to 46°F)

Manufactured for

St. Renatus, LLC

Fort Collins, CO 80526