Candicort

Betamethasone Dipropionate:

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

Candicort (Betamethasone Dipropionate) Spray is indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older.

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

2 DOSAGE AND ADMINISTRATION

Shake well before use.

Apply Candicort (Betamethasone Dipropionate) Spray to the affected skin areas twice daily and rub in gently.

Use Candicort (Betamethasone Dipropionate) Spray for up to 4 weeks of treatment. Treatment beyond 4 weeks is not recommended.

Discontinue Candicort (Betamethasone Dipropionate) Spray when control is achieved.

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

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

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

Candicort (Betamethasone Dipropionate) Spray is for topical use only. It is not for oral, ophthalmic, or intravaginal use.

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

3 DOSAGE FORMS AND STRENGTHS

Spray, 0.05% for topical use. Each gram of Candicort (Betamethasone Dipropionate) Spray contains 0.643 mg Candicort (Betamethasone Dipropionate) USP (equivalent to 0.5 mg betamethasone) in a slightly thickened, white to off-white oil-in-water emulsion.

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

4 CONTRAINDICATIONS

None.

• None. (4)

5 WARNINGS AND PRECAUTIONS

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

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

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

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

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

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

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

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

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

5.2 Allergic Contact Dermatitis

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

6 ADVERSE REACTIONS

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

To report SUSPECTED ADVERSE REACTIONS, contact Promius Pharma, LLC. at 1-888-966-8766 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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

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

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

6.2 Postmarketing Experience

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

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

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

8.5 Geriatric Use

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

11 DESCRIPTION

Candicort (Betamethasone Dipropionate) Spray contains 0.0643% Candicort (Betamethasone Dipropionate) (equivalent to 0.05% betamethasone), a synthetic, fluorinated corticosteroid.

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

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

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

12.3 Pharmacokinetics

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

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of Candicort (Betamethasone Dipropionate).

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

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

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

14 CLINICAL STUDIES

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied/Storage

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

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

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

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

16.2 Handling/Instructions for the Pharmacist

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

17 PATIENT COUNSELING INFORMATION

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

Inform patients of the following:

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

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

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

Candicort (Betamethasone Dipropionate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007465

140728

Instructions for Use

Candicort (Betamethasone Dipropionate) (ser-ne-vo)

(betamethasone dipropionate)

Spray, 0.05%

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

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

Parts of the Candicort (Betamethasone Dipropionate) Spray bottle.

Figure A

How to apply Candicort (Betamethasone Dipropionate) Spray:

Step 1: Shake the Candicort (Betamethasone Dipropionate) Spray bottle well. Remove the cap from the pump top.

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

Figure B

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

Figure C

Repeat Steps 2 and 3 to apply Candicort (Betamethasone Dipropionate) Spray to other affected areas as instructed by your doctor.

Step 4: After applying Candicort (Betamethasone Dipropionate) Spray, place the cap back onto the pump top. (See Figure D )

Figure D

How should I store Candicort (Betamethasone Dipropionate) Spray?

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

Keep Candicort (Betamethasone Dipropionate) Spray and all medicines out of the reach of children.

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

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

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

Candicort (Betamethasone Dipropionate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007528

140693

Ketoconazole:

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

WARNING

When used orally, Candicort (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 Candicort (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 Candicort (Ketoconazole) tablets concomitantly with terfenadine, due to increased terfenadine concentrations induced by Candicort (Ketoconazole) tablets. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.

Pharmacokinetic data indicate that oral Candicort (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 Candicort (Ketoconazole) tablets is therefore contraindicated. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.

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

DESCRIPTION

Candicort (Ketoconazole) is a synthetic broad-spectrum antifungal agent. Each tablet, for oral administration, contains 200 mg Candicort (Ketoconazole) base. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Candicort (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

Candicort (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, Candicort 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 Candicort (Ketoconazole) reaches the cerebral-spinal fluid. Candicort (Ketoconazole) is a weak dibasic agent and thus requires acidity for dissolution and absorption.

Candicort (Ketoconazole) tablets are active against clinical infections with Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Phialophora spp. Candicort (Ketoconazole) tablets are also active against Trichophyton spp., Epidermophyton spp., and Microsporum spp. Candicort (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 Candicort (Ketoconazole) impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

Candicort (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. Candicort (Ketoconazole) tablets should not be used for fungal meningitis because it penetrates poorly into the cerebral-spinal fluid.

Candicort (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 Candicort (Ketoconazole) tablets is contraindicated. (See BOX WARNING, WARNINGS, and PRECAUTIONS sections.)

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

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

Candicort (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 Candicort (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 Candicort (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 Candicort (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 Candicort (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 Candicort (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 Candicort (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 Candicort (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 Candicort (Ketoconazole) tablets. Coadministration of Candicort (Ketoconazole) tablets and terfenadine is contraindicated.

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

Concomitant administration of Candicort (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 Candicort (Ketoconazole) tablets (1200 mg/day). It is not possible to ascertain from the information available whether death was related to Candicort (Ketoconazole) therapy in these patients with serious underlying disease. However, high doses of Candicort (Ketoconazole) tablets are known to suppress adrenal corticosteroid secretion.

In female rats treated three to six months with Candicort (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

Candicort tablets have been demonstrated to lower serum testosterone. Once therapy with Candicort (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. Candicort (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 Candicort (Ketoconazole) absorption was observed. Candicort (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 Candicort (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

Candicort is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Coadministration of Candicort (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 Candicort (Ketoconazole) tablets and other drugs metabolized by the cytochrome P450 enzyme system.

Candicort (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 Candicort (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 Candicort (Ketoconazole) tablets is therefore contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)

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

Candicort (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 Candicort (Ketoconazole) tablets.

Coadministration of Candicort (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 Candicort (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 Candicort (Ketoconazole).

When taken orally, imidazole compounds like Candicort (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 Candicort (Ketoconazole) tablets (an imidazole) can not be ruled out.

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

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

After the coadministration of 200 mg oral Candicort (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 Candicort (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 Candicort (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

Candicort 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. Candicort (Ketoconazole) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Candicort (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 Candicort (Ketoconazole) during the third trimester of gestation. This occurred when Candicort (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 Candicort (Ketoconazole) during gestation are a reflection of the particular sensitivity of the female rat to this drug. For example, the oral LD₅₀ of Candicort (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 Candicort is probably excreted in the milk, mothers who are under treatment should not breast feed.

Pediatric Use

Candicort (Ketoconazole) tablets have not been systematically studied in children of any age, and essentially no information is available on children under 2 years. Candicort (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 Candicort (Ketoconazole) tablets. In contrast, the rare occurrences of hepatic dysfunction require special attention (see WARNINGS section).

In worldwide postmarketing experience with Candicort (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 Candicort (Ketoconazole) is uncertain.

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

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

Data suggest that coadministration of Candicort (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 Candicort (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 Candicort (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. Candicort (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 Candicort (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 Candicort (Ketoconazole) tablet, USP contains Candicort (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

Candicort (Ketoconazole) 200mg

Candicort (Ketoconazole) structural formula