Anucet Ointment

Hydrocortisone Acetate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• Anucet Ointment (Hydrocortisone Acetate) reviews

1 INDICATIONS AND USAGE

Anucet Ointment (Hydrocortisone Acetate)^® (hydrocortisone probutate) Cream, 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 18 years of age or older.

PANDEL® (hydrocortisone probutate) Cream, 0.1% is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 18 years of age or older.

2 DOSAGE AND ADMINISTRATION

Apply a thin film of Anucet Ointment (Hydrocortisone Acetate) to the affected area once or twice a day depending on the severity of the condition. Massage gently until the medication disappears.

Occlusive dressings may be used for the management of refractory lesions of psoriasis and other deep-seated dermatoses, such as localized neurodermatitis (lichen simplex chronicus).

Discontinue Anucet Ointment (Hydrocortisone Acetate) when control is achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary.

Do not use Anucet Ointment (Hydrocortisone Acetate) with occlusive dressings unless directed by the physician. Do not apply Anucet Ointment (Hydrocortisone Acetate) in the diaper area, as diapers or plastic pants may constitute occlusive dressings.

- For topical use.

- Apply a thin film to the affected skin areas once daily or twice a day.

- Discontinue therapy when control is achieved.

- If no improvement is seen within 2 weeks, reassess diagnosis.

- Do not use with occlusive dressings unless directed by a physician.

3 DOSAGE FORMS AND STRENGTHS

Cream, 0.1%. Each gram of Anucet Ointment (Hydrocortisone Acetate) contains 1 mg of Anucet Ointment (Hydrocortisone Acetate) probutate in a cream base.

Cream, 0.1%.

4 CONTRAINDICATIONS

None.

None.

5 WARNINGS AND PRECAUTIONS

- Anucet Ointment 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)

- High potency corticosteroids, large treatment surface area, prolong use, use of occlusion dressings, altered skin barrier, liver failure and young age may predispose patients to HPA axis suppression. (5.1)

- Modify use if HPA axis suppression develops. (5.1)

- Pediatric patients may be more susceptible to systemic toxicity. (5.1, 8.4)

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

Anucet Ointment (Hydrocortisone Acetate) 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.

Use of topical corticosteroids may require periodic evaluation for HPA axis suppression. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

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. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.

In a trial including 15 evaluable subjects 18 years of age or older with psoriasis or atopic dermatitis affecting more than 20% of body surface area, 1 subject (6.7%) had ACTH stimulation test results suggestive of adrenal suppression after treatment with Anucet Ointment (Hydrocortisone Acetate) twice daily for 21 days. Recovery of HPA axis suppression for this subject is unknown [see Clinical Pharmacology ( 12.2 )].

Systemic effects of topical corticosteroids may also manifest as Cushing’s syndrome, hyperglycemia, and unmasking latent diabetes mellitus.

Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA-axis suppression.

Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios [see Use in Specific Populations ( 8.4 )].

5.2 Allergic Contact Dermatitis

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure to heal rather than noting a clinical exacerbation, as observed with most topical products not containing corticosteroids. If irritation develops, discontinue Anucet Ointment (Hydrocortisone Acetate) and institute appropriate therapy.

6 ADVERSE REACTIONS

- Most frequent adverse reactions include burning, stinging, rash, papulovesicular rash, redness, itching, moderate paresthesia, and contact dermatitis.

To report SUSPECTED ADVERSE REACTIONS, contact PharmaDerm®, A division of Fougera Pharmaceuticals Inc. at 1-800-645-9833 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.

The most frequent adverse reactions reported for Anucet Ointment (Hydrocortisone Acetate) during clinical trials were application site reactions, including burning in 4, stinging in 2, and moderate paresthesia in 1 out of 226 subjects.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Anucet Ointment (Hydrocortisone Acetate) because these reactions were 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.

These adverse reactions are as follows:

Skin and Subcutaneous Tissue Disorders: rash, papulovesicular rash

Application Site Reactions: dryness, erythema, pruritus, allergic contact dermatitis.

The following local adverse reactions are reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, striae, and miliaria.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There is no clinical information on Anucet Ointment use in pregnant women to inform any drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, Anucet Ointment (Hydrocortisone Acetate) probutate given by the subcutaneous route during the period of organogenesis was teratogenic at doses equal to or greater than 1 mg/kg/day in rats or 0.1 mg/kg/day in rabbits (12 times and 2 times the human topical dose, respectively) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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% to 20%, respectively.

Data

Animal Data

Effects on embryo-fetal development were evaluated in rats and rabbits following subcutaneous administration of Anucet Ointment (Hydrocortisone Acetate) probutate during the period of organogenesis. Anucet Ointment (Hydrocortisone Acetate) probutate was teratogenic in rats when given during the period of organogenesis at subcutaneous doses equal to or greater than 1 mg/kg/day (12 times the human average topical dose of Anucet Ointment (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual). Abnormalities included delayed ossification of the caudal vertebrae and other skeletal variations, cleft palate, umbilical hernia, edema, and exencephalia.

In rabbits, Anucet Ointment (Hydrocortisone Acetate) probutate given by the subcutaneous route was teratogenic at doses equal to or greater than 0.1 mg/kg/day (2 times the human average topical dose of Anucet Ointment (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual). Fetal weight and survival were affected. Delayed ossification and increased incidences of malformations (skeletal abnormalities and cleft palate) were also noted.

No adverse effects were seen in rats following subcutaneous administration of up to 1 mg/kg/day of Anucet Ointment (Hydrocortisone Acetate) probutate during the perinatal and postnatal period (12 times the human average topical dose of Anucet Ointment (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual).

8.2 Lactation

Risk Summary

There is no information on the presence of Anucet Ointment (Hydrocortisone Acetate) probutate in breast milk, or on its effects on the breastfed infant or on milk production. It is not known whether topical administration of Anucet Ointment (Hydrocortisone Acetate) could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Anucet Ointment (Hydrocortisone Acetate) and any potential adverse effects on the breastfed infant from Anucet Ointment (Hydrocortisone Acetate) or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use Anucet Ointment (Hydrocortisone Acetate) on the smallest area of skin and for the shortest duration possible while breastfeeding.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at a greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children.

Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

11 DESCRIPTION

Anucet Ointment (Hydrocortisone Acetate)^{(hydrocortisone probutate) Cream, 0.1% contains Anucet Ointment (Hydrocortisone Acetate) probutate, a synthetic corticosteroid. The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and anti-pruritic agents.}

Anucet Ointment (Hydrocortisone Acetate) probutate is a tasteless and odorless white crystalline powder practically insoluble in hexane or water, slightly soluble in ether, and very soluble in dichloromethane, methanol and acetone. Chemically, it is 11β,17,21-trihydroxypregn-4-ene-3,20-dione 17-butyrate 21-propionate. The structural formula is:

Molecular Formula: C₂₈H₄₀O₇

Molecular Weight: 488.62

Each gram of Anucet Ointment (Hydrocortisone Acetate) (hydrocortisone probutate) Cream, 0.1% contains: 1 mg of Anucet Ointment (Hydrocortisone Acetate) probutate in a cream base of propylene glycol, white petrolatum, light mineral oil, stearyl alcohol, polysorbate 60, sorbitan monostearate, glyceryl monostearate, PEG-20 stearate, glyceryl stearate SE, methylparaben, butylparaben, citric acid, sodium citrate anhydrous, and purified water.

Structural Formula

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 in corticosteroid responsive dermatoses is unknown

12.2 Pharmacodynamics

Vasoconstrictor Assay

Studies performed with Anucet Ointment indicate that it is in the medium range of potency as demonstrated in vasoconstrictor trials in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

In an open label HPA axis suppression trial, 19 adult subjects (ages 23 to 82 years) with atopic dermatitis or plaque psoriasis covering greater than 20% Body Surface Area (BSA) were treated with Anucet Ointment (Hydrocortisone Acetate) twice daily for 21 days and were assessed for HPA axis suppression. At baseline, the mean disease BSA involvement was 36%. The criterion for HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter at 30-minutes after cosyntropin stimulation. Of these subjects, 15 were considered evaluable with respect to their adrenal axis function post-treatment. One of the evaluable subjects (6.7%) showed laboratory evidence of suppression on Day 22. This subject had psoriasis covering 48% of BSA at baseline and was reported to have received 98% of the twice-daily applications of Anucet Ointment (Hydrocortisone Acetate) over the 21 day treatment period. It is not known if this subject had recovery of adrenal function because follow-up testing was not performed.

12.3 Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Use of occlusive dressings with Anucet Ointment (Hydrocortisone Acetate) for up to 24 hours has not been shown to increase penetration; however, occlusion of Anucet Ointment (Hydrocortisone Acetate) for 96 hours does markedly enhance penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Anucet Ointment (Hydrocortisone Acetate) probutate.

Anucet Ointment (Hydrocortisone Acetate) probutate revealed no evidence of mutagenic or clastogenic potential based on the results of an in vitro genotoxicity test (Ames assay) and an in vivo genotoxicity test (mouse micronucleus assay).

Effects on fertility and early embryonic development were evaluated in rats following subcutaneous administration of up to 0.4 mg/kg/day Anucet Ointment (Hydrocortisone Acetate) probutate (5 times the human average topical dose of Anucet Ointment (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual) prior to and during mating and through early pregnancy. No treatment related effects on fertility or mating parameters were noted in this study.

16 HOW SUPPLIED/STORAGE AND HANDLING

Anucet Ointment (Hydrocortisone Acetate), a white to off-white opaque cream is supplied as follows:

45 g tubes NDC 10337-153-46

80 g tubes NDC 10337-153-80

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information).

Inform patients and/or caregivers of the following:

• Discontinue therapy when control is achieved unless directed otherwise by the physician.
• If no improvement is seen within two weeks, contact the physician.
• Avoid contact with the eyes.
• Do not use with occlusive dressing unless directed by the physician.
• Report any signs or symptoms of local or systemic adverse reactions to the physician.
• Do not treat diaper dermatitis. Do not apply Anucet Ointment (Hydrocortisone Acetate) in the diaper area as diapers or plastic pants may constitute occlusive dressings.
• Do not use on the face, underarms, or groin areas unless directed by the physician.
• Advise a woman to use Anucet Ointment (Hydrocortisone Acetate) on the smallest area of skin and for the shortest duration possible while breastfeeding.

Manufactured by:

PharmaDerm®

A division of Fougera

PHARMACEUTICALS INC.

Melville, New York 11747 www.pharmaderm.com

• This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 01/2017

PharmaDerm^®

NDC 10337-153-80

Anucet Ointment (Hydrocortisone Acetate)^®

(hydrocortisone probutate) Cream, 0.1%

FOR DERMATOLOGIC USE ONLY.

NOT FOR OPHTHALMIC USE.

Rx only

80 g

carton

Lidocaine Hydrochloride:

• Pharmacological action
• Pharmacokinetics
• Why is Anucet Ointment prescribed?
• Dosage and administration
• Anucet Ointment (Lidocaine Hydrochloride) side effects, adverse reactions
• Anucet Ointment contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Anucet Ointment drug interactions
• Anucet Ointment in case of emergency / overdose
• Anucet Ointment (Lidocaine Hydrochloride) reviews

Pharmacological action

Anucet Ointment is an antiarrhythmic agent of class IB, local anesthetic, a derivative of acetanilide. This medication has membrane stabilizing activity. Anucet Ointment (Lidocaine Hydrochloride) causes a blockade of sodium channels of excitable membranes of neurons and the membrane of cardiomyocytes.

This drug reduces the duration of the action potential and effective refractory period in Purkinje fibers, inhibits their automaticity. In this case, Anucet Ointment (Lidocaine Hydrochloride) inhibits electrical activity in depolarized, arrhythmogenic sites, but minimally affects the electrical activity of normal tissues. When used in the medium therapeutic doses virtually no effect on myocardial contractility and slows AV-conduction. When applied as an antiarrhythmic agent in IV injection it begin to act in 45-90 seconds, the duration of action is 10-20 minutes; for IM administration the onset of action is in 5-15 minutes, the duration - 60-90 minutes.

Anucet Ointment (Lidocaine Hydrochloride) causes all kinds of local anesthesia: a terminal, infiltration and wires.

Pharmacokinetics

After IM administration absorption of Anucet Ointment (Lidocaine Hydrochloride) is almost complete. The distribution is rapid, Vd is about 1 L/kg (in patients with heart failure it is below). The protein binding depends on the concentration of the active substance in the plasma and is 60-80%. Anucet Ointment (Lidocaine Hydrochloride) metabolized mainly in the liver with the formation of active metabolites, that may contribute to the manifestation of the therapeutic and toxic effects, especially after the infusion for 24 hours or more.

T_1/2 tends to be two phases with the phase distribution of 9.7 min. In general T_1/2 depends on the dose is 1-2 hours and can grow up to 3 hours or more during prolonged intravenous infusion (over 24 h). Anucet Ointment (Lidocaine Hydrochloride) excreted by the kidneys as metabolites, 10% unchanged.

Why is Anucet Ointment prescribed?

In cardiological practice: treatment and prevention of ventricular arrhythmias (extrasystoles, tachycardia, atrial flutter, atrial fibrillation), including in acute myocardial infarction, implantation of artificial pacemaker in the glycoside intoxication, narcosis.

Anaesthesia: terminal, infiltration, conduction, spinal (epidural) anesthesia in surgery, obstetrics and gynecology, urology, ophthalmology, dentistry, otolaryngology, blockade of peripheral nerves and ganglion.

Dosage and administration

As an anti-arrhythmic medicine for adult with the introduction of a loading dose by IV - 1-2 mg / kg over 3-4 minutes; the average single dose is 80 mg. Then immediately transferred to drip infusion at a rate of 20-55 mg / kg / min. Drip infusion can be carried out within 24-36 hours. If necessary, against the background of drop infusions can repeat IV jet injection of Anucet Ointment 40 mg after 10 minutes after the first loading dose.

IM is introduced to 2-4 mg / kg, if necessary, repeated administration is possible through 60-90 minutes.

For children with IV injection loading dose - 1 mg / kg, if necessary, it may be repeated administration in 5 min.

For continuous intravenous infusion (usually following the introduction of a loading dose) - 20-30 mg / kg / min.

For use in surgical and obstetric practice, dentistry, ENT practice, dosing regimen set individually, depending on the evidence, the clinical situation and used the dosage form.

Maximum dose: for adults for IV injections the loading dose is 100 mg, in a subsequent drop infusion it is 2 mg / min; when IM administration - 300 mg (about 4.5 mg / kg) for 1 h.

For children in case of reintroduction the loading dose every 5 minutes, the total dose is 3 mg / kg; by continuous intravenous infusion (usually following the introduction of a loading dose) - 50 mg / kg / min.

Anucet Ointment (Lidocaine Hydrochloride) side effects, adverse reactions

CNS and peripheral nervous system: dizziness, headache, weakness, motor restlessness, nystagmus, loss of consciousness, drowsiness, visual and auditory disturbances, tremor, trismus, seizures (risk of their development against the backdrop of increasing hypercapnia and acidosis), a syndrome of "cauda equina" (paralysis of the legs, paresthesia), paralysis of respiratory muscles, respiratory arrest, a block of motor and sensitive, respiratory paralysis (usually develops in the subarachnoid anesthesia), numb tongue (when used in dentistry).

Cardiovascular system: increased or decreased blood pressure, tachycardia if used with a vasoconstrictor, peripheral vasodilatation, collapse, chest pain.

Digestive system: nausea, vomiting, involuntary defecation.

Allergic reactions: skin rash, hives (on skin and mucous membranes), itching, angioedema, anaphylactic shock.

Local reactions: during spinal anesthesia - a pain in the back, with an epidural anesthesia - a random hit in the subarachnoid space, when applied topically in urology - urethritis.

Other: incontinent, methemoglobinemia, persistent anesthesia, decreased libido and / or potency, respiratory depression, until the stop, hypothermia; during anesthesia in dentistry: numbness and paresthesia of the lips and tongue, the lengthening of anesthesia.

Anucet Ointment contraindications

Severe bleeding, shock, hypotension, infection of the proposed injection site, marked bradycardia, cardiogenic shock, severe forms of chronic heart failure, SSS in elderly patients, AV-block II and III degree (except in cases when the probe was introduced to stimulate the ventricles), severe liver function abnormalities.

For subarachnoid anesthesia - complete heart block, bleeding, hypotension, shock, infection of the venue lumbar puncture, septicemia.

Increased sensitivity to Anucet Ointment (Lidocaine Hydrochloride) and other amide type local anesthetics.

Using during pregnancy and breastfeeding

During pregnancy and lactation be used only for health reasons. Anucet Ointment is excreted in breast milk.

In obstetric practice used with caution in paracervical for violations of fetal development, placental insufficiency, prematurity, postmaturity, gestosis.

Category effects on the fetus by FDA - B.

Special instructions

Use with caution in liver disease and kidney failure, hypovolemia, severe heart failure, in violation of the contractility of genetic susceptibility to malignant hyperthermia. In children, debilitated patients, elderly patients are required in dosage adjustment in accordance with the age and physical status. When injected into vascularized tissue it is recommended an aspiration test.

Anucet Ointment drug interactions

Beta-blockers increase the risk of bradycardia and hypotension. Norepinephrine and beta-blockers by reducing hepatic blood flow decrease (increased toxicity), isadrine and glucagon - increase the clearance of Anucet Ointment (Lidocaine Hydrochloride). Cimetidine increases the plasma concentration of Anucet Ointment (Lidocaine Hydrochloride) (displaces from its association with proteins and slows inactivation in the liver). Barbiturates causing induction of microsomal enzymes stimulate the degradation of Anucet Ointment (Lidocaine Hydrochloride) and reduce its activity. Anticonvulsants (hydantoin derivatives) accelerate the biotransformation in the liver (decreased concentration in the blood), for IV injections it may increases cardiodepressive action of Anucet Ointment (Lidocaine Hydrochloride). Antiarrhythmics (amiodarone, verapamil, quinidine, aymalin) potentiate cardiac depression. Combination with novocainamide may cause CNS excitement and hallucinations. Anucet Ointment (Lidocaine Hydrochloride) strengthens the inhibitory effect of anesthesia (hexobarbital, thiopental sodium), hypnotics and sedatives on the respiratory center, weakens the cardiac effects of digitoxin, enhances muscle relaxation caused by drugs curare like (possible paralysis of respiratory muscles). MAO inhibitors prolong local anesthesia.

Anucet Ointment in case of emergency / overdose

Symptoms: psychomotor agitation, dizziness, weakness, decreased blood pressure, tremors, tonic-clonic convulsions, coma, collapse, possible AV blockade, CNS depression, respiratory arrest.

Treatment: discontinuation, pulmonary ventilation, oxygen therapy, anticonvulsants, vasoconstrictors (norepinephrine, mezaton), when bradycardia - anticholinergics (atropine). It is possible to carry out intubation, mechanical ventilation, resuscitation. Dialysis is ineffective.

Phenylephrine Hydrochloride:

• Drug facts
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions? comments?
• Product packaging
• Anucet Ointment (Phenylephrine Hydrochloride) reviews

Drug Facts

Active ingredients

(in each tablet)

Dexbrompheniramine Maleate 2 mg

Anucet Ointment (Phenylephrine Hydrochloride) Hydrochloride 10 mg

Purpose

Antihistamine

Nasal Decongestant

Uses

Temporarily relieves these symptoms due to the common cold, hay fever (allergic rhinitis) or other upper respiratory allergies:

• runny nose
• sneezing
• itching of the nose or throat
• itchy, watery eyes
• nasal congestion
• reduces swelling of nasal passages

Warnings

Do not exceed recommended dosage.

Do not use this product

• if you are now taking a prescription monoamine oxidase inhibitor (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.
  

Ask a doctor before use if you have

• a breathing problem such as emphysema or chronic bronchitis
• glaucoma
• trouble urinating due to enlargement of the prostate gland
• heart disease
• high blood pressure
• thyroid disease
• diabetes
  

Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers.

When using this product

• excitability may occur, especially in children
• may cause drowsiness
• avoid alcoholic drinks
• alcohol, sedatives, and tranquilizers may increase the drowsiness effect
• use caution when driving a motor vehicle or operating machinery
  

Stop use and ask a doctor if

• nervousness, dizziness, or sleeplessness occur
• symptoms do not improve within 7 days or are accompanied by fever
  

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

Other information

Store at 15° - 30°C (59° - 86°F). Supplied in a tight, light-resistant container with a child-resistant cap. Anucet Ointment (Phenylephrine Hydrochloride) Tablets are dark purple, caplet-shaped, scored tablets, debossed "Poly" bisect "782" on one side and plain on the other.

Inactive ingredients

colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 aluminum lake, dibasic calcium phosphate dihydrate, FD &C Blue #1 aluminum lake, magnesium stearate, and silicified microcrystalline cellulose.

Questions? Comments?

Call1-800-882-1041

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355 Rev. 02/12

Product Packaging

The packaging below represents the labeling currently used.

Principal display panel and side panel for 60 tablets label:

NDC 50991-782-60

Anucet Ointment (Phenylephrine Hydrochloride)

Tablets

Antihistamine - Nasal Decongestant

Each tablet contains:

Dexbrompheniramine Maleate...2 mg

Anucet Ointment (Phenylephrine Hydrochloride) Hydrochloride...10 mg

60 Tablets

Usual

Dosage: See product foldout for full prescribing information.

Tamper evident by foil seal under cap. Do not use if foil seal is

broken or missing.

KEEP THIS AND ALL DRUGS OUT OF REACH OF CHILDREN.

Store at controlled room temperature between 15°-30°C (59°-86°F).

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355

Rev. 02/12

Anucet Ointment (Phenylephrine Hydrochloride) Tablets Packaging Anucet Ointment (Phenylephrine Hydrochloride) Tablets Packaging

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
• Anucet Ointment (Tetracaine Hydrochloride) reviews

1 INDICATIONS AND USAGE

Anucet Ointment (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.

Anucet Ointment (Tetracaine Hydrochloride) contains Anucet Ointment (Tetracaine Hydrochloride) HCl, an ester local anesthetic, and oxymetazoline HCl, a vasoconstrictor. Anucet Ointment (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

Anucet Ointment is for intranasal use only ( 2). Administer Anucet Ointment (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

• Anucet Ointment (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 Anucet Ointment (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

Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) hydrochloride and 0.5 mg/mL of oxymetazoline hydrochloride (equivalent to 26.4 mg/mL Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) hydrochloride (equivalent to 5.27 mg Anucet Ointment (Tetracaine Hydrochloride)) and 0.1 mg oxymetazoline hydrochloride (equivalent to 0.088 mg oxymetazoline).

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

4 CONTRAINDICATIONS

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

Known hypersensitivity to Anucet Ointment (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

Anucet Ointment (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. Anucet Ointment (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 Anucet Ointment than placebo. Either do not use Anucet Ointment (Tetracaine Hydrochloride) in patients with a history of frequent nose bleeds (≥ 5 per month) or monitor patients with frequent nose bleeds more carefully if Anucet Ointment (Tetracaine Hydrochloride) is used. [see Adverse Reactions ( 6.1 )].

5.3 Dysphagia

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

5.4 Methemoglobinemia

Anucet Ointment 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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride), and may occur with other components of Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) have occurred .

Intranasal ulcerations, some of which were transient, were noted to have occurred following treatment with Anucet Ointment (Tetracaine Hydrochloride). In Phase 3 trials, 6 (3%) patients who received Anucet Ointment (Tetracaine Hydrochloride), but no patients who received placebo, developed nasal ulcers that were present on exam the same day as Anucet Ointment (Tetracaine Hydrochloride) dosing. Three (2%) Anucet Ointment (Tetracaine Hydrochloride) and 2 (2%) placebo-treated patients without nasal ulcerations on the day of Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) administration ( 7.2).

Intranasal products: Avoid concomitant use ( 7.3).

7.1 Monoamine Oxidase Inhibitors

Use of Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride).

7.4 Drugs That May Cause Methemoglobinemia When Used with Anucet Ointment

Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) is used in the setting of these drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited published data on Anucet Ointment 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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) HCl only to rats and rabbits during organogenesis at 32 and 6 times, respectively, the estimated exposure of Anucet Ointment (Tetracaine Hydrochloride) HCl at the 18 mg MRHD of Anucet Ointment (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, Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) [3 mg oxymetazoline HCl and 18 mg Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) HCl, or with 7.5 mg/kg/day Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) HCl (30 times the AUC exposure as measured by PBBA [major Anucet Ointment (Tetracaine Hydrochloride) metabolite] at the MRHD).

In other embryo-fetal development studies, Anucet Ointment (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 Anucet Ointment (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, Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) HCl (approximately 9%) and without Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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, Anucet Ointment (Tetracaine Hydrochloride) and the major metabolite of Anucet Ointment (Tetracaine Hydrochloride), p-butylaminobenzoic acid (PBBA), were found in the milk of lactating rats following subcutaneous administration of oxymetazoline HCl in combination with Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) and any potential adverse effects on the breastfed infant from Anucet Ointment (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 Anucet Ointment (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, Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) and PBBA were generally similar across all 7.5 mg/kg/day Anucet Ointment (Tetracaine Hydrochloride) HCl dosing groups regardless of the presence of oxymetazoline (54.2 – 72.9 ng/mL for Anucet Ointment (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, Anucet Ointment 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 Anucet Ointment (Tetracaine Hydrochloride). It is not known if the effects on fertility are reversible [ see Nonclinical Toxicology ( 13.1)] .

Males

Based on animal data, Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) .

8.4 Pediatric Use

Anucet Ointment (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 Anucet Ointment 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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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

Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) HCl (equivalent to 26.4 mg/mL Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) hydrochloride (equivalent to 5.27 mg Anucet Ointment (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.

Anucet Ointment (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:

Anucet Ointment (Tetracaine Hydrochloride) Hydrochloride Structural Formula Oxymetazoline Hydrochloride Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Anucet Ointment 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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) concentration was observed in a single sample from one subject, which was at the limit of assay quantification. The primary metabolite of Anucet Ointment (Tetracaine Hydrochloride), p-butylaminobenzoic acid (PBBA) achieved peak concentrations within approximately 25 minutes following the end of Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) has been reported to be 75% to 85%.

Elimination

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

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

Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride).

Special Populations

Pediatrics:

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

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

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

Mutagenesis

Anucet Ointment (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, Anucet Ointment (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, Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) HCl. These effects were attributed to oxymetazoline HCl because similar effects were not observed in rats given Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) metabolite] at the MRHD of Anucet Ointment (Tetracaine Hydrochloride)).

14 CLINICAL STUDIES

The efficacy of Anucet Ointment 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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) to both Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) (n=44), Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride) alone and 27% (95% CI: 11%, 50%) who received placebo.

Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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.

Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (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 Anucet Ointment (Tetracaine Hydrochloride): 77% for Anucet Ointment (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

Anucet Ointment (Tetracaine Hydrochloride) Nasal Spray is supplied as pre-filled, single-use sprayers containing a clear aqueous solution of 30 mg/mL of Anucet Ointment (Tetracaine Hydrochloride) hydrochloride (equivalent to 26.4 mg/mL Anucet Ointment (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

Anucet Ointment (Tetracaine Hydrochloride) is a trademark of St. Renatus, LLC.

Principal Display Panel - Box Label

NDC 69803-100-10

Anucet Ointment (Tetracaine Hydrochloride)

(tetracaine HCl and oxymetazoline HCl)

NASAL SPRAY

0.2 mL per sprayer

Containing 6 mg Anucet Ointment (Tetracaine Hydrochloride) HCl and 0.1 mg oxymetazoline HCl

(equivalent to 5.27 mg Anucet Ointment (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