Micozol Compuesto

Gentamicin:

• Micozol Compuesto (Gentamicin) reviews

F-27078915

NADA #141-177, Approved by FDA.

PRODUCT

INFORMATION

VETERINARY

For Otic Use in Dogs Only

CAUTION Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Keep this and all drugs out of the reach of children.

DESCRIPTION Each gram of Micozol Compuesto (Gentamicin) Otic Suspension contains Micozol Compuesto (Gentamicin) sulfate, USP equivalent to 3 mg Micozol Compuesto (Gentamicin) base; mometasone furoate monohydrate equivalent to 1 mg mometasone; and 10 mg clotrimazole, USP in a mineral oilbased system containing a plasticized hydrocarbon gel.

PHARMACOLOGY

Micozol Compuesto (Gentamicin): Micozol Compuesto (Gentamicin) sulfate is an aminoglycoside antibiotic active against a wide variety of gram-negative and grampositive bacteria. In vitro tests have determined that Micozol Compuesto (Gentamicin) is bactericidal and acts by inhibiting normal protein synthesis in susceptible microorganisms. In clinical trials, Micozol Compuesto (Gentamicin) was shown to have a range of activity against the following organisms commonly isolated from infected canine ears:

Pseudomonas spp. (including P. aeruginosa), coagulasepositive staphylococci, Enterococcus faecalis, Proteus mirabilis and beta-hemolytic streptococci.

Mometasone: Mometasone furoate monohydrate is a synthetic adrenocorticoid characterized by a novel (2') furoate 17-ester having chlorine at the 9 and 21 positions, which have shown to possess high topical potency.

Systemic absorption of mometasone furoate ointment was found to be minimal (2%) over 1 week when applied topically to dogs with intact skin. In a 6-month dermal toxicity study using 0.1% mometasone ointment on healthy intact skin in dogs, systemic effects typical of corticosteroid therapy were noted.

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the integrity of the epidermal barrier. Topical corticosteroids can be absorbed from normal, intact skin. Inflammation can increase percutaneous absorption. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.

Clotrimazole: Clotrimazole is a broad-spectrum antifungal agent that is used for the treatment of dermal infections caused by various species of dermatophytes and yeast. The primary action of clotrimazole is against dividing and growing organisms.

In vitro, clotrimazole exhibits fungistatic and fungicidal activity against isolates of Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, Candida spp., and Malassezia pachydermatis. Resistance to clotrimazole is very rare among the fungi that cause superficial mycoses. In an induced otitis externa study using dogs infected with Malassezia pachydermatis, 1% clotrimazole in the vehicle formulation was effective both microbiologically and clinically in terms of reduction of exudate, odor, and swelling.

In studies of the mechanism of action, the minimum fungicidal concentration of clotrimazole caused leakage of intracellular phosphorus compounds into the ambient medium with concomitant breakdown of cellular nucleic acids and accelerated potassium efflux. These events began rapidly and extensively after addition of the drug. Clotrimazole is very poorly absorbed following dermal application.

Gentamicin-Mometasone-Clotrimazole: By virtue of its three active ingredients, Micozol Compuesto (Gentamicin) Otic Suspension has antibacterial, anti-inflammatory, and antifungal activity. In clinical field trials, Micozol Compuesto (Gentamicin) Otic Suspension was effective in the treatment of otitis externa associated with bacteria and Malassezia pachydermatis. Micozol Compuesto (Gentamicin) Otic Suspension reduced discomfort, redness, swelling, exudate, and odor.

INDICATIONS Micozol Compuesto (Gentamicin) Otic Suspension is indicated for the treatment of otitis externa in dogs caused by susceptible strains of yeast (Malassezia pachydermatis) and bacteria (Pseudomonas spp. [including P. aeruginosa], coagulasepositive staphylococci, Enterococcus faecalis, Proteus mirabilis, and beta-hemolytic streptococci).

CONTRAINDICATIONS If hypersensitivity to any of the components occurs, treatment should be discontinued and appropriate therapy instituted. Concomitant use of drugs known to induce ototoxicity should be avoided. Do not use in dogs with known perforation of eardrums.

WARNINGS The use of these components has been associated with deafness or partial hearing loss in a small number of sensitive dogs (eg, geriatric). The hearing deficit is usually temporary. If hearing or vestibular dysfunction is noted during the course of treatment, discontinue use of Micozol Compuesto (Gentamicin) Otic Suspension immediately and flush the ear canal thoroughly with a nonototoxic solution.

Corticosteroids administered to dogs, rabbits, and rodents during pregnancy have resulted in cleft palate in offspring. Other congenital anomalies including deformed forelegs, phocomelia, and anasarca have been reported in offspring of dogs that received corticosteroids during pregnancy.

Field and experimental data have demonstrated that corticostroids administered orally or parenterally to animals may induce the first stage of parturition if used during the last trimester of pregnancy and may precipitate premature parturition followed by dystocia, fetal death, retained placenta, and metritis.

PRECAUTIONS Before instilling any medication into the ear, examine the external ear canal thoroughly to be certain the tympanic membrane is not ruptured in order to avoid the possibility of transmitting infection to the middle ear as well as damaging the cochlea or vestibular apparatus from prolonged contact.

Administration of recommended doses of Micozol Compuesto (Gentamicin) Otic Suspension beyond 7 days may result in delayed wound healing. If overgrowth of nonsusceptible bacteria or fungi occurs, treatment should be discontinued and appropriate therapy instituted.

Avoid ingestion. Adverse systemic reactions have been observed following the oral ingestion of some topical corticosteroid preparations. Patients should be closely observed for the usual signs of adrenocorticoid overdosage which include sodium retention, potassium loss, fluid retention, weight gain, polydipsia, and/or polyuria. Prolonged use or overdosage may produce adverse immunosuppressive effects.

Use of corticosteroids, depending on dose, duration, and specific steroid, may result in endogenous steroid production inhibition following drug withdrawal. In patients presently receiving or recently withdrawn from corticosteroid treatments, therapy with a rapidly acting corticosteroid should be considered in especially stressful situations.

TOXICOLOGY Field and safety studies with Micozol Compuesto (Gentamicin) Otic Suspension have shown a wide safety margin at the recommended dose level in dogs (see PRECAUTIONS/ADVERSE REACTIONS ).

ADVERSE REACTIONS

Micozol Compuesto (Gentamicin): While aminoglycosides are absorbed poorly from skin, intoxication may occur when aminoglycosides are applied topically for prolonged periods of time to large wounds, burns, or any denuded skin, particularly if there is renal insufficiency. All aminoglycosides have the potential to produce reversible and irreversible vestibular, cochlear, and renal toxicity.

Mometasone: ALP (SAP) and ALT (SGPT) enzyme elevations, weight loss, anorexia, polydipsia, polyuria, neutrophilia, and lymphopenia have occurred following the use of parenteral, high-dose, and/or prolonged or systemic synthetic corticosteroids in dogs. Cushing's syndrome in dogs has been reported in association with prolonged or repeated steroid therapy.

Clotrimazole: The following have been reported occasionally in humans in connection with the use of clotrimazole: erythema, stinging, blistering, peeling, edema, pruritus, urticaria, and general irritation of the skin not present before therapy.

Micozol Compuesto (Gentamicin) Otic Suspension: In field studies following once daily teatment with Micozol Compuesto (Gentamicin) Otic Suspension, ataxia, proprioceptive deficits, and increased water consumption were observed in less than 1% of 164 dogs. In a field study following twice-daily treatment with Micozol Compuesto (Gentamicin) Otic Suspension, inflammation of the pinna and diarrhea were observed in less than 1% of 141 dogs.

DOSAGE AND ADMINISTRATION

The external ear canal should be thoroughly cleaned and dried before treatment. Verify that the eardrum is intact. For dogs weighing less than 30 lbs, instill 4 drops from the 7.5 g, 15 g, and 30 g bottles (2 drops from the 215 g bottle) of Micozol Compuesto (Gentamicin) Otic Suspension once daily into the ear canal. For dogs weighing 30 lbs or more, instill 8 drops from the 7.5 g, 15 g, and 30 g bottles (4 drops from the 215 g bottle) once daily into the ear canal. Therapy should continue for 7 consecutive days.

HOW SUPPLIED Micozol Compuesto (Gentamicin) Otic Suspension is available in 7.5 g (NDC 14043-120-75), 15 g (NDC 14043-120-15), 30 g (NDC 14043-120-30), and 215 g (NDC 14043-120-21) plastic bottles.

Store between 2° and 25°C (36° and 77°F). Shake well before use.

U.S. Patent No. 6,127,353.

Distributed by

PATTERSON VETERINARY

137 Barnum Road, Devens, MA 01434

www.pattersonvet.com

Made in Canada.

9/15

85239791

Hydrocortisone:

• 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
• Micozol Compuesto (Hydrocortisone) reviews

1 INDICATIONS AND USAGE

Micozol Compuesto (Hydrocortisone)^® (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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) when control is achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary.

Do not use Micozol Compuesto (Hydrocortisone) with occlusive dressings unless directed by the physician. Do not apply Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) contains 1 mg of Micozol Compuesto (Hydrocortisone) probutate in a cream base.

Cream, 0.1%.

4 CONTRAINDICATIONS

None.

None.

5 WARNINGS AND PRECAUTIONS

- Micozol Compuesto 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

Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto use in pregnant women to inform any drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) probutate during the period of organogenesis. Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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, Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) probutate during the perinatal and postnatal period (12 times the human average topical dose of Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) probutate in breast milk, or on its effects on the breastfed infant or on milk production. It is not known whether topical administration of Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) and any potential adverse effects on the breastfed infant from Micozol Compuesto (Hydrocortisone) or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use Micozol Compuesto (Hydrocortisone) 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

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

Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) (hydrocortisone probutate) Cream, 0.1% contains: 1 mg of Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) for up to 24 hours has not been shown to increase penetration; however, occlusion of Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) probutate.

Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) probutate (5 times the human average topical dose of Micozol Compuesto (Hydrocortisone) 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

Micozol Compuesto (Hydrocortisone), 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 Micozol Compuesto (Hydrocortisone) 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 Micozol Compuesto (Hydrocortisone) 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

Micozol Compuesto (Hydrocortisone)^®

(hydrocortisone probutate) Cream, 0.1%

FOR DERMATOLOGIC USE ONLY.

NOT FOR OPHTHALMIC USE.

Rx only

80 g

carton

Ketoconazole:

• Warning
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Micozol Compuesto (Ketoconazole) reviews

WARNING

When used orally, Micozol Compuesto (Ketoconazole) has been associated with hepatic toxicity, including some fatalities. Patients receiving this drug should be informed by the physician of the risk and should be closely monitored. See WARNINGS and PRECAUTIONS sections.

Coadministration of terfenadine with Micozol Compuesto (Ketoconazole) tablets is contraindicated. Rare cases of serious cardiovascular adverse events, including death, ventricular tachycardia and torsades de pointes have been observed in patients taking Micozol Compuesto (Ketoconazole) tablets concomitantly with terfenadine, due to increased terfenadine concentrations induced by Micozol Compuesto (Ketoconazole) tablets. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.

Pharmacokinetic data indicate that oral Micozol Compuesto (Ketoconazole) inhibits the metabolism of astemizole, resulting in elevated plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong QT intervals. Coadministration of astemizole with Micozol Compuesto (Ketoconazole) tablets is therefore contraindicated. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.

Coadministration of cisapride with Micozol Compuesto (Ketoconazole) is contraindicated. Serious cardiovascular adverse events including ventricular tachycardia, ventricular fibrillation and torsades de pointes have occurred in patients taking Micozol Compuesto (Ketoconazole) concomitantly with cisapride. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.

DESCRIPTION

Micozol Compuesto (Ketoconazole) is a synthetic broad-spectrum antifungal agent. Each tablet, for oral administration, contains 200 mg Micozol Compuesto (Ketoconazole) base. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Micozol Compuesto (Ketoconazole) is (±)cis-1-Acetyl-4-[p-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-piperazine and has the following structural formula:

C₂₆H₂₈Cl₂N₄O₄ M.W. 531.44

Micozol Compuesto (Ketoconazole) is a white to slightly beige, odorless powder that is soluble in acids.

CLINICAL PHARMACOLOGY

Mean peak plasma levels of approximately 3.5 mcg/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Subsequent plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Following absorption from the gastrointestinal tract, Micozol Compuesto is converted into several inactive metabolites. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract. In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Only a negligible proportion of Micozol Compuesto (Ketoconazole) reaches the cerebral-spinal fluid. Micozol Compuesto (Ketoconazole) is a weak dibasic agent and thus requires acidity for dissolution and absorption.

Micozol Compuesto (Ketoconazole) tablets are active against clinical infections with Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Phialophora spp. Micozol Compuesto (Ketoconazole) tablets are also active against Trichophyton spp., Epidermophyton spp., and Microsporum spp. Micozol Compuesto (Ketoconazole) is also active in vitro against a variety of fungi and yeast. In animal models, activity has been demonstrated against Candida spp., Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Coccidioides immitis, and Cryptococcus neoformans.

Mode Of Action

In vitro studies suggest that Micozol Compuesto (Ketoconazole) impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

Micozol Compuesto (Ketoconazole) tablets are indicated for the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Micozol Compuesto (Ketoconazole) tablets should not be used for fungal meningitis because it penetrates poorly into the cerebral-spinal fluid.

Micozol Compuesto (Ketoconazole) tablets are also indicated for the treatment of patients with severe recalcitrant cutaneous dermatophyte infections who have not responded to topical therapy or oral griseofulvin, or who are unable to take griseofulvin.

CONTRAINDICATIONS

Coadministration of terfenadine or astemizole with Micozol Compuesto (Ketoconazole) tablets is contraindicated. (See BOX WARNING, WARNINGS, and PRECAUTIONS sections.)

Concomitant administration of Micozol Compuesto (Ketoconazole) tablets with cisapride is contraindicated. (See BOX WARNINGS, WARNINGS and PRECAUTIONS sections.)

Concomitant administration of Micozol Compuesto (Ketoconazole) tablets with oral triazolam is contraindicated. (See PRECAUTIONS section.)

Micozol Compuesto (Ketoconazole) is contraindicated in patients who have shown hypersensitivity to the drug.

WARNINGS

Hepatotoxicity, primarily of the hepatocellular type, has been associated with the use of Micozol Compuesto (Ketoconazole) tablets, including rare fatalities. The reported incidence of hepatotoxicity has been about 1:10,000 exposed patients, but this probably represents some degree of under-reporting, as is the case for most reported adverse reactions to drugs. The median duration of Micozol Compuesto (Ketoconazole) tablet therapy in patients who developed symptomatic hepatotoxicity was about 28 days, although the range extended to as low as 3 days. The hepatic injury has usually, but not always, been reversible upon discontinuation of Micozol Compuesto (Ketoconazole) tablet treatment. Several cases of hepatitis have been reported in children.

Prompt recognition of liver injury is essential. Liver function tests (such as SGGT, alkaline phosphatase, SGPT, SGOT and bilirubin) should be measured before starting treatment and at frequent intervals during treatment. Patients receiving Micozol Compuesto (Ketoconazole) tablets concurrently with other potentially hepatotoxic drugs should be carefully monitored, particularly those patients requiring prolonged therapy or those who have had a history of liver disease.

Most of the reported cases of hepatic toxicity have to date been in patients treated for onychomycosis. Of 180 patients worldwide developing idiosyncratic liver dysfunction during Micozol Compuesto (Ketoconazole) tablet therapy, 61.3% had onychomycosis and 16.8% had chronic recalcitrant dermatophytoses.

Transient minor elevations in liver enzymes have occurred during treatment with Micozol Compuesto (Ketoconazole) tablets. The drug should be discontinued if these persist, if the abnormalities worsen, or if the abnormalities become accompanied by symptoms of possible liver injury.

In rare cases anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported.

Coadministration of Micozol Compuesto (Ketoconazole) tablets and terfenadine has led to elevated plasma concentrations of terfenadine which may prolong QT intervals, sometimes resulting in life- threatening cardiac dysrhythmias. Cases of torsades de pointes and other serious ventricular dysrhythmias, in rare cases leading to fatality, have been reported among patients taking terfenadine concurrently with Micozol Compuesto (Ketoconazole) tablets. Coadministration of Micozol Compuesto (Ketoconazole) tablets and terfenadine is contraindicated.

Coadministration of astemizole with Micozol Compuesto (Ketoconazole) tablets is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS sections.)

Concomitant administration of Micozol Compuesto (Ketoconazole) tablets with cisapride is contraindicated because it has resulted in markedly elevated cisapride plasma concentrations and prolonged QT interval, and has rarely been associated with ventricular arrhythmias and torsades de pointes. (See BOXED WARNING, CONTRAINDICATIONS and PRECAUTIONS sections.)

In European clinical trials involving 350 patients with metastatic prostatic cancer, eleven deaths were reported within two weeks of starting treatment with high doses of Micozol Compuesto (Ketoconazole) tablets (1200 mg/day). It is not possible to ascertain from the information available whether death was related to Micozol Compuesto (Ketoconazole) therapy in these patients with serious underlying disease. However, high doses of Micozol Compuesto (Ketoconazole) tablets are known to suppress adrenal corticosteroid secretion.

In female rats treated three to six months with Micozol Compuesto (Ketoconazole) at dose levels of 80 mg/kg and higher, increased fragility of long bones, in some cases leading to fracture, was seen. The maximum "no-effect" dose level in these studies was 20 mg/kg (2.5 times the maximum recommended human dose). The mechanism responsible for this phenomenon is obscure. Limited studies in dogs failed to demonstrate such an effect on the metacarpals and ribs.

PRECAUTIONS

General

Micozol Compuesto tablets have been demonstrated to lower serum testosterone. Once therapy with Micozol Compuesto (Ketoconazole) has been discontinued, serum testosterone levels return to baseline values. Testosterone levels are impaired with doses of 800 mg per day and abolished by 1600 mg per day. Micozol Compuesto (Ketoconazole) tablets also decrease ACTH induced corticosteroid serum levels at similar high doses. The recommended dose of 200 mg to 400 mg daily should be followed closely.

In four subjects with drug-induced achlorhydria, a marked reduction in Micozol Compuesto (Ketoconazole) absorption was observed. Micozol Compuesto (Ketoconazole) tablets require acidity for dissolution. If concomitant antacids, anticholinergics, and H₂-blockers are needed, they should be given at least two hours after administration of Micozol Compuesto (Ketoconazole) tablets. In cases of achlorhydria, the patients should be instructed to dissolve each tablet in 4 mL aqueous solution of 0.2 N HCl. For ingesting the resulting mixture, they should use a drinking straw so as to avoid contact with the teeth. This administration should be followed with a cup of tap water.

Information for Patients

Patients should be instructed to report any signs and symptoms which may suggest liver dysfunction so that appropriate biochemical testing can be done. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine or pale stools.

Drug Interactions

Micozol Compuesto is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Coadministration of Micozol Compuesto (Ketoconazole) tablets and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and adverse effects. Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary. The following drug interactions have been identified involving Micozol Compuesto (Ketoconazole) tablets and other drugs metabolized by the cytochrome P450 enzyme system.

Micozol Compuesto (Ketoconazole) tablets inhibit the metabolism of terfenadine, resulting in an increased plasma concentration of terfenadine and a delay in the elimination of its acid metabolite. The increased plasma concentration of terfenadine or its metabolite may result in prolonged QT intervals. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)

Pharmacokinetic data indicate that oral Micozol Compuesto (Ketoconazole) inhibits the metabolism of astemizole, resulting in elevated plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong QT intervals. Coadministration of astemizole with Micozol Compuesto (Ketoconazole) tablets is therefore contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)

Human pharmacokinetics data indicate that oral Micozol Compuesto (Ketoconazole) potently inhibits the metabolism of cisapride resulting in a mean eight-fold increase in AUC of cisapride. Data suggest that coadministration of oral Micozol Compuesto (Ketoconazole) and cisapride can result in prolongation of the QT interval on the ECG. Therefore concomitant administration of Micozol Compuesto (Ketoconazole) tablets with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS and WARNINGS sections.)

Micozol Compuesto (Ketoconazole) tablets may alter the metabolism of cyclosporine, tacrolimus, and methylprednisolone, resulting in elevated plasma concentrations of the latter drugs. Dosage adjustment may be required if cyclosporine, tacrolimus, or methylprednisolone are given concomitantly with Micozol Compuesto (Ketoconazole) tablets.

Coadministration of Micozol Compuesto (Ketoconazole) tablets with midazolam or triazolam has resulted in elevated plasma concentrations of the latter two drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. These agents should not be used in patients treated with Micozol Compuesto (Ketoconazole) tablets. If midazolam is administered parenterally, special precaution is required since the sedative effect may be prolonged.

Rare cases of elevated plasma concentrations of digoxin have been reported. It is not clear whether this was due to the combination of therapy. It is, therefore, advisable to monitor digoxin concentrations in patients receiving Micozol Compuesto (Ketoconazole).

When taken orally, imidazole compounds like Micozol Compuesto (Ketoconazole) may enhance the anticoagulant effect of coumarin-like drugs. In simultaneous treatment with imidazole drugs and coumarin drugs, the anticoagulant effect should be carefully titrated and monitored.

Because severe hypoglycemia has been reported in patients concomitantly receiving oral miconazole (an imidazole) and oral hypoglycemic agents, such a potential interaction involving the latter agents when used concomitantly with Micozol Compuesto (Ketoconazole) tablets (an imidazole) can not be ruled out.

Concomitant administration of Micozol Compuesto (Ketoconazole) tablets with phenytoin may alter the metabolism of one or both of the drugs. It is suggested to monitor both Micozol Compuesto (Ketoconazole) and phenytoin.

Concomitant administration of rifampin with Micozol Compuesto (Ketoconazole) tablets reduces the blood levels of the latter. INH (Isoniazid) is also reported to affect Micozol Compuesto (Ketoconazole) concentrations adversely. These drugs should not be given concomitantly.

After the coadministration of 200 mg oral Micozol Compuesto (Ketoconazole) twice daily and one 20 mg dose of loratadine to 11 subjects, the AUC and C_max of loratadine averaged 302% (± 142 S.D.) and 251% (± 68 S.D.), respectively, of those obtained after co-treatment with placebo. The AUC and C_max of descarboethoxyloratadine, an active metabolite, averaged 155% (± 27 S.D.) and 141% (± 35 S.D.), respectively. However, no related changes were noted in the QT_c on ECG taken at 2, 6, and 24 hours after the coadministration. Also, there were no clinically significant differences in adverse events when loratadine was administered with or without Micozol Compuesto (Ketoconazole).

Rare cases of disulfiram-like reaction to alcohol have been reported. These experiences have been characterized by flushing, rash, peripheral edema, nausea, and headache. Symptoms resolved within a few hours.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

The dominant lethal mutation test in male and female mice revealed that single oral doses of Micozol Compuesto (Ketoconazole) as high as 80 mg/kg produced no mutation in any stage of germ cell development. The Ames Salmonella microsomal activator assay was also negative. A long term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity.

Pregnancy

Teratogenic effects

Pregnancy Category C

Micozol Compuesto has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given in the diet at 80 mg/kg/day (10 times the maximum recommended human dose). However, these effects may be related to maternal toxicity, evidence of which also was seen at this and higher dose levels.

There are no adequate and well controlled studies in pregnant women. Micozol Compuesto (Ketoconazole) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Micozol Compuesto (Ketoconazole) has also been found to be embryotoxic in the rat when given in the diet at doses higher than 80 mg/kg during the first trimester of gestation. In addition, dystocia (difficult labor) was noted in rats administered oral Micozol Compuesto (Ketoconazole) during the third trimester of gestation. This occurred when Micozol Compuesto (Ketoconazole) was administered at doses higher than 10 mg/kg (higher than 1.25 times the maximum human dose).

It is likely that both the malformations and the embryotoxicity resulting from the administration of oral Micozol Compuesto (Ketoconazole) during gestation are a reflection of the particular sensitivity of the female rat to this drug. For example, the oral LD₅₀ of Micozol Compuesto (Ketoconazole) given by gavage to the female rat is 166 mg/kg whereas in the male rat the oral LD₅₀ is 287 mg/kg.

Nursing Mothers

Since Micozol Compuesto is probably excreted in the milk, mothers who are under treatment should not breast feed.

Pediatric Use

Micozol Compuesto (Ketoconazole) tablets have not been systematically studied in children of any age, and essentially no information is available on children under 2 years. Micozol Compuesto (Ketoconazole) should not be used in pediatric patients unless the potential benefit outweighs the risks.

ADVERSE REACTIONS

In rare cases, anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported. However, the most frequent adverse reactions were nausea and/or vomiting in approximately 3%, abdominal pain in 1.2%, pruritus in 1.5%, and the following in less than 1% of the patients: headache, dizziness, somnolence, fever and chills, photophobia, diarrhea, gynecomastia, impotence, thrombocytopenia, leukopenia, hemolytic anemia, and bulging fontanelles. Oligospermia has been reported in investigational studies with the drug at dosages above those currently approved. Oligospermia has not been reported at dosages up to 400 mg daily, however sperm counts have been obtained infrequently in patients treated with these dosages. Most of these reactions were mild and transient and rarely required discontinuation of Micozol Compuesto (Ketoconazole) tablets. In contrast, the rare occurrences of hepatic dysfunction require special attention (see WARNINGS section).

In worldwide postmarketing experience with Micozol Compuesto (Ketoconazole) tablets there have been rare reports of alopecia, paresthesia, and signs of increased intracranial pressure including bulging fontanelles and papilledema. Hypertriglyceridemia has also been reported but a causal association with Micozol Compuesto (Ketoconazole) is uncertain.

Neuropsychiatric disturbances, including suicidal tendencies and severe depression, have occurred rarely in patients using Micozol Compuesto (Ketoconazole) tablets.

Ventricular dysrhythmias (prolonged QT intervals) have occurred with the concomitant use of terfenadine with Micozol Compuesto (Ketoconazole) tablets. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)

Data suggest that coadministration of Micozol Compuesto (Ketoconazole) tablets and cisapride can result in prolongation of the QT interval and has rarely been associated with ventricular arrhythmias. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.)

OVERDOSAGE

In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.

DOSAGE AND ADMINISTRATION

Adults: The recommended starting dose of Micozol Compuesto (Ketoconazole) tablets is a single daily administration of 200 mg (one tablet). In very serious infections or if clinical responsiveness is insufficient within the expected time, the dose of Micozol Compuesto (Ketoconazole) may be increased to 400 mg (two tablets) once daily.

Children: In small numbers of children over 2 years of age, a single daily dose of 3.3 to 6.6 mg/kg has been used. Micozol Compuesto (Ketoconazole) tablets have not been studied in children under 2 years of age.

There should be laboratory as well as clinical documentation of infection prior to starting Micozol Compuesto (Ketoconazole) therapy. Treatment should be continued until tests indicate that active fungal infection has subsided. Inadequate periods of treatment may yield poor response and lead to early recurrence of clinical symptoms. Minimum treatment for candidiasis is one or two weeks. Patients with chronic mucocutaneous candidiasis usually require maintenance therapy. Minimum treatment for the other indicated systemic mycoses is six months.

Minimum treatment for recalcitrant dermatophyte infections is four weeks in cases involving glabrous skin. Palmar and plantar infections may respond more slowly. Apparent cures may subsequently recur after discontinuation of therapy in some cases.

HOW SUPPLIED

Each Micozol Compuesto (Ketoconazole) tablet, USP contains Micozol Compuesto (Ketoconazole) 200 mg available in bottles of 100 and 500. The tablets are white, round, flat-beveled tablets, debossed “93”-“900” on the scored side, plain on the other side.

Store at controlled room temperature between 20° and 25° C (68° and 77° F).

Protect from moisture.

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Printed in USA

Rev. C 11/2003

Micozol Compuesto (Ketoconazole) 200mg

Micozol Compuesto (Ketoconazole) structural formula