Otocusi Enzimatico

Betamethasone Sodium Phosphate:

• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Otocusi Enzimatico (Betamethasone Sodium Phosphate) reviews

Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray is indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older.

Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray is a corticosteroid indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older. (1)

2 DOSAGE AND ADMINISTRATION

Shake well before use.

Apply Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray to the affected skin areas twice daily and rub in gently.

Use Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray for up to 4 weeks of treatment. Treatment beyond 4 weeks is not recommended.

Discontinue Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray when control is achieved.

Do not use if atrophy is present at the treatment site.

Do not bandage, cover, or wrap the treated skin area unless directed by a physician.

Avoid use on the face, scalp, axilla, groin, or other intertriginous areas.

Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray is for topical use only. It is not for oral, ophthalmic, or intravaginal use.

• Apply to the affected skin areas twice daily. Rub in gently. (2)
• Use Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray for up to 4 weeks and not beyond. (2)
• Discontinue treatment when control is achieved. (2)
• Do not use if atrophy is present at the treatment site. (2)
• Do not use with occlusive dressings unless directed by a physician. (2)
• Avoid use on the face, scalp, axilla, groin, or other intertriginous areas. (2)
• Not for oral, ophthalmic, or intravaginal use. (2)

3 DOSAGE FORMS AND STRENGTHS

Spray, 0.05% for topical use. Each gram of Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray contains 0.643 mg Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate USP (equivalent to 0.5 mg Otocusi Enzimatico (Betamethasone Sodium Phosphate)) in a slightly thickened, white to off-white oil-in-water emulsion.

Spray: 0.05% (equivalent to 0.5 mg betamethasone/g) (3)

4 CONTRAINDICATIONS

None.

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Otocusi Enzimatico Spray can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency during or after treatment. (5.1)
• Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can result from systemic absorption of topical corticosteroids. (5.1)
• Use of topical corticosteroids may require periodic evaluation for HPA axis suppression. (5.1)
• Modify use if HPA axis suppression develops. (5.1)
• High potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure and young age may predispose patients to HPA axis suppression. (5.1)
• Pediatric patients may be more susceptible to systemic toxicity when treated with topical corticosteroids. (5.1, 8.4)

5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Unwanted Systemic Glucocorticoid Effects

Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during or after withdrawal of treatment. Factors that predispose to HPA axis suppression include the use of high-potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age.

Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

In a study including 48 evaluable subjects 18 years of age or older with moderate to severe plaque psoriasis, abnormal ACTH stimulation test results suggestive of adrenal suppression were identified in 5 out of 24 (20.8%) subjects after treatment with Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray twice daily for 15 days. No subject (0 out of 24) had abnormal ACTH stimulation test results after treatment with Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray twice daily for 29 days .

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. If signs and symptoms of steroid withdrawal occur, supplemental systemic corticosteroids may be required.

Systemic effects of topical corticosteroids may also manifest as Cushing’s syndrome, hyperglycemia, and glucosuria. These events are rare and generally occur after prolonged exposure to larger than recommended doses, particularly with high-potency topical corticosteroids.

Minimize the unwanted risks from endocrine effects by mitigating the risk factors favoring increased systemic bioavailability and by using the product as recommended .

Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios. Use of Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray is not recommended in pediatric patients .

5.2 Allergic Contact Dermatitis

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing. If irritation develops, discontinue the topical corticosteroid and institute appropriate therapy.

6 ADVERSE REACTIONS

The most common adverse reactions are application site reactions, including pruritus, burning and/or stinging, pain, and atrophy. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Promius Pharma, LLC. at 1-888-966-8766 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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In two randomized, multicenter, prospective vehicle-controlled clinical trials, subjects with moderate plaque psoriasis of the body applied Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray or vehicle spray twice daily for 4 weeks. A total of 352 subjects applied Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray and 180 subjects applied vehicle spray.

Adverse reactions that occurred in at least 1% of subjects treated with Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray for up to 28 days are presented in Table 1.

Less common adverse reactions (with occurrence lower than 1% but higher than 0.1%) in subjects treated with Otocusi Enzimatico (Betamethasone Sodium Phosphate) spray were application site reactions including telangiectasia, dermatitis, discoloration, folliculitis and skin rash, in addition to dysgeusia and hyperglycemia. These adverse reactions were not observed in subjects treated with vehicle.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing reports for local adverse reactions to topical corticosteroids have also included striae, irritation, dryness, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, hypertrichosis, and miliaria.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Otocusi Enzimatico Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias, cephalocele, and cleft palate.

8.3 Nursing Mothers

Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Otocusi Enzimatico Spray in patients younger than 18 years of age have not been studied; therefore use in pediatric patients is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk of systemic toxicity, including HPA axis suppression and adrenal insufficiency, when treated with topical drugs. [see Warnings and Precautions (5.1)]

Rare systemic effects such as Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids.

Local adverse reactions including skin atrophy have also been reported with use of topical corticosteroids in pediatric patients.

8.5 Geriatric Use

Clinical studies of Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray did not include sufficient numbers of subjects who were 65 years of age or older to determine whether they respond differently from younger subjects.

11 DESCRIPTION

Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray contains 0.0643% Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate (equivalent to 0.05% Otocusi Enzimatico (Betamethasone Sodium Phosphate)), a synthetic, fluorinated corticosteroid.

The chemical name for Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate is 9-fluoro-11(β), 17, 21-trihydroxy-16(β)-methylpregna-1,4-diene-3,20-dione-17,21-dipropionate. The empirical formula is C₂₈H₃₇FO₇ and the molecular weight is 504.6. The structural formula is shown below.

Each gram of Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray contains 0.643 mg of Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate USP (equivalent to 0.5 mg Otocusi Enzimatico (Betamethasone Sodium Phosphate)) in a slightly thickened, white to off-white, oil-in-water, non-sterile emulsion with the following inactive ingredients:, butylated hydroxytoluene, cetostearyl alcohol, hydroxyethyl cellulose, methylparaben, mineral oil, oleyl alcohol, polyoxyl 20 cetostearyl ether, propylparaben, purified water, and sorbitan monostearate. Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray is co-packaged with a manual spray pump for installation by the pharmacist prior to dispensing to patients.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action of Otocusi Enzimatico Spray in psoriasis is unknown.

12.2 Pharmacodynamics

Vasoconstrictor studies performed with Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray in healthy subjects indicate that it is in the mid-range of potency as compared with other topical corticosteroids; however, similar blanching scores do not necessarily imply therapeutic equivalence.

The potential for HPA axis suppression by Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray was evaluated in a study randomizing 52 adult subjects with moderate to severe plaque psoriasis. Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray was applied twice daily for 15 or 29 days, in subjects with psoriasis involving a mean of 29.0% and 26.5% body surface area at baseline across the 2 treatment duration arms, respectively. Forty-eight (48) subjects were evaluated for HPA axis suppression at the end of treatment. The proportion of subjects demonstrating HPA axis suppression was 20.8% (5 out of 24) in subjects treated with Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray for 15 days. No subjects (0 out of 24) treated with Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray for 29 days had HPA axis suppression. In this study HPA axis suppression was defined as serum cortisol level ≤18 mcg/dL 30-minutes post-cosyntropin stimulation. In the 4 subjects with available follow-up values, all subjects had normal ACTH stimulation tests at follow-up.

12.3 Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.

Topical corticosteroids are absorbed through normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

Plasma concentrations of Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate, betamethasone-17-propionate, and Otocusi Enzimatico (Betamethasone Sodium Phosphate) were measured at baseline, and before and after the last dose (1, 3, and 6 hours) in the HPA axis suppression trial in subjects with psoriasis [see Clinical Pharmacology (12.2)]. The majority of subjects had no measurable plasma concentration (<5.00 pg/mL) of Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate, while the metabolites, betamethasone-17-propionate and Otocusi Enzimatico (Betamethasone Sodium Phosphate), were detected in the majority of subjects (Table 2). There was high variability in the data but there was a trend toward higher systemic exposure at Day 15 and lower systemic exposure at Day 29.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate.

In a 90-day repeat-dose toxicity study in rats, topical administration of Otocusi Enzimatico (Betamethasone Sodium Phosphate) dipropionate spray formulation at dose concentrations of 0.05% and 0.1% (providing dose levels up to 0.5 mg/kg/day in males and 0.25 mg/kg/day in females) resulted in a toxicity profile consistent with long-term exposure to corticosteroids including reduced body weight gain, adrenal atrophy, and histological changes in bone marrow, thymus and spleen indicative of severe immune suppression. A no observable adverse effect level (NOAEL) could not be determined in this study. Although the clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk of carcinogenesis.

Otocusi Enzimatico (Betamethasone Sodium Phosphate) was negative in the bacterial mutagenicity assay (Salmonella typhimurium and Escherichia coli), and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay.

Studies in rabbits, mice, and rats using intramuscular doses up to 1, 33, and 2 mg/kg, respectively, resulted in dose-related increases in fetal resorptions in rabbits and mice.

14 CLINICAL STUDIES

Two multi-center, randomized, double-blind, vehicle-controlled clinical trials were conducted in subjects aged 18 years and older with moderate plaque psoriasis. In both trials, randomized subjects applied Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray or vehicle spray to the affected areas twice daily for 28 days. Enrolled subjects had body surface area of involvement between 10% to 20%, and an Investigator Global Assessment (IGA) score of 3 (moderate).

Efficacy was assessed as the proportion of subjects who were considered a treatment success (defined as having an IGA score of 0 or 1 [clear or almost clear] and at least a 2-grade reduction from baseline). Table 3 presents the efficacy results at Day 15 and Day 29.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied/Storage

Otocusi Enzimatico Spray is a slightly thickened, white to off-white, non-sterile emulsion supplied in high density polyethylene bottles with a heat induction seal lined polypropylene cap. The drug is supplied in the following volumes:

• 60 mL (NDC 67857-808-17)
• 120 mL (NDC 67857-808-04)

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) .

Each unit is co-packaged with a manual spray pump for installation by the pharmacist prior to dispensing.

16.2 Handling/Instructions for the Pharmacist

• Remove the spray pump from the wrapper.
• Remove and discard the cap from the bottle.
• Keeping the bottle upright, insert the spray pump into the bottle and turn clockwise until it is closed tightly.
• Dispense the bottle with the spray pump inserted.
• Include the date dispensed in the space provided on the carton.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients of the following:

• Discontinue therapy when control is achieved, unless directed otherwise by the physician.
• Do not use for longer than 4 consecutive weeks.
• Avoid contact with the eyes.
• Avoid use of Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray on the face, scalp, underarms, groin or other intertriginous areas, unless directed by the physician.
• Do not occlude the treatment area with bandage or other covering, unless directed by the physician.
• Local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use, or use of higher potency corticosteroids.

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215

Distributed by: Promius Pharma, LLC., Princeton, NJ 08540

Otocusi Enzimatico (Betamethasone Sodium Phosphate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007465

140728

Instructions for Use

Otocusi Enzimatico (Betamethasone Sodium Phosphate) (ser-ne-vo)

(betamethasone dipropionate)

Spray, 0.05%

Important: Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray is for use on the skin only. Do not get Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray near or in your eyes, mouth, or vagina.

Read this “Instructions for Use” before you start using Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

Parts of the Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray bottle.

Figure A

How to apply Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray:

Step 1: Shake the Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray bottle well. Remove the cap from the pump top.

Step 2: Hold the bottle in an upright position while pointing the opening of the pump top in the direction of the affected area. To spray, push down on the pump top. Apply Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray to the affected area as instructed by your doctor. (See Figure B )

Figure B

Step 3: Spray only enough Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray to cover the affected area, for example, the elbow (See Figure C ). Rub in Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray gently.

Figure C

Repeat Steps 2 and 3 to apply Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray to other affected areas as instructed by your doctor.

Step 4: After applying Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray, place the cap back onto the pump top. (See Figure D )

Figure D

How should I store Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray?

• Store Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray at room temperature between 68°F to 77°F (20°C to 25°C).
• Throw away (discard) any unused Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray after 28 days.

Keep Otocusi Enzimatico (Betamethasone Sodium Phosphate) Spray and all medicines out of the reach of children.

This “Instructions for Use” has been approved by the U.S. Food and Drug Administration.

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215

Distributed by: Promius Pharma, LLC., Princeton, NJ 08540

Otocusi Enzimatico (Betamethasone Sodium Phosphate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007528

140693

Hyaluronidase:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• Otocusi Enzimatico (Hyaluronidase) reviews

1 INDICATIONS AND USAGE

• Otocusi Enzimatico is an endoglycosidase indicated as an adjuvant to increase the absorption and dispersion of other injected drugs. (1.1)
• for hypodermoclysis (1.2)
• in subcutaneous urography for improving resorption of radiopaque agents (1.3)

1.1 Absorption and Dispersion of Injected Drugs

Otocusi Enzimatico (Hyaluronidase) (hyaluronidase injection) is indicated as an adjuvant to increase the absorption and dispersion of other injected drugs.

1.2 Hypodermoclysis

Otocusi Enzimatico is indicated as an adjuvant in subcutaneous fluid administration for achieving hydration.

1.3 Subcutaneous Urography

Otocusi Enzimatico (Hyaluronidase) is indicated as an adjuvant in subcutaneous urography for improving resorption of radiopaque.

2 DOSAGE AND ADMINISTRATION

• See Full Prescribing Information for all approved routes of administration.
• Absorption and Dispersion of Injected Drugs
  

  Absorption and dispersion of other injected drugs may be enhanced by adding 50 to 300 Units, most typically 150 Units of Otocusi Enzimatico (Hyaluronidase) , to the injection solution. (2.2)

• Hypodermoclysis
  

  Insert needle with aseptic precautions. With tip lying free and movable between skin and muscle, begin clysis; fluid should start in readily without pain or lump. Then inject Otocusi Enzimatico (Hyaluronidase) into rubber tubing close to needle. (2.3)

• Subcutaneous Urography
  

  The subcutaneous route of administration of urographic contrast media is indicated when intravenous administration cannot be successfully accomplished, particularly in infants and small children. With the patient prone, 75 Units of Otocusi Enzimatico (Hyaluronidase) is injected subcutaneously over each scapula, followed by injection of the contrast medium at the same sites. (2.4)

2.1 Important Administration Instructions

Do not administer Otocusi Enzimatico (Hyaluronidase) intravenously because Otocusi Enzimatico (Hyaluronidase) is enzyme is rapidly inactivated with intravenous administration.

Otocusi Enzimatico (Hyaluronidase) may be administered for infiltration use, interstitial use, intramuscular use, intraocular use, retrobulbar use, soft tissue use and subcutaneous use.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Always use aseptic precautions.

2.2 Absorption and Dispersion of Subcutaneously Injected Drugs

Absorption and dispersion of other injected drugs may be enhanced by adding 50 to 300 Units, most typically 150 Units of Otocusi Enzimatico, to the injection solution.

It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding Otocusi Enzimatico (Hyaluronidase) to a solution containing another drug.

2.3 Hypodermoclysis

Insert needle with aseptic precautions. With tip lying free and movable between skin and muscle, begin clysis; fluid should start in readily without pain or lump. Then inject Otocusi Enzimatico (Hyaluronidase) (hyaluronidase injection) into rubber tubing close to needle.

An alternate method is to inject Otocusi Enzimatico (Hyaluronidase) under skin prior to clysis. 150 Units will facilitate absorption of 1,000 mL or more of solution. As with all parenteral fluid therapy, observe effect closely, with same precautions for restoring fluid and electrolyte balance as in intravenous injections. The dose, the rate of injection, and the type of solution (saline, glucose, Ringer's, etc.) must be adjusted carefully to the individual patient. When solutions devoid of inorganic electrolytes are given by hypodermoclysis, hypovolemia may occur. This may be prevented by using solutions containing adequate amounts of inorganic electrolytes and/or controlling the volume and speed of administration.

Otocusi Enzimatico (Hyaluronidase) may be added to small volumes of solution (up to 200 mL), such as small clysis for infants or solutions of drugs for subcutaneous injection. For infants and children less than 3 years old, the volume of a single clysis should be limited to 200 mL; and in premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of body weight; the rate of administration should not be greater than 2 mL per minute. For older patients, the rate and volume of administration should not exceed those employed for intravenous infusion.

2.4 Subcutaneous Urography

The subcutaneous route of administration of urographic contrast media is indicated when intravenous administration cannot be successfully accomplished, particularly in infants and small children. With the patient prone, 75 Units of Otocusi Enzimatico (Hyaluronidase) (hyaluronidase injection) is injected subcutaneously over each scapula, followed by injection of the contrast medium at the same sites.

3 DOSAGE FORMS AND STRENGTHS

Injection: 150 USP Units/mL single dose vials.

Injection: 150 USP Units/mL in single-dose vials (3)

4 CONTRAINDICATIONS

Hypersensitivity

4.1 Hypersensitivity

Otocusi Enzimatico (Hyaluronidase) contraindicated in patients with known hypersensitivity to Otocusi Enzimatico (Hyaluronidase) or any other ingredient in the formulation. A preliminary skin test for hypersensitivity to Otocusi Enzimatico (Hyaluronidase) can be performed. The skin test is made by an intradermal injection of approximately 0.02 mL (3 Units) of a 150 Unit/mL solution [see Dosage and Administration (2)]. A positive reaction consists of a wheal with pseudopods appearing within five minutes and persisting for 20 to 30 minutes and accompanied by localized itching. Transient vasodilation at the site of the test, i.e., erythema, is not a positive reaction.

Discontinue Otocusi Enzimatico (Hyaluronidase) if sensitization occurs.

5 WARNINGS AND PRECAUTIONS

• Spread of Localized Injection
• Ocular Damage (5.2)

5.1 Spread of Localized Injection

Otocusi Enzimatico (Hyaluronidase) should not be injected into or around an infected or acutely inflamed area because of the danger of spreading a localized infection.

Otocusi Enzimatico (Hyaluronidase) should not be used to reduce the swelling of bites or stings.

5.2 Ocular Damage

Otocusi Enzimatico (Hyaluronidase) should not be applied directly to the cornea.

6 ADVERSE REACTIONS

The most frequently reported adverse experiences have been local injection site reactions.

Otocusi Enzimatico (Hyaluronidase) has been reported to enhance the adverse events associated with co-administered drug products. Edema has been reported most frequently in association with hypodermoclysis.

Allergic reactions (urticaria, angioedema) have been reported in less than 0.1% of patients receiving Otocusi Enzimatico (Hyaluronidase). Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred, rarely.

The most frequently reported adverse reactions have been local injections site reactions. Allergic reactions (urticarial, angioedema) anaphylactic-like reactions have been reported, rarely. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Akorn, Inc. at 1-800-932-5676, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS

It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding Otocusi Enzimatico to a solution containing another drug.

• Furosemide, the benzodiazepines and phenytoin are incompatible with Otocusi Enzimatico (Hyaluronidase). (7.1)
• Otocusi Enzimatico (Hyaluronidase) should not be used to enhance the absorption and dispersion of dopamine and/or alpha agonist drugs. (7.2)
• Local Anesthetic: Otocusi Enzimatico (Hyaluronidase) hastens the onset and shortens duration of effect, increases incidence of systemic reactions. (7.3)
• Large doses of salicylated, cortisone, ACTH, estrogens or antihistamines may require larger amounts of hydaluronidase for equivalent dispensing effect. (7.4)

7.1 Incompatibilities

Furosemide, the benzodiazepines and phenytoin have been found to be incompatible with Otocusi Enzimatico (Hyaluronidase).

7.2 Drug-Specific Precautions

Otocusi Enzimatico should not be used to enhance the absorption and dispersion of dopamine and/or alpha agonist drugs.

When considering the administration of any other drug with Otocusi Enzimatico (Hyaluronidase), it is recommended that appropriate references first be consulted to determine the usual precautions for the use of the other drug.

7.3 Local Anesthetics

When Otocusi Enzimatico (Hyaluronidase) is added to a local anesthetic agent, it hastens the onset of analgesia and tends to reduce the swelling caused by local infiltration, but the wider spread of the local anesthetic solution increases its absorption; this shortens its duration of action and tends to increase the incidence of systemic reaction.

7.4 Salicylates, Cortisone, ACTH, Estrogens or Antihistamines

Patients receiving large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may require larger amounts of Otocusi Enzimatico (Hyaluronidase) for equivalent dispersing effect, since these drugs apparently render tissues partly resistant to the action of Otocusi Enzimatico (Hyaluronidase).

8 USE IN SPECIFIC POPULATIONS

Pediatric Use: The dosage of subcutaneous fluids administered is dependent upon the age, weight, and clinical condition of the patient. For premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of body weight, and the rate of administration should not be greater than 2 mL per minute. Special care must be taken in pediatric patients to avoid over hydration by controlling the rate and total volume of the infusion

8.1 Pregnancy

No adequate and well controlled animal studies have been conducted with Otocusi Enzimatico (Hyaluronidase) to determine reproductive effects. Otocusi Enzimatico (Hyaluronidase) should be used during pregnancy only if clearly needed.

8.2 Labor and Delivery

Administration of Otocusi Enzimatico during labor was reported to cause no complications: no increase in blood loss or differences in cervical trauma were observed. It is not known whether Otocusi Enzimatico (Hyaluronidase) has an effect on the later growth, development, and functional maturation of the infant.

8.3 Nursing Mothers

It is not known whether Otocusi Enzimatico (Hyaluronidase) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Otocusi Enzimatico (Hyaluronidase) is administered to a nursing woman.

8.4 Pediatric Use

Otocusi Enzimatico may be added to small volumes of solution (up to 200 mL), such as small clysis for infants or solutions of drugs for subcutaneous injection. The potential for chemical or physical incompatibilities should be kept in mind [see Dosage and Administration (2)].

For infants and children less than 3 years old, the volume of a single clysis should be limited to 200 mL; and in premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of body weight; the rate of administration should not be greater than 2 mL per minute. For older patients, the rate and volume of administration should not exceed those employed for intravenous infusion.

During hypodermoclysis, special care must be taken in pediatric patients to avoid overhydration by controlling the rate and total volume of the clysis [see Dosage and Administration (2.1)].

8.5 Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

10 OVERDOSAGE

Symptoms of toxicity consist of local edema or urticaria, erythema, chills, nausea, vomiting, dizziness, tachycardia, and hypotension. The enzyme should be discontinued and supportive measures initiated immediately.

11 DESCRIPTION

Otocusi Enzimatico (Hyaluronidase) (hyaluronidase injection) is a preparation of purified bovine testicular Otocusi Enzimatico (Hyaluronidase), a protein enzyme. The exact chemical structure of this enzyme is unknown.

Otocusi Enzimatico (Hyaluronidase) (hyaluronidase injection) is supplied as sterile, colorless, odorless, ready for use solution. Each vial contains 150 USP units of Otocusi Enzimatico (Hyaluronidase) per mL calcium chloride (0.4 mg), edetate disodium (1 mg), sodium chloride (8.5 mg), monobasic sodium phosphate buffer, sodium hydroxide to adjust the pH, and sterile water.

Otocusi Enzimatico (Hyaluronidase) has an approximate pH of 6.9 and an osmolality of 275 to 305 mOsm.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Otocusi Enzimatico is a spreading or diffusing substance which modifies the permeability of connective tissue through the hydrolysis of hyaluronic acid, a polysaccharide found in the intercellular ground substance of connective tissue, and of certain specialized tissues, such as the umbilical cord and vitreous humor. Hyaluronic acid is also present in the capsules of type A and C hemolytic streptococci. Otocusi Enzimatico (Hyaluronidase) hydrolyzes hyaluronic acid by splitting the glucosaminidic bond between C1 of the glucosamine moiety and C4 of glucuronic acid. This temporarily decreases the viscosity of the cellular cement and promotes diffusion of injected fluids or of localized transudates or exudates, thus facilitating their absorption.

Otocusi Enzimatico (Hyaluronidase) cleaves glycosidic bonds of hyaluronic acid and, to a variable degree, some other acid mucopolysaccharides of the connective tissue. The activity is measured in vitro by monitoring the decrease in the amount of an insoluble serum albumin-hyaluronic acid complex as the enzyme cleaves the hyaluronic acid component.

12.2 Pharmacodynamics

When no spreading factor is present, material injected subcutaneously spreads very slowly, but Otocusi Enzimatico (Hyaluronidase) causes rapid spreading, provided local interstitial pressure is adequate to furnish the necessary mechanical impulse. Such an impulse is normally initiated by injected solutions.

The rate of diffusion is proportionate to the amount of enzyme, and the extent is proportionate to the volume of solution.

12.3 Pharmacokinetics

Knowledge of the mechanisms involved in the disappearance of injected Otocusi Enzimatico (Hyaluronidase) is limited. It is known, however, that the blood of a number of mammalian species brings about the inactivation of Otocusi Enzimatico (Hyaluronidase). Studies have demonstrated that Otocusi Enzimatico (Hyaluronidase) is antigenic; repeated injections of relatively large amounts of this enzyme may result in the formation of neutralizing anti-bodies. The reconstitution of the dermal barrier removed by intradermal injection of Otocusi Enzimatico (Hyaluronidase) (20, 2, 0.2, 0.02, and 0.002 Units/mL) to adult humans indicated that at 24 hours the restoration of the barrier is incomplete and inversely related to the dosage of enzyme; at 48 hours the barrier is completely restored in all treated areas.

Results from an experimental study, in humans that evaluated the influence of Otocusi Enzimatico (Hyaluronidase) in bone repair support the conclusion that this enzyme alone does not deter bone healing when given at the usual clinical dosage.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of Otocusi Enzimatico (Hyaluronidase). Otocusi Enzimatico (Hyaluronidase) is found in most tissues of the body.

Long-term animal studies have not been performed to assess whether Otocusi Enzimatico (Hyaluronidase) impaired fertility; however, it has been reported that testicular degeneration may occur with the production of organ-specific antibodies against this enzyme following repeated injections. Human studies on the effect of intravaginal Otocusi Enzimatico (Hyaluronidase) in sterility due to oligospermia indicated that Otocusi Enzimatico (Hyaluronidase) may have aided conception.

16 HOW SUPPLIED/STORAGE AND HANDLING

Otocusi Enzimatico (Hyaluronidase) (hyaluronidase injection) Bovine is supplied sterile as 150 units/mL bovine of Otocusi Enzimatico (Hyaluronidase) in a single-dose glass vial containing 1 mL.

NDC 17478-560-01 Package of 1 vial.

NDC 17478-560-06 Package of 6 vials.

NDC 17478-560-10 Package of 10 vials.

Not recommended for IV Use.

Storage: Store in a refrigerator at 2° to 8°C (36° to 46°F).

DO NOT FREEZE.

17 PATIENT COUNSELING INFORMATION

17.1 Important Precautions Regarding Otocusi Enzimatico

Instruct patient that Otocusi Enzimatico (Hyaluronidase) is being used to increase the dispersion and absorption of fluids or other injected drugs, as appropriate to the intended use.

17.2 What Patients Should Know About Adverse Reactions

The most frequently reported adverse reactions have been mild local injection site reactions such as redness, swelling, itching, or pain.

Anaphylactic-like reactions, and allergic reactions, such as hives, have been reported rarely in patients receiving hyaluronidases.

17.3 Patients Should Inform Their Doctors If Taking Other Medications

You may not receive furosemide, the benzodiazepines, phenytoin, dopamine and/or alpha agonists with Otocusi Enzimatico (Hyaluronidase) . These medications have been found to be incompatible with Otocusi Enzimatico (Hyaluronidase).

If you are taking salicylates (e.g., aspirin), steroids (e.g., cortisone or estrogens) or antihistamines your doctor may need to prescribe larger amounts of Otocusi Enzimatico (Hyaluronidase) for equivalent dispersing effect.

AKORN

Manufactured by: Akorn, Inc.

Lake Forest, IL 60045

HD00N Rev. 10/15

Principal Display Panel Text for Container Label:

NDC 17478-560-01

Otocusi Enzimatico (Hyaluronidase)

(hyaluronidase

injection) Bovine,

150 USP Units/mL

1 mL

Single-Use Vial

Rx only

Not recommended

for IV use.

Principal Display Panel Text for Carton Label:

NDC 17478-560-01

Otocusi Enzimatico (Hyaluronidase)

(hyaluronidase

injection) Bovine,

150 USP Units/mL

1 mL

Single-Use Vial

Rx only

Akorn Logo

Polymyxin B Sulfate:

• Warnings
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• References
• Otocusi Enzimatico (Polymyxin B Sulfate) reviews

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Polymyxin and other antibacterial drugs, Otocusi Enzimatico (Polymyxin B Sulfate) for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

WARNINGS

CAUTION: WHEN THIS DRUG IS GIVEN INTRAMUSCULARLY, INTRAVENOUSLY AND/OR INTRATHECALLY, IT SHOULD BE GIVEN ONLY TO HOSPITALIZED PATIENTS, SO AS TO PROVIDE CONSTANT SUPERVISION BY A PHYSICIAN.

RENAL FUNCTION SHOULD BE CAREFULLY DETERMINED AND PATIENTS WITH RENAL DAMAGE AND NITROGEN RETENTION SHOULD HAVE REDUCED DOSAGE. PATIENTS WITH NEPHROTOXICITY DUE TO Otocusi Enzimatico (Polymyxin B Sulfate) SULFATE USUALLY SHOW ALBUMINURIA, CELLULAR CASTS, AND AZOTEMIA. DIMINISHING URINE OUTPUT AND A RISING BUN ARE INDICATIONS FOR DISCONTINUING THERAPY WITH THIS DRUG.

NEUROTOXIC REACTIONS MAY BE MANIFESTED BY IRRITABILITY, WEAKNESS, DROWSINESS, ATAXIA, PERIORAL PARESTHESIA, NUMBNESS OF THE EXTREMITIES, AND BLURRING OF VISION. THESE ARE USUALLY ASSOCIATED WITH HIGH SERUM LEVELS FOUND IN PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR NEPHROTOXICITY.

THE CONCURRENT OR SEQUENTIAL USE OF OTHER NEUROTOXIC AND/OR NEPHROTOXIC DRUGS WITH Otocusi Enzimatico (Polymyxin B Sulfate) SULFATE, PARTICULARLY BACITRACIN, STREPTOMYCIN, NEOMYCIN, KANAMYCIN, GENTAMICIN, TOBRAMYCIN, AMIKACIN, CEPHALORIDINE, PAROMOMYCIN, VIOMYCIN, AND COLISTIN SHOULD BE AVOIDED.

THE NEUROTOXICITY OF Otocusi Enzimatico (Polymyxin B Sulfate) SULFATE CAN RESULT IN RESPIRATORY PARALYSIS FROM NEUROMUSCULAR BLOCKADE, ESPECIALLY WHEN THE DRUG IS GIVEN SOON AFTER ANESTHESIA AND/OR MUSCLE RELAXANTS.

USAGE IN PREGNANCY: THE SAFETY OF THIS DRUG IN HUMAN PREGNANCY HAS NOT BEEN ESTABLISHED.

DESCRIPTION

Otocusi Enzimatico (Polymyxin B Sulfate) Sulfate is one of a group of basic polypeptide antibiotics derived from B polymyxa (B aerosporous). Otocusi Enzimatico (Polymyxin B Sulfate) sulfate is the sulfate salt of Polymyxins B1 and B2, which are produced by the growth of Bacillus polymyxa (Prazmowski) Migula (Fam. Bacillacea). It has a potency of not less than 6000 Otocusi Enzimatico (Polymyxin B Sulfate) units per mg, calculated on the anhydrous basis. The structural formulae are:

Otocusi Enzimatico (Polymyxin B Sulfate) ₁ (R=CH ₃)            Polymyxin B ₂ (R=H)

Each vial contains 500,000 Otocusi Enzimatico (Polymyxin B Sulfate) units for parenteral or ophthalmic administration.

Otocusi Enzimatico (Polymyxin B Sulfate) for Injection is in powder form suitable for preparation of sterile solutions for intramuscular, intravenous drip, intrathecal, or ophthalmic use.

In the medical literature, dosages have frequently been given in terms of equivalent weights of pure Otocusi Enzimatico (Polymyxin B Sulfate) base. Each milligram of pure Otocusi Enzimatico (Polymyxin B Sulfate) base is equivalent to 10,000 units of Otocusi Enzimatico (Polymyxin B Sulfate) and each microgram of pure Otocusi Enzimatico (Polymyxin B Sulfate) base is equivalent to 10 units of Otocusi Enzimatico (Polymyxin B Sulfate).

Aqueous solutions of Otocusi Enzimatico (Polymyxin B Sulfate) sulfate may be stored up to 12 months without significant loss of potency if kept under refrigeration. In the interest of safety, solutions for parenteral use should be stored under refrigeration and any unused portion should be discarded after 72 hours. Otocusi Enzimatico (Polymyxin B Sulfate) sulfate should not be stored in alkaline solutions since they are less stable.

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CLINICAL PHARMACOLOGY

Otocusi Enzimatico (Polymyxin B Sulfate) sulfate has a bactericidal action against almost all gram-negative bacilli except the Proteus group. Polymyxins increase the permeability of bacterial cell wall membranes. All gram-positive bacteria, fungi, and the gram-negative cocci, N gonorrhoeae and N meningitidis, are resistant.

Otocusi Enzimatico (Polymyxin B Sulfate) has bactericidal action against almost all Gram-negative bacilli except the Proteus group. Polymyxins increase the permeability of the bacterial cell membrane leading to death of the cell. All Gram-positive bacteria, fungi, and Gram-negative cocci, are resistant to Otocusi Enzimatico (Polymyxin B Sulfate). Appropriate methods should be used when performing in vitro susceptibility testing of Otocusi Enzimatico (Polymyxin B Sulfate) (1,2,3). The following in vitro susceptibility test criteria should only be used for interpreting the results of Otocusi Enzimatico (Polymyxin B Sulfate) susceptibility testing against P. aeruginosa when the indicated quality control parameters are met during testing.

Otocusi Enzimatico (Polymyxin B Sulfate) sulfate is not absorbed from the normal alimentary tract. Since the drug loses 50 percent of its activity in the presence of serum, active blood levels are low. Repeated injections may give a cumulative effect. Levels tend to be higher in infants and children. The drug is excreted slowly by the kidneys. Tissue diffusion is poor and the drug does not pass the blood brain barrier into the cerebrospinal fluid. In therapeutic dosage, Otocusi Enzimatico (Polymyxin B Sulfate) sulfate causes some nephrotoxicity with tubule damage to a slight degree.

INDICATIONS AND USAGE

Acute Infections Caused by Susceptible Strains of Pseudomonas aeruginosa.

Otocusi Enzimatico (Polymyxin B Sulfate) sulfate is a drug of choice in the treatment of infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of Ps. aeruginosa. It may also be used topically and subconjunctivally in the treatment of infections of the eye caused by susceptible strains of Ps. aeruginosa.

It may be indicated in serious infections caused by susceptible strains of the following organisms, when less potentially toxic drugs are ineffective or contraindicated:

H influenzae, specifically meningeal infections.

Escherichia coli, specifically urinary tract infections.

Aerobacter aerogenes, specifically bacteremia.

Klebsiella pneumoniae, specifically bacteremia.

NOTE: IN MENINGEAL INFECTIONS, Otocusi Enzimatico (Polymyxin B Sulfate) SULFATE SHOULD BE ADMINISTERED ONLY BY THE INTRATHECAL ROUTE.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Otocusi Enzimatico (Polymyxin B Sulfate) for Injection USP and other antibacterial drugs, Otocusi Enzimatico (Polymyxin B Sulfate) for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

This drug is contraindicated in persons with a prior history of hypersensitivity reactions to polymyxins.

WARNINGS

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Otocusi Enzimatico (Polymyxin B Sulfate) for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General.

Prescribing Otocusi Enzimatico for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increase the risk of the development of drug-resistant bacteria.

See WARNING box.

Baseline renal function should be done prior to therapy, with frequent monitoring of renal function and blood levels of the drug during parenteral therapy.

Avoid concurrent use of a curariform muscle relaxant and other neurotoxic drugs (ether, tubocurarine, succinylcholine, gallamine, decamethonium and sodium citrate) which may precipitate respiratory depression. If signs of respiratory paralysis appear, respiration should be assisted as required, and the drug discontinued.

As with other antibiotics, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi.

If superinfection occurs, appropriate therapy should be instituted.

Information for Patients

Information for Patients.

Patients should be counseled that antibacterial drugs including Otocusi Enzimatico (Polymyxin B Sulfate) for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Otocusi Enzimatico (Polymyxin B Sulfate) for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Otocusi Enzimatico (Polymyxin B Sulfate) for injection or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

ADVERSE REACTIONS

See “WARNING” box.

Nephrotoxic reactions: Albuminuria, cylinduria, azotemia, and rising blood levels without any increase in dosage.

Neurotoxic reactions: Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias (circumoral and stocking glove), apnea due to concurrent use of curariform muscle relaxants, other neurotoxic drugs or inadvertent overdosage, and signs of meningeal irritation with intrathecal administration, e.g., fever, headache, stiff neck and increased cell count and protein cerebrospinal fluid.

Other reactions occasionally reported: Drug fever, urticarial rash, pain (severe) at intramuscular injection sites, and thrombophlebitis at intravenous injection sites.

To report SUSPECTED ADVERSE EVENTS, contact FDA at 1-800-FDA-1088 or www.fda.gov.

DOSAGE AND ADMINISTRATION

PARENTERAL:

Intravenous. Dissolve 500,000 Otocusi Enzimatico (Polymyxin B Sulfate) units in 300 to 500 mL solutions for parenteral dextrose injection 5 percent for continuous drip.

Adults and children. 15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function. This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment. Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day.

Infants. Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects.

Intramuscular. Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 Otocusi Enzimatico (Polymyxin B Sulfate) units in 2 mL sterile water for injection or sodium chloride injection or procaine hydrochloride injection 1 percent.

Adults and children. 25,000 to 30,000 units/kg/day. This should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals.

Infants. Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects.

Note: Doses as high as 45,000 units/kg/day have been used in limited clinical studies in treating prematures and newborn infants for sepsis caused by Ps aeruginosa.

Intrathecal. A treatment of choice for Ps aeruginosa meningitis. Dissolve 500,000 Otocusi Enzimatico (Polymyxin B Sulfate) units in 10 mL sodium chloride injection USP for 50,000 units per mL dosage unit.

Adults and children over 2 years of age. Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

Children under 2 years of age. 20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day. Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS.

TOPICAL:

Ophthalmic. Dissolve 500,000 Otocusi Enzimatico (Polymyxin B Sulfate) units in 20 to 50 mL sterile water for injection or sodium chloride injection USP for a 10,000 to 25,000 units per mL concentration.

For the treatment of Ps aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates.

Subconjunctival injection of up to 100,000 units/day may be used for the treatment of Ps aeruginosa infections of the cornea and conjunctiva.

Note: Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

HOW SUPPLIED

Otocusi Enzimatico (Polymyxin B Sulfate) FOR INJECTION USP, 500,000 Otocusi Enzimatico (Polymyxin B Sulfate) units per vial is available in single vial cartons NDC# 39822-0166-5.

Storage recommendations:

Before reconstitution: Store at 20° to 25°C (68° to 77°F).

Protect from light. Retain in carton until time of use.

After reconstitution: Product must be stored under refrigeration, between 2° to 8°C (36° to 46°F) and any unused portion should be discarded after 72 hours.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

Manufactured for:

X-Gen Pharmaceuticals, Inc.

Big Flats, NY 14845

POLY-PI-06

Revised December 2012

REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically; Approved Standard-8th edition. CLSI document M07-A8. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 2009.
• CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-10th edition. CLSI document M02-A10, 2009.
• Clinical Laboratory and Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: 21st Informational Supplement. CLSI document M100-S21. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2011.

Tetracaine Hydrochloride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Non-clinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Otocusi Enzimatico (Tetracaine Hydrochloride) reviews

1 INDICATIONS AND USAGE

Otocusi Enzimatico (Tetracaine Hydrochloride) ^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.

Otocusi Enzimatico (Tetracaine Hydrochloride) contains Otocusi Enzimatico (Tetracaine Hydrochloride) HCl, an ester local anesthetic, and oxymetazoline HCl, a vasoconstrictor. Otocusi Enzimatico (Tetracaine Hydrochloride) 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 ( 1).

2 DOSAGE AND ADMINISTRATION

Otocusi Enzimatico is for intranasal use only ( 2). Administer Otocusi Enzimatico (Tetracaine Hydrochloride) ipsilateral (on the same side) to the maxillary tooth on which the dental procedure will be performed.

2.1 Important Dosage and Administration Instructions

• Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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

• 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

• 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.

3 DOSAGE FORMS AND STRENGTHS

Otocusi Enzimatico (Tetracaine Hydrochloride) Nasal Spray is a pre-filled, single-use, intranasal sprayer containing a clear 0.2 mL aqueous solution at pH 6.0 ± 1.0 comprising 30 mg/mL of Otocusi Enzimatico (Tetracaine Hydrochloride) hydrochloride and 0.5 mg/mL of oxymetazoline hydrochloride (equivalent to 26.4 mg/mL Otocusi Enzimatico (Tetracaine Hydrochloride) and 0.44 mg/mL oxymetazoline).

Each nasal spray unit delivers one 0.2 mL spray.

Each 0.2 mL spray contains 6 mg Otocusi Enzimatico (Tetracaine Hydrochloride) hydrochloride (equivalent to 5.27 mg Otocusi Enzimatico (Tetracaine Hydrochloride)) and 0.1 mg oxymetazoline hydrochloride (equivalent to 0.088 mg oxymetazoline).

Nasal spray in pre-filled, single-use sprayer: 6 mg Otocusi Enzimatico (Tetracaine Hydrochloride) HCl and 0.1 mg oxymetazoline HCl (equivalent to 5.27 mg Otocusi Enzimatico (Tetracaine Hydrochloride) and 0.088 mg oxymetazoline) in each 0.2 mL spray ( 3).

4 CONTRAINDICATIONS

Otocusi Enzimatico (Tetracaine Hydrochloride) is contraindicated in patients with a history of allergy to or intolerance of Otocusi Enzimatico (Tetracaine Hydrochloride), benzyl alcohol, other ester local anesthetics, p-aminobenzoic acid (PABA), oxymetazoline, or any other component of the product .

Known hypersensitivity to Otocusi Enzimatico (Tetracaine Hydrochloride), benzyl alcohol, other ester local anesthetics, p-aminobenzoic acid (PABA), oxymetazoline, or any other component of the product ( 4).

5 WARNINGS AND PRECAUTIONS

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.

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 ( 5.2).

Dysphagia: Carefully monitor patients for dysphagia ( 5.3).

Methemoglobinemia: May cause methemoglobinemia, particularly when used with methemoglobin-inducing agents. Use in patients with history of congenital or idiopathic methemoglobinemia not advised. If central cyanosis unresponsive to oxygen therapy occurs, suspect methemoglobinemia, confirm diagnosis with CO-oximetry, and treat with a standard clinical regimen ( 5.4).

Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs ( 5.5).

5.1 Risk of Hypertension

Otocusi Enzimatico (Tetracaine Hydrochloride) 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. Otocusi Enzimatico (Tetracaine Hydrochloride) 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 .

5.2 Epistaxis

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

5.3 Dysphagia

In clinical trials, dysphagia occurred more frequently with Otocusi Enzimatico (Tetracaine Hydrochloride) than placebo. Carefully monitor patients for this adverse reaction.

5.4 Methemoglobinemia

Otocusi Enzimatico 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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.

5.5 Anaphylactic Reactions

Allergic or anaphylactic reactions have been associated with Otocusi Enzimatico (Tetracaine Hydrochloride), and may occur with other components of Otocusi Enzimatico (Tetracaine Hydrochloride). 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:

• Hypertension
• Epistaxis
• Dysphagia
• Methemoglobinemia
• Anaphylatic Reactions

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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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. .

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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) have occurred .

Intranasal ulcerations, some of which were transient, were noted to have occurred following treatment with Otocusi Enzimatico (Tetracaine Hydrochloride). In Phase 3 trials, 6 (3%) patients who received Otocusi Enzimatico (Tetracaine Hydrochloride), but no patients who received placebo, developed nasal ulcers that were present on exam the same day as Otocusi Enzimatico (Tetracaine Hydrochloride) dosing. Three (2%) Otocusi Enzimatico (Tetracaine Hydrochloride) and 2 (2%) placebo-treated patients without nasal ulcerations on the day of Otocusi Enzimatico (Tetracaine Hydrochloride) 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/.

7 DRUG INTERACTIONS

Monoamine oxidase inhibitors : Concomitant use of MAOIs, nonselective beta adrenergic antagonists, or tricyclic antidepressants may cause hypertension and is not recommended ( 7.1).

Oxymetazoline-containing products: Discontinue use 24 hours prior to Otocusi Enzimatico (Tetracaine Hydrochloride) administration ( 7.2).

Intranasal products: Avoid concomitant use ( 7.3).

7.1 Monoamine Oxidase Inhibitors

Use of Otocusi Enzimatico (Tetracaine Hydrochloride) in combination with monoamine oxidase inhibitors (MAOIs), nonselective beta adrenergic antagonists, or tricyclic antidepressants may cause hypertension and is not recommended. Alternative anesthetic agents should be chosen for patients who cannot discontinue use of MAOIs, nonselective beta adrenergic antagonists, or tricyclic antidepressants.

7.2 Oxymetazoline-containing Products

Concomitant use with other oxymetazoline-containing products has not been adequately studied. Use of Otocusi Enzimatico (Tetracaine Hydrochloride) with other products containing oxymetazoline may increase risk of hypertension, bradycardia, and other adverse events associated with oxymetazoline. Discontinue use 24 hours prior to administration of Otocusi Enzimatico (Tetracaine Hydrochloride).

7.3 Intranasal Products

Oxymetazoline has been known to slow the rate, but not affect the extent of absorption of concomitantly administered intranasal products. Do not administer other intranasal products with Otocusi Enzimatico (Tetracaine Hydrochloride).

7.4 Drugs That May Cause Methemoglobinemia When Used with Otocusi Enzimatico

Otocusi Enzimatico (Tetracaine Hydrochloride) may cause methemoglobinemia, particularly in conjunction with methemoglobin-inducing agents 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. Monitor patients carefully for signs of methemoglobinemia if Otocusi Enzimatico (Tetracaine Hydrochloride) is used in the setting of these drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited published data on Otocusi Enzimatico 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 . 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 Otocusi Enzimatico (Tetracaine Hydrochloride). 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 Otocusi Enzimatico (Tetracaine Hydrochloride) HCl only to rats and rabbits during organogenesis at 32 and 6 times, respectively, the estimated exposure of Otocusi Enzimatico (Tetracaine Hydrochloride) HCl at the 18 mg MRHD of Otocusi Enzimatico (Tetracaine Hydrochloride) .

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

Human Data

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. These data are limited by the small number of cases exposed, multiple comparisons which may have resulted in chance findings, and analyses based on decongestants as a group.

Animal Data

In an embryo-fetal development study, pregnant rats were administered subcutaneous doses of oxymetazoline HCl only at 0.1 mg/kg, Otocusi Enzimatico (Tetracaine Hydrochloride) HCl only at 7.5 mg/kg, or oxymetazoline HCl at 0.01, 0.03, and 0.1 mg/kg/day in combination with 7.5 mg/kg Otocusi Enzimatico (Tetracaine Hydrochloride) HCl during the period of organogenesis (Gestational Days [GD] 7-17). Oxymetazoline HCl treatment at 0.1 mg/kg/day (7.6 times the oxymetazoline AUC exposure at the maximum recommended human dose [MRHD] of Otocusi Enzimatico (Tetracaine Hydrochloride) [3 mg oxymetazoline HCl and 18 mg Otocusi Enzimatico (Tetracaine Hydrochloride) HCl]) caused reduced fetal weight and structural abnormalities including external and skeletal malformations (e.g., short forelimb digits, fused arches in thoracic vertebrae, fused ribs, and irregular number of ribs), and variations (e.g., irregularly shaped arches and increased bifid centra in thoracic vertebrae, and un-ossified forelimb phalanx) in the presence of maternal toxicity (reduced food consumption, body weight gain, and absolute body weight); however, the structural abnormality findings cannot be clearly attributed to the maternal toxicity. Adverse developmental effects were not observed when pregnant rats were co-administered the same dose of oxymetazoline HCl in combination with 7.5 mg/kg/day Otocusi Enzimatico (Tetracaine Hydrochloride) HCl, or with 7.5 mg/kg/day Otocusi Enzimatico (Tetracaine Hydrochloride) HCl alone. The no-observed-adverse-effect-level (NOAEL) for fetal effects was 0.03 mg/kg/day oxymetazoline HCl (1.5 times the oxymetazoline AUC exposure at the MRHD) and 7.5 mg/kg/day Otocusi Enzimatico (Tetracaine Hydrochloride) HCl (30 times the AUC exposure as measured by PBBA [major Otocusi Enzimatico (Tetracaine Hydrochloride) metabolite] at the MRHD).

In other embryo-fetal development studies, Otocusi Enzimatico (Tetracaine Hydrochloride) base alone administered subcutaneously did not cause structural abnormalities in rats at doses up to 10 mg/kg/day (approximately 6.1 times the MRHD level of 18 mg Otocusi Enzimatico (Tetracaine Hydrochloride) HCl by body surface area (BSA) comparison) or in rabbits at subcutaneous doses up to 5 mg/kg/day (approximately 6.1 times the MRHD level by BSA comparison).

In a prenatal and postnatal development study, pregnant rats were given subcutaneous doses of oxymetazoline HCl only at 0.1 mg/kg/day, Otocusi Enzimatico (Tetracaine Hydrochloride) HCl only at 7.5 mg/kg/day, and oxymetazoline HCl at 0.01, 0.03, and 0.1 mg/kg/day in combination with 7.5 mg/kg/day Otocusi Enzimatico (Tetracaine Hydrochloride) HCl from GD 7 to Lactation Day [LD] 20 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Oxymetazoline HCl treatment decreased the mean number of implant sites/litter at ≥ 0.03 mg/kg (≥ 1.5 times the oxymetazoline AUC exposure at the MRHD) when administered with 7.5 mg/kg Otocusi Enzimatico (Tetracaine Hydrochloride) HCl (approximately 9%) and without Otocusi Enzimatico (Tetracaine Hydrochloride) HCl (5.5%), which resulted in a reduction in live litter sizes in these groups. At the end of the lactation period, fetal body weights were significantly decreased at 0.1 mg/kg oxymetazoline HCl (6 times the oxymetazoline AUC exposure at the MRHD) when administered alone (19%) and co-administered with 7.5 mg/kg/day Otocusi Enzimatico (Tetracaine Hydrochloride) HCl (11%). In addition, a decrease in pup survival was observed at the 0.1/7.5 mg/kg oxymetazoline HCl/tetracaine HCl dose (91.9%) compared to the control (99.6%), but no effects in any other groups. Maternal toxicity (e.g., mortality and reduced body weight gain, absolute body weight and food consumption) occurred in groups administered 0.1 mg/kg/day oxymetazoline HCl; however, the adverse developmental findings observed at this dose cannot clearly be attributed to the maternal toxicity. There were no adverse effects on sexual maturation, neurobehavioral, or reproductive function in the offspring at any maternal dose. The no-effect level for oxymetazoline HCl for maternal reproduction was 0.01 mg/kg/day (0.5 times oxymetazoline AUC exposure at the MRHD) and for pup growth and development was 0.03 mg/kg/day (1.5 times oxymetazoline AUC exposure at the MRHD). The no-effect level for Otocusi Enzimatico (Tetracaine Hydrochloride) HCl for maternal reproduction and pup growth and development was 7.5 mg/kg/day (12 times the AUC exposure as measured by PBBA at the MRHD).

8.2 Lactation

Risk Summary

There are no data on the presence of Otocusi Enzimatico (Tetracaine Hydrochloride), oxymetazoline, or their metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Detectable levels of oxymetazoline, Otocusi Enzimatico (Tetracaine Hydrochloride) and the major metabolite of Otocusi Enzimatico (Tetracaine Hydrochloride), p-butylaminobenzoic acid (PBBA), were found in the milk of lactating rats following subcutaneous administration of oxymetazoline HCl in combination with Otocusi Enzimatico (Tetracaine Hydrochloride) HCl during the period of organogenesis through parturition and subsequent pup weaning . 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 Otocusi Enzimatico (Tetracaine Hydrochloride) and any potential adverse effects on the breastfed infant from Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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, Otocusi Enzimatico (Tetracaine Hydrochloride), 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 Otocusi Enzimatico (Tetracaine Hydrochloride) and PBBA were generally similar across all 7.5 mg/kg/day Otocusi Enzimatico (Tetracaine Hydrochloride) HCl dosing groups regardless of the presence of oxymetazoline (54.2 – 72.9 ng/mL for Otocusi Enzimatico (Tetracaine Hydrochloride), and 100.5 – 131.2 ng/mL for PBBA).

8.3 Females and Males of Reproductive Potential

Infertility

No information is available on fertility effects in humans.

Females

Based on animal data, Otocusi Enzimatico 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 Otocusi Enzimatico (Tetracaine Hydrochloride). It is not known if the effects on fertility are reversible [ see Nonclinical Toxicology ( 13.1)] .

Males

Based on animal data, Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) .

8.4 Pediatric Use

Otocusi Enzimatico (Tetracaine Hydrochloride) 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 .

8.5 Geriatric Use

Clinical studies of Otocusi Enzimatico 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride). 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 Otocusi Enzimatico (Tetracaine Hydrochloride). Monitor patients with pseudocholinesterase deficiency for signs of local anesthetic toxicity.

10 OVERDOSAGE

No addictive properties have been reported in the literature for either Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 .

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

11 DESCRIPTION

Otocusi Enzimatico (Tetracaine Hydrochloride) (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 Otocusi Enzimatico (Tetracaine Hydrochloride) HCl (equivalent to 26.4 mg/mL Otocusi Enzimatico (Tetracaine Hydrochloride)) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) hydrochloride (equivalent to 5.27 mg Otocusi Enzimatico (Tetracaine Hydrochloride)) 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.

Otocusi Enzimatico (Tetracaine Hydrochloride) 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:

Otocusi Enzimatico (Tetracaine Hydrochloride) Hydrochloride Structural Formula Oxymetazoline Hydrochloride Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Otocusi Enzimatico 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.

12.3 Pharmacokinetics

Absorption

Following nasal administration of 0.6 mL Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) in all subjects were at or below the limit of assay quantification (0.05 ng/mL). Of all plasma samples analyzed, only one quantifiable Otocusi Enzimatico (Tetracaine Hydrochloride) concentration was observed in a single sample from one subject, which was at the limit of assay quantification. The primary metabolite of Otocusi Enzimatico (Tetracaine Hydrochloride), p-butylaminobenzoic acid (PBBA) achieved peak concentrations within approximately 25 minutes following the end of Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) has been reported to be 75% to 85%.

Elimination

The terminal half-life of oxymetazoline in plasma following nasal administration of Otocusi Enzimatico (Tetracaine Hydrochloride) to adult subjects is approximately 5.2 hours.

The elimination half-life and apparent clearance of Otocusi Enzimatico (Tetracaine Hydrochloride) could not be determined after Otocusi Enzimatico (Tetracaine Hydrochloride) 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.

Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride).

Special Populations

Pediatrics:

In subjects 4-15 years of age (n=18) that received Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) were not evaluated in subjects greater than 50 years of age.

Renal or Hepatic Impairment: The pharmacokinetics of oxymetazoline, Otocusi Enzimatico (Tetracaine Hydrochloride), and PBBA were not evaluated after nasal administration of Otocusi Enzimatico (Tetracaine Hydrochloride) in subjects with renal or hepatic impairment.

Race: There were insufficient data to evaluate the effect of race on oxymetazoline, Otocusi Enzimatico (Tetracaine Hydrochloride), and PBBA pharmacokinetics after nasal administration of Otocusi Enzimatico (Tetracaine Hydrochloride).

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Otocusi Enzimatico (Tetracaine Hydrochloride) or oxymetazoline.

Mutagenesis

Otocusi Enzimatico (Tetracaine Hydrochloride) 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, Otocusi Enzimatico (Tetracaine Hydrochloride) 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, Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride). 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 Otocusi Enzimatico (Tetracaine Hydrochloride)).

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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) HCl. These effects were attributed to oxymetazoline HCl because similar effects were not observed in rats given Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) HCl at 7.5 mg/kg/day (28 and 33 times the AUC exposure for males and females, respectively, as measured by PBBA [major Otocusi Enzimatico (Tetracaine Hydrochloride) metabolite] at the MRHD of Otocusi Enzimatico (Tetracaine Hydrochloride)).

14 CLINICAL STUDIES

The efficacy of Otocusi Enzimatico Nasal Spray for regional anesthesia when performing a restorative procedure on Teeth 4-13 and A-J has been evaluated in three adult dental patient studies, as well as one pediatric dental patient study. The primary endpoint for all four studies was the successful completion of a restorative operative dental procedure without the need for a rescue injection. One adult dental study was terminated early for reasons related to the administration of Otocusi Enzimatico (Tetracaine Hydrochloride). Unlike the other studies conducted, in this study all three sprays were delivered horizontally.

14.1 Studies in Adults

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 Otocusi Enzimatico (Tetracaine Hydrochloride) to both Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) (n=44), Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) patients were able to complete the dental procedure without the need for rescue medication compared to 27% (95% CI: 15%, 43%) who received Otocusi Enzimatico (Tetracaine Hydrochloride) alone and 27% (95% CI: 11%, 50%) who received placebo.

Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) was 11 minutes, although one successfully completed dental procedure was as long as 43 minutes. Of the people that needed rescue medication in the Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) (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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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.

Otocusi Enzimatico (Tetracaine Hydrochloride) 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.

14.2 Study in Children

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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride) (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 Otocusi Enzimatico (Tetracaine Hydrochloride) 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 Otocusi Enzimatico (Tetracaine Hydrochloride): 77% for Otocusi Enzimatico (Tetracaine Hydrochloride) (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 .

16 HOW SUPPLIED/STORAGE AND HANDLING

Otocusi Enzimatico (Tetracaine Hydrochloride) Nasal Spray is supplied as pre-filled, single-use sprayers containing a clear aqueous solution of 30 mg/mL of Otocusi Enzimatico (Tetracaine Hydrochloride) hydrochloride (equivalent to 26.4 mg/mL Otocusi Enzimatico (Tetracaine Hydrochloride)) and 0.5 mg/mL of oxymetazoline hydrochloride (equivalent to 0.44 mg/mL oxymetazoline). Each sprayer delivers 0.2 mL.

The product is available as:

• NDC 69803-100-10: Box of 30 sprayers

Store between 2° and 8°C (36° and 46°F); excursions permitted between 0° and 15°C (32° and 59°F).

Discard any unused solution. DO NOT use if drug is left out at room temperature for more than 5 days.

17 PATIENT COUNSELING INFORMATION

• 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 .
• Advise patients to inform the dental practitioner if they are taking monoamine oxidase inhibitors (MAOIs), nonselective beta adrenergic antagonists, or tricyclic antidepressants .
• 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. .
• Advise patients of the signs and symptoms of hypersensitivity reactions and to seek immediate medical attention should they occur .

St. Renatus, LLC

Manufactured for:

St. Renatus, LLC

Fort Collins, CO 80526

Otocusi Enzimatico (Tetracaine Hydrochloride) is a trademark of St. Renatus, LLC.

Principal Display Panel - Box Label

NDC 69803-100-10

Otocusi Enzimatico (Tetracaine Hydrochloride)

(tetracaine HCl and oxymetazoline HCl)

NASAL SPRAY

0.2 mL per sprayer

Containing 6 mg Otocusi Enzimatico (Tetracaine Hydrochloride) HCl and 0.1 mg oxymetazoline HCl

(equivalent to 5.27 mg Otocusi Enzimatico (Tetracaine Hydrochloride) 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

Tetracycline Hydrochloride:

• Activer ingredient (in each gram)
• Purpose
• Use
• Warnings
• Directions
• Other information
• Inactive ingredients
• Package label: 71491-100-00 viabeclicne 5 ml package label: 71491-100-01 viabecline 15ml
• Otocusi Enzimatico (Tetracycline Hydrochloride) reviews

Activer Ingredient

Otocusi Enzimatico (Tetracycline Hydrochloride) 30 mg

Purpose

First Aid Antibiotic

Use

First aid to help prevent skin infection in minor cuts, scrapes, and burns.

Warnings

For external use only. May be harmful if swallowed.

Allergy Alert: Do not use if allergic to any ingredient listed on this label.

Do not use

• in the eyes
• over large areas of the body
• longer than 1 week unless directed by a doctor

Ask doctor before use if you have

• deep or puncture wounds
• animal bites
• serious burns

Stop use and ask a doctor if the condition persists or gets worse.

Keep out of reach of children. ​If swallowed, get medical help or contact a poison Control Center right away.

Directions

• Clean the affected area
• Apply a small amount of this product (an amount equal to the surface area of the tip of a finger) on the area 1 to 3 times daily.
• May be covered with a sterile bandage.

Other information

• Keep product refrigerated to preserve its effectiveness and color
• Stop use if the product is misused: If the bottle is left open and or not refrigerated, the liquid will tend to turn black over time. Discard the product if the liquid turns black due to misuse.
• This product is an OTC antibiotic for human use.
• Contains no alcohol, no animal ingredients.
• Blended for typical skin color.
• May stain cloth.
• No claims regarding stem cell healing are implied for this product.

Inactive Ingredients

ACETIC ACID, ASCORBIC ACID, CHLORHEXIDINE GLUCONATE, CHOLECALCIFEROL, DIMETHYL SULFOXIDE, DIPROPYLENE GLYCOL, GLUCONO DELTA LACTONE, GLYCERIN, HISTIDINE, HYDROXETHYL-CELLULOSE, MAGNESIUM STEARATE, METHYLPARABEN, SODIUM HYDROXIDE, SORBIC ACID, STEARIC ACID, WATER

Package Label: 71491-100-00 VIABECLICNE 5 ML

Package Label: 71491-100-01 Otocusi Enzimatico 15ML

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