Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action The mechanism of action of ketoconazole in the treatment of seborrheic dermatitis is unknown. Pharmacodynamics Pharmacodynamic markers for seborrheic dermatitis have not been identified. Pharmacokinetics In a pharmacokinetic absorption trial, eighteen subjects, both males and females, with severe seborrheic dermatitis (range 1-14% of body surface area) applied XOLEGEL once daily for 2 weeks. The median total amount of gel applied was 4.6 g (range 1.65–46.3 g). Daily doses ranged from 0.05 to 3.47 g. Mean (± standard deviation [SD]) peak plasma levels were 1.35 (± 3.18) ng/mL on Day 7 (range from < 0.1 ng/mL, to 13.9 ng/mL), and 0.80 (± 1.22) ng/mL on Day 14 (range from < 0.1 ng/mL to 5.4 ng/mL). Median Tmax was 8 hours on Day 7 and 7 hours on Day 14. Mean (± SD) AUC0-24 values were 20.8 (± 44.7) ng•h/mL and 15.6 (± 26.4) ng•h/mL on Day 7 and 14, respectively. The plasma levels from an oral dose of 200 mg ketoconazole taken with a meal are approximately 250 times higher than the resulting plasma levels of ketoconazole following topical application of XOLEGEL. Clinical Studies Study 1 was a multicenter, double-blind, randomized, vehicle-controlled trial which enrolled 459 subjects 12 years of age and older with moderate to severe seborrheic dermatitis. A total of 229 subjects were treated with XOLEGEL, and 230 subjects were treated with vehicle. All subjects were treated once daily for 14 days, and efficacy was assessed at Day 28 (i.e., 2 weeks after end of treatment). Effective Treatment was defined as: an Investigator's Global Assessment score of ≤ 1 (completely clear or almost clear) and erythema and scaling scores of 0 (none) if the baseline score was 2, or 1 (mild) if the baseline score was 3. The proportion of subjects effectively treated is shown in Table 1. Table 1: Trial Results XOLEGEL N=229 Vehicle N=230 Number and proportion of subjects effectively treated 58 (25.3%) 32 (13.9%) Two additional double-blind, randomized, vehicle-controlled, parallel, and multicenter trials that included a total of 316 subjects treated with XOLEGEL provided supportive evidence of the efficacy of XOLEGEL for treatment of seborrheic dermatitis. Subjects applied either XOLEGEL or vehicle study treatment to the affected area(s) once daily for 14 days and were followed through Day 28. Efficacy was assessed by the proportion of subjects who were completely clear at Day 28. The contribution to efficacy of individual components of the vehicle has not been established.

SIDE EFFECTS 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 practice. The following adverse reactions were reported in clinical trials: Immune System Disorders: anaphylactoid reaction Endocrine Disorders: gynecomastia Metabolism and Nutrition Disorders: alcohol intolerance, anorexia, hyperlipidemia, increased appetite Psychiatric Disorders: insomnia, nervousness Nervous System Disorders: headache, dizziness, paresthesia, somnolence Eye Disorders: photophobia Vascular Disorders: orthostatic hypotension Respiratory, Thoracic and Mediastinal Disorders: epistaxis Gastrointestinal Disorders: vomiting, diarrhea, nausea, constipation, abdominal pain, abdominal pain upper, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration Hepatobiliary Disorders: hepatitis, jaundice, hepatic function abnormal Skin and Subcutaneous Tissues Disorders: erythema multiforme, rash, dermatitis, erythema, urticaria, pruritus, alopecia, xeroderma Musculoskeletal and Connective Tissue Disorders: myalgia Reproductive System and Breast Disorders: menstrual disorder General Disorders and Administration Site Conditions: asthenia, fatigue, hot flush, malaise, edema peripheral, pyrexia, chills Investigations: platelet count decreased. Post-Marketing Experience The following adverse reactions have been identified during postapproval use of Nizoral tablets. Because these 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. The following adverse reactions were reported during post-marketing experience: Blood and Lymphatic System Disorders: thrombocytopenia Immune System Disorders: allergic conditions including anaphylactic shock, anaphylactic reaction, angioneurotic edema Endocrine Disorders: adrenocortical insufficiency Nervous System Disorders: reversible intracranial pressure increased (e.g. papilloedema, fontanelle bulging in infants) Hepatobiliary Disorders: serious hepatotoxicity including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis, photosensitivity Musculoskeletal and Connective Tissue Disorders: arthralgia Reproductive System and Breast Disorders: erectile dysfunction; with doses higher than the recommended therapeutic dose of 200 or 400mg daily, azoospermia. DRUG INTERACTIONS Drugs that affect the absorption, distribution, metabolism, and excretion of ketoconazole may alter the plasma concentrations of ketoconazole. For example, gastric acid suppressants (e.g., antacids, histamine H2-blockers, proton pump inhibitors) have been shown to reduce plasma concentrations of ketoconazole. Ketoconazole is a substrate and potent inhibitor of CYP3A4. Therefore, the following drug interactions may occur when NIZORAL® is co-administered with other drugs that interact with CYP3A4. (See Table 1 and Table 2 for an overview of these drug interactions; details are provided in the text that follows these tables.) NIZORAL® may decrease the elimination of drugs metabolized by CYP3A4, thereby increasing their plasma concentrations. Increased exposure to these drugs may cause an increase or prolongation of their therapeutic and/or adverse effects. Concomitant use with NIZORAL® Tablets is contraindicated for drugs known to present a risk of serious side effects with increased exposure (see BOXED WARNING, CONTRAINDICATIONS section, and, Table 1). For others, monitoring of plasma concentrations is advised when possible. Clinical signs and symptoms associated with these drugs should be monitored, with dosage adjusted as needed. Inducers of CYP3A4 may decrease the plasma concentrations of ketoconazole (see Table 2). NIZORAL® may not be effective in patients concomitantly taking one of these drugs. Therefore, administration of these drugs with NIZORAL® is not recommended. Other inhibitors of CYP3A4 may increase the plasma concentrations of ketoconazole (see Table 2). Patients who must take NIZORAL® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of NIZORAL® . Table 1: Selected Drugs That Have Been Shown To or Are Predicted To Have Their Plasma Concentrations Altered By NIZORAL®* Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is contraindicated. Alprazolam, midazolam, triazolam HMG-CoA reductase inhibitors (lovastatin, simvastatin) Cisapride Nisoldipine Dofetilide Pimozide Eplerenone Quinidine Ergot alkaloids (ergotamine, dihydroergotamine) Systemic exposure to these drugs is increased by ketoconazole: Careful monitoring, with possible adjustment in dosage, is recommended. Alfentanil, fentanyl, sulfentanil Indinavir, saquinavir Amlodipine, felodipine, nicardipine, nifedipine Methylprednisolone Bosentan Rifabutin Buspirone Sildenafil Busulfan Sirolimus (co-administration not recommended) Carbamazepine Tacrolimus Cilostazol Telithromycin Cyclosporine Tolterodine Digoxin Trimetrexate Docetaxel, paclitaxel Verapamil Oral anti-coagulants Vinca alkaloids (vincristine, - vinblastine, vinorelbine) * This list is not all-inclusive. Table 2: Selected Drugs That Have Been Shown To or Are Predicted To Alter The Plasma Concentration Of NIZORAL® Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended. Carbamazepine Phenytoin Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate) Rifampin, rifabutin, isoniazid Nevirapine Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered Ritonavir * This list is not all-inclusive. Effects of ketoconazole on other drugs Systemic exposure to the following drugs is significantly increased by co­administration of ketoconazole. Concomitant use of these drugs with NIZORAL® Tablets is contraindicated: Alprazolam, midazolam, triazolam Co-administration of NIZORAL® Tablets with alprazolam, midazolam, or triazolam has resulted in elevated plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated or chronic administration of these agents. Concomitant administration of NIZORAL® Tablets with alprazolam, oral midazolam, and oral triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.) Special precaution and patient monitoring are required with concomitant parenteral midazolam, because the sedative effect may be prolonged. Cisapride Oral ketoconazole potently inhibits the metabolism of cisapride resulting in a mean eight-fold increase in AUC of cisapride, which can lead to prolongation of QT interval. Therefore concomitant administration of NIZORAL® Tablets with cisapride is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Dofetilide The class III antiarrhythmic dofetilide is known to prolong the QT interval. The potential increase in dofetilide plasma concentrations when administered concomitantly with ketoconazole could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes. Therefore, concomitant administration of NIZORAL® Tablets with dofetilide is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Eplerenone Ketoconazole increases the eplerenone AUC by roughly 5-fold, thereby increasing the risk for hyperkalemia and hypotension. Co-administration of NIZORAL® and eplerenone is contraindicated. (See CONTRAINDICATIONS section.) Ergot Alkaloids Elevated concentrations of ergot alkaloids can cause ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine and ergotamine with NIZORAL® Tablets is contraindicated. (See CONTRAINDICATIONS section.) HMG-CoA Enzyme Inhibitors (lovastatin, simvastatin) Co-administration of ketoconazole with CYP3A4-metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin, may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of NIZORAL® Tablets with these HMG-CoA reductase inhibitors is contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.) Nisoldipine Pre-treatment with and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold increase in mean AUC and Cmax of nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone. Concomitant administration of ketoconazole with nisoldipine is contraindicated. (See CONTRAINDICATIONS section.) Pimozide Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of NIZORAL® and pimozide could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes, and is therefore contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Quinidine The class IA antiarhythmic quinidine is known to prolong the QT interval. The potential increase in quinidine plasma concentrations when administered concomitantly with ketoconazole could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes. Therefore, concomitant administration of NIZORAL® Tablets with quinidine is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Co-administration of ketoconazole with the following agents was shown or is expected to result in increased exposure to these drugs. Therefore, careful monitoring of plasma concentrations or adverse events of these drugs is recommended. Adjustment of dosage of these drugs may be needed. Alfentanil, sufentanil, fentanyl In vitro data suggest that alfentanil, sufentanil and fentanyl are metabolized by CYP3A4. Concomitant administration of NIZORAL® Tablets and alfentanil, sufentanil, or fentanyl may increase plasma concentrations of the latter drugs. Amlodipine, felodipine, nicardipine, nifedipine CYP3A4 metabolized calcium channel blockers such as amlodipine, felodipine, nicardipine, and nifedipine should be used cautiously with NIZORAL® Tablets as ketoconazole may cause several-fold increases in plasma concentrations of these calcium channel blockers. Bosentan Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1- and 2.3 – fold, respectively. No dosage adjustment of bosentan is needed but close monitoring for increased bosentan-associated adverse effects is recommended. Buspirone Concomitant administration of buspirone with ketoconazole may result in significant increases in plasma concentrations of buspirone. When administered with NIZORAL® Tablets, a low initial dose of buspirone with subsequent dosage adjustment based on clinical assessment is recommended. Busulfan NIZORAL® Tablets may decrease the clearance and thus increase the systemic exposure to busulfan. Carbamazepine In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Close monitoring of plasma carbamazepine concentrations is recommended whenever ketoconazole is given to patients stabilized on carbamazepine therapy. Cilostazol Ketoconazole had been shown to increase both cilostazol AUC and Cmax by about two-fold when administered concurrently. Co-administration of ketoconazole with cilostazol resulted in increased incidences of adverse effects, such as headache. When NIZORAL® Tablets is administered concomitantly with cilostazol, the prescriber should consider up to a 50% reduction in cilostazol dosage. Cyclosporine Ketoconazole tablets may alter the metabolism of cyclosporine, thereby resulting in elevated cyclosporine plasma concentrations. Dosage adjustment may be required if cyclosporine or tacrolimus is given concomitantly with NIZORAL® Tablets. Digoxin 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 ketoconazole. Docetaxel In the presence of ketoconazole, the clearance of docetaxel in cancer patients was shown to decrease by 50%. When docetaxel and NIZORAL® are administered together, dosage reduction in docetaxel may be necessary in order to minimize the incidence of toxicities associated with docetaxel. Indinavir, saquinavir Concomitant administration of NIZORAL® and protease inhibitors metabolized by CYP3A4, such as indinavir and saquinavir, may increase plasma concentrations of these protease inhibitors. Dosage reduction of indinavir is recommended when administering ketoconazole concomitantly. No dosage adjustments are recommended when saquinavir and ketoconazole are coadministered for a short period of time. Methylprednisolone NIZORAL® Tablets may alter the metabolism of methylprednisolone, resulting in elevated plasma concentrations of methylprednisolone. Dose adjustments may be required if methylprednisolone is given concomitantly with NIZORAL® Tablets. Oral anti-coagulants Oral imidazole compounds such as ketoconazole may enhance the anticoagulant effect of coumarin-like drugs, thus the anticoagulant effect should be carefully titrated and monitored. Oral hypoglycemic agents 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 ketoconazole tablets (an imidazole) cannot be ruled out. Rifabutin Ketoconazole was shown to inhibit the CYP-mediated metabolism of rifabutin in vitro. Co-administration with NIZORAL® Tablets may result in elevated plasma concentrations of rifabutin. Sildenafil Ketoconazole had been shown to increase sildenafil plasma concentrations. When used concomitantly with NIZORAL® Tablets, a 50% reduction in sildenafil starting dose should be considered. Sirolimus Multiple-dose ketoconazole had been shown to increase sirolimus Cmax and AUC by 4.3-fold and 10.9-fold, respectively. The concomitant use of NIZORAL® Tablets and sirolimus is not recommended. Tacrolimus Ketoconazole had been shown to decrease the oral clearance of tacrolimus thereby leading to a 2-fold increase in tacrolimus oral bioavailability. Adjustment in tacrolimus dosage may be required if tacrolimus is given concomitantly with NIZORAL® Tablets. Telithromycin Ketoconazole increased the AUC of telithromycin by 1.5 to 2-fold. Use caution when administering telithromycin concurrently with NIZORAL® Tablets since this may result in an increased risk for telithromycin associated adverse events. Tolterodine In the presence of ketoconazole, the apparent oral clearance of tolterodine decreased resulting in at least a two-fold increase in tolterodine. For patients receiving ketoconazole, a 50% reduction in the initial tolterodine dosage is recommended. Trimetrexate In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Patients treated concomitantly with trimetrexate and NIZORAL® Tablets should be carefully monitored for trimetrexate-associated toxicities. Verapamil Findings of in vitro metabolic studies indicate that verapamil is metabolized by enzymes including CYP3A4. Ketoconazole may increase verapamil serum concentrations. Caution should be taken when co-administering verapamil with NIZORAL® Tablets. Vinca Alkaloids (vincristine, vinblastine, vinorelbine) NIZORAL® may inhibit the metabolism of vinca alkaloids metabolized by CYP3A4. Close monitoring for toxicities associated with vincristine, vinblastine, or vinorelbine is recommended when co-administered with NIZORAL® Tablets. Effects of other drugs on ketoconazole Drugs affecting the absorption of ketoconazole Gastric Acid Suppressors/Neutralizers Studies have shown that absorption of ketoconazole is impaired when gastric acid production is decreased. Reduced plasma concentrations of ketoconazole were reported when NIZORAL® Tablets were administered with antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors (omeprazole, lansoprazole) and sucralfate. (See DRUG INTERACTIONS (General) section.) Drugs that were shown or are expected to significantly reduce the systemic exposure to ketoconazole Co-administration of ketoconazole with potent CYP3A4 enzyme inducers is not recommended. Carbamazepine Concomitant administration of ketoconazole tablets with carbamazepine may alter the metabolism of one or both of the drugs. Close monitoring for both plasma concentrations of carbamazepine and reduced ketoconazole efficacy is recommended. Nevirapine Ketoconazole AUC and Cmax decreased by a median of 63% and 40%, respectively, in HIV-infected patients who were given nevirapine 200 mg once daily for two weeks along with ketoconazole 400 mg daily. Concomitant administration of NIZORAL® Tablets and nevirapine is not recommended. Phenytoin Concomitant administration of ketoconazole with phenytoin may alter the metabolism of one or both of the drugs. Close monitoring for both plasma concentrations of phenytoin and reduced efficacy of NIZORAL® Tablets is recommended. Rifampin, rifabutin, isoniazid Concomitant administration of rifampin and rifabutin with ketoconazole tablets reduces the blood concentrations of the latter. INH (Isoniazid) was also reported to affect ketoconazole concentrations adversely. These antitubercular drugs should not be given concomitantly with NIZORAL® Tablets. Drugs that significantly increase the systemic exposure to ketoconazole Ritonavir Concomitant administration of ritonavir with ketoconazole tablets increases was shown to increase the oral bioavailability of ketoconazole. Therefore, when ritonavir is to be given concomitantly, higher doses ( > 200 mg/day) of NIZORAL® Tablets should not be used. Other drug interactions Alcohol Rare cases of a 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. Loratadine After the co-administration of 200 mg oral ketoconazole twice daily and one 20 mg dose of loratadine to 11 subjects, the AUC and Cmax of loratadine averaged 302% (±142 S.D.) and 251% (± 68 S.D.), respectively, of those obtained after cotreatment with placebo. The AUC and Cmax of descarboethoxyloratadine, an active metabolite, averaged 155% (± 27 S.D.) and 141% (± 35 S.D.), respectively. However, no related changes were noted in the QTc 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 ketoconazole.

CLINICAL PHARMACOLOGY When Ketoconazole Cream 2% was applied dermally to intact or abraded skin of Beagle dogs for 28 consecutive days at a dose of 80 mg, there were no detectable plasma levels using an assay method having a lower detection limit of 2 ng/ml. After a single topical application to the chest, back and arms of normal volunteers, systemic absorption of ketoconazole was not detected at the 5 ng/ml level in blood over a 72-hour period. Two dermal irritancy studies, a human sensitization test, a phototoxicity study and a photoallergy study conducted in 38 male and 62 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity and no photoallergenic potential due to Ketoconazole Cream 2%. Microbiology Ketoconazole is a broad spectrum synthetic antifungal agent which inhibits the in vitro growth of the following common dermatophytes and yeasts by altering the permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum; yeasts: Candida albicans, Malassezia ovate (Pityrosporum ovale) and C. tropicalis; and the organism responsible for tinea versicolor, Malassezia furfur (Pityrosporum orbiculare). Only those organisms listed in the INDICATIONS Section have been proven to be clinically affected. Development of resistance to ketoconazole has not been reported. Mode of Action In vitro studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. It is postulated that the therapeutic effect of ketoconazole in seborrheic dermatitis is due to the reduction of M. ovale, but this has not yet been proven.

Find Lowest Prices on XOLEGEL® (ketoconazole) DESCRIPTION XOLEGEL contains the antifungal agent ketoconazole USP at 2% in a topical anhydrous gel vehicle for topical administration. Chemically, ketoconazole is (±)-cis-1-Acetyl-4-[p-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4yl]methoxy]phenyl]piperazine, with the molecular formula C26H28Cl2N4O4 and a molecular weight of 531.43. Figure 1 Each gram contains: 20 mg ketoconazole USP, dehydrated alcohol (34%), ascorbic acid, butylated hydroxytoluene, citric acid monohydrate, glycerin, hydroxypropyl cellulose, polyethylene glycol 400, PPG-15 stearyl ether, propylene glycol, FD&C yellow No. 6, and FD&C yellow No.10. XOLEGEL is a smooth, translucent to clear, amber gel.

Find Lowest Prices on NIZORAL® (ketoconazole) Tablets WARNING NIZORAL® Tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks. Hepatotoxicity Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Patients receiving this drug should be informed by the physician of the risk and should be closely monitored. See WARNINGS section. QT Prolongation and Drug Interactions Leading to QT Prolongation Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: DRUG INTERACTIONS sections. DESCRIPTION NIZORAL® is a synthetic broad-spectrum antifungal agent available in scored white tablets, each containing 200 mg ketoconazole base for oral administration. Inactive ingredients are colloidal silicon dioxide, corn starch, lactose, magnesium stearate, microcrystalline cellulose, and povidone. Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl] piperazine and has the following structural formula: Ketoconazole is a white to slightly beige, odorless powder, soluble in acids, with a molecular weight of 531.44.

Kuric™ (ketoconazole) 2% Cream For external use only DESCRIPTION Kuric™ (ketoconazole) 2% cream, for topical administration only, contains the broad-spectrum synthetic antifungal agent, ketoconazole 2% cream, formulated in an aqueous cream vehicle consisting of propylene glycol, stearyl and cetyl alcohols, sorbitan monostearate, polysorbate 60, isopropyl myristate, sodium sulfite anhydrous, polysorbate 80 and purified water. Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine and has the following structural formula:

INDICATIONS XOLEGEL is indicated for the topical treatment of seborrheic dermatitis in immunocompetent adults and children 12 years of age and older. Safety and efficacy of XOLEGEL for treatment of fungal infections have not been established. DOSAGE AND ADMINISTRATION XOLEGEL is for topical use only, and not for oral, ophthalmic, or intravaginal use. XOLEGEL should be applied once daily to the affected area for 2 weeks. HOW SUPPLIED Dosage Forms And Strengths XOLEGEL is a translucent to clear amber colored gel containing 2% ketoconazole. XOLEGEL® (ketoconazole) Gel, 2% is supplied in 45-gram (NDC 16110-080-45) white-coated aluminum tubes with white caps, and is dispensed with FDA-Approved Patient Labeling. (17.2) Storage and Handling Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F). Contents are flammable. Keep out of reach of children. MANUFACTURED BY: DPT Laboratories, Ltd. 307 E. Josephine Street San Antonio, TX 78215. FOR: Aqua Pharmaceuticals, West Chester, PA 19380. Revised 05/2012

INDICATIONS NIZORAL® Tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks. NIZORAL® (ketoconazole) Tablets are indicated for the treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. NIZORAL® Tablets should not be used for fungal meningitis because it penetrates poorly into the cerebrospinal fluid. DOSAGE AND ADMINISTRATION There should be laboratory as well as clinical documentation of infection prior to starting ketoconazole therapy. The usual duration of therapy for systemic infection is 6 months. Treatment should be continued until active fungal infection has subsided. Adults The recommended starting dose of NIZORAL® (ketoconazole) Tablets is a single daily administration of 200 mg (one tablet). If clinical responsiveness is insufficient within the expected time, the dose of NIZORAL® Tablets 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. NIZORAL® Tablets have not been studied in children under 2 years of age. HOW SUPPLIED NIZORAL® (ketoconazole) is available as white, scored tablets containing 200 mg of ketoconazole debossed “JANSSEN” and on the reverse side debossed “NIZORAL”. They are supplied in bottles of 100 tablets (NDC 50458-220-10). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from moisture. Keep out of reach of children. Janssen Pharmaceuticals, Inc, Titusville, New Jersey 08560. Revised: July 2013

INDICATIONS Kuric™ is indicated for the topical treatment of tinea corporis, tinea cruris and tinea pedis caused by Trichophyton rubrum, T. mentagrophytes and Epidermophyton floccosum; in the treatment of tinea (pityriasis) versicolor caused by Malassezia furfur (Pityrosporum orbiculare); in the treatment of cutaneous candidiasis caused by Candida spp. and in the treatment of seborrheic dermatitis. DOSAGE AND ADMINISTRATION Cutaneous candidiasis, tinea corporis, tinea cruris, tinea pedis and tinea (pityriasis) versicolor: It is recommended that Kuric™ be applied once daily to cover the affected and immediate surrounding area. Clinical improvement may be seen fairly soon after treatment is begun; however, candidal infections and tinea cruris and corporis should be treated for two weeks in order to reduce the possibility of recurrence. Patients with tinea versicolor usually require two weeks of treatment. Patients with tinea pedis require six weeks of treatment. Seborrheic dermatitis: Kuric™ should be applied to the affected area twice daily for four weeks or until clinical clearing. If a patient shows no clinical improvement after the treatment period, the diagnosis should be redetermined. HOW SUPPLIED Kuric™ (ketoconazole) 2% cream is supplied as follows: 75 gram NDC 68712 006 03 Store below 77°F (25°C). Manufactured for: JSJ Pharmaceuticals, 140 East Bay Street, Suite C, Charleston, SC 29401. www.jsjpharm.com, www.KuricCream.com. Manufactured by: Altana Inc. Melville, NY 11747. Revised: April 2007

PATIENT INFORMATION XOLEGEL® (Xol-a-gel) (ketoconazole) Gel, 2% Read the Patient Information that comes with XOLEGEL carefully before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your health care provider. If you have any questions about XOLEGEL, ask your health care provider. What is XOLEGEL? XOLEGEL is a prescription medicine used on the skin to treat a skin condition called seborrheic dermatitis. Patients with seborrheic dermatitis can have areas of dry, flaky skin on the scalp, face, ears, chest, or upper back. XOLEGEL is only to be used in adults and in children older than 12 years of age who have a normal (healthy) immune system. XOLEGEL has not been studied in children below the age of 12. It is not known whether XOLEGEL can be used to treat fungal infections. XOLEGEL is a translucent to clear, amber colored gel. What should I tell my health care provider before using XOLEGEL? Tell your health care provider about all of your medical conditions, including if you are pregnant or planning to become pregnant, or are breastfeeding or planning to breastfeed. XOLEGEL should be used during pregnancy and breastfeeding only if needed. Tell your health care provider about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Keep a list of your medicines and show it to your health care provider and pharmacist. Tell your health care provider and pharmacist when you get a new medicine. It is not known if XOLEGEL and other medicines can interact with each other. How should I use XOLEGEL? Use XOLEGEL exactly as prescribed. Talk to your health care provider if your condition gets worse or does not get better by the end of your treatment. Wash your hands before and after applying XOLEGEL. Spread a thin layer of XOLEGEL evenly on the affected skin with your fingertips. Be sure to cover all affected areas. Do not wash the areas where you applied XOLEGEL for at least 3 hours after you apply it. Wait at least 20 minutes after you spread XOLEGEL on your skin before you put makeup or sunscreens on the affected areas. Use XOLEGEL once daily for 2 weeks. What should I avoid while using XOLEGEL? XOLEGEL is only to be used on the skin. It is not for eye, mouth, or vaginal use. Do not touch your eyes, nose, or mouth while you are applying XOLEGEL. Wash your hands well after you apply it. Irritation may occur if you get XOLEGEL in your eyes, nose, or mouth. If used during breastfeeding and XOLEGEL is applied on the chest, take care to avoid accidental ingestion of XOLEGEL by the baby. XOLEGEL is flammable (it can catch fire). Stay away from heat, flame, or smoking while you are applying XOLEGEL and right after you apply it. This medication should not be used for any disorder other than that for which it has been prescribed. What are the possible side effects of XOLEGEL? The effects of XOLEGEL during pregnancy, including whether XOLOGEL can harm your unborn baby, are not known. It is not known if XOLEGEL can pass into your breastmilk or if it can harm your breastfed baby. Stop using XOLEGEL and talk to your health care provider if you develop itching, a rash, or any skin irritation after using XOLEGEL. Stop using XOLEGEL and talk to your health care provider if your skin condition (seborrheic dermatitis) gets worse. The most common side effect is a burning feeling where XOLEGEL is applied. Report any side effects to your health care provider to receive immediate medical attention. You can also report suspected side effects by calling the US Food and Drug Administration at 1-800-FDA-1088, or reporting via the internet at www.fda.gov/medwatch. These are not all of the side effects of XOLEGEL. For more information, ask your health care provider or pharmacist. How should I store XOLEGEL? Store XOLEGEL at 59°F to 86°F (15° to 30°C). Keep XOLEGEL and all medicines out of the reach of children. Contents are flammable. Avoid storing XOLEGEL near heat or flame. General information about XOLEGEL Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use XOLEGEL for a condition for which it was not prescribed. Do not give XOLEGEL to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about XOLEGEL. If you would like more information, talk with your health care provider. You can also ask your pharmacist or health care provider for information about XOLEGEL that is written for health professionals. What are the ingredients in XOLEGEL? Active ingredient: ketoconazole, USP Inactive ingredients: dehydrated alcohol, ascorbic acid, butylated hydroxytoluene, citric acid monohydrate, glycerin, hydroxypropyl cellulose, polyethylene glycol 400, PPG-15 stearyl ether, propylene glycol, FD&C yellow No. 6, and FD&C Yellow No. 10. This Patient Information leaflet has been approved by the U.S. Food and Drug Administration. The Patient Information leaflet was last revised: May 2012.

PATIENT INFORMATION NIZORAL® (ketoconazole) Tablets What is the most important information I should know about NIZORAL® Tablets? NIZORAL® Tablets is not the only medicine available to treat fungal infections and should only be used when other medicines are not right for you. Talk to your healthcare provider to find out if NIZORAL® Tablets are right for you. NIZORAL® Tablets can cause serious side effects, including: liver problems (hepatotoxicity). Some people who were treated with ketoconazole the active ingredient in NIZORAL® Tablets, had serious liver problems that led to death or the need for a liver transplant. Call your healthcare provider right away if you have any of the following symptoms: loss of appetite or start losing weight (anorexia) nausea or vomiting feel tired stomach pain or tenderness dark urine or light colored stools yellowing of your skin or the whites of your eyes fever or rash changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heart beats that can be life threatening. This can happen when NIZORAL® Tablets are taken with certain medicines, such as dofetilide, quinidine, pimozide, and cisapride. Talk to your healthcare provider about other medicines you are taking before you start taking NIZORAL® Tablets. Tell your healthcare provider right away if you feel faint, lightheaded, dizzy, or feel your heart beating irregularly or fast. These may be symptoms related to QT prolongation. What are NIZORAL® Tablets? NIZORAL® Tablets are prescription medicine used to treat serious fungal infections including: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. NIZORAL® Tablets are not for people with fungal nail infections. NIZORAL® Tablets have not been approved for the treatment of advanced prostate cancer or Cushing's syndrome. The safety and efficacy have not been established. NIZORAL® Tablets should only be used in children if prescribed by the healthcare provider who has determined that the benefits outweigh the risks. Who should not take NIZORAL® Tablets? Do not take NIZORAL® Tablets if you: have liver problems take simvastatin, and lovastatin. NIZORAL® Tablets when taken with these medicines may cause muscle problems. take eplerenone, dihydroergotamine, ergotamine, and nisoldipine. take triazolam, midazolam, or alprazolam. Taking NIZORAL® Tablets with these medicines may make you very drowsy and make your drowsiness last longer. are allergic to ketoconazole or any of the ingredients in NIZORAL® Tablets. See the end of this Medication Guide for a complete list of ingredients in NIZORAL® Tablets. Before you take NIZORAL® Tablets, tell your healthcare provider if you: have had an abnormal heart rhythm tracing (ECG) or anyone in your family have or have had a heart problem called “congenital long QT syndrome”. have adrenal insufficiency. are pregnant or plan to become pregnant. It is not known if NIZORAL® Tablets will harm your unborn baby. are breastfeeding or plan to breastfeed. NIZORAL® Tablets can pass into your breast milk. You and your healthcare provider should decide if you will take NIZORAL® Tablets or breastfeed. You should NOT do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using NIZORAL® Tablets with certain other medicines may affect each other. Using NIZORAL® Tablets with other medicines can cause serious side effects. How should I take NIZORAL® Tablets? Take NIZORAL® 1 time each day. Do not stop taking NIZORAL® Tablets without first talking to your healthcare provider. What should I avoid while taking NIZORAL® Tablets? Do not drink alcohol while taking NIZORAL® Tablets. What are the possible side effects of NIZORAL® Tablets? NIZORAL® Tablets may cause serious side effects, including: See “What is the most important information I should know about NIZORAL® Tablets?” adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. NIZORAL® Tablets may cause adrenal insufficiency if you take a high dose. Your healthcare provider will follow you closely if you have adrenal insufficiency or if you are taking prednisone or other similar medicines for long periods of time. Call your healthcare provider right away if you have symptoms of adrenal insufficiency such as tiredness, weakness, dizziness, nausea, and vomiting. serious allergic reactions. Some people can have a serious allergic reaction to NIZORAL® Tablets. Stop taking NIZORAL® Tablets and go to the nearest hospital emergency room right away if you get a rash, itching, hives, fever, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious allergic reaction. muscle problems. Taking certain medicines with NIZORAL® Tablets may cause muscle problems. See “Who should not take NIZORAL® Tablets?” The most common side effects of NIZORAL® Tablets include nausea, headache, diarrhea, stomach pain, and abnormal liver function tests. These are not all the possible side effects of NIZORAL® Tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NIZORAL® Tablets? Store NIZORAL® Tablets at room temperature between 59°F to 77°F (15°C to 25°C). Keep NIZORAL® Tablets dry. General information about the safe and effective use of NIZORAL® Tablets. Medications are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NIZORAL® Tablets for a condition for which it was not prescribed. Do not give NIZORAL® Tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about NIZORAL® Tablets. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about NIZORAL® Tablets that is written for health professionals. What are the ingredients in NIZORAL® Tablets? Active ingredient: ketoconazole. Inactive ingredients: colloidal silicon dioxide, corn starch, lactose, magnesium stearate, microcrystalline cellulose, and povidone.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE XOLEGEL is intended for topical use only. There has been no experience of overdose with XOLEGEL. No incidents of accidental ingestion have been reported. A health care provider or poison control center should be contacted in the event of accidental ingestion. CONTRAINDICATIONS None.

OVERDOSE In the event of acute accidental overdose, treatment consists of supportive and symptomatic measures. Within the first hour after ingestion, activated charcoal may be administered. CONTRAINDICATIONS Drug Interactions Coadministration of a number of CYP3A4 substrates is contraindicated with NIZORAL® Tablets. Coadministration with ketoconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both therapeutic and adverse effects. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. See WARNINGS section, and PRECAUTIONS: DRUG INTERACTIONS section for specific examples. Liver Disease The use of NIZORAL® Tablets is contraindicated in patients with acute or chronic liver disease. Hypersensitivity NIZORAL® is contraindicated in patients who have shown hypersensitivity to the drug.

OVERDOSE No information provided. CONTRAINDICATIONS Kuric™ is contraindicated in persons who have shown hypersensitivity to the active or excipient ingredients of this formulation.

SIDE EFFECTS Clinical Trial Experiences 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 the 3 safety and efficacy trials, 65 of 933 subjects (7%) experienced at least one treatment-related adverse event. The most common treatment-related adverse reaction was application site burning (4%). Treatment-related application site reactions that were reported in < 1% of subjects were: dermatitis, discharge, dryness, erythema, irritation, pain, pruritus, and pustules. Other treatment-related adverse reactions that were reported in < 1% of subjects were: eye irritation, eye swelling, keratoconjunctivitis sicca, impetigo, pyogenic granuloma, dizziness, headache, paresthesia, acne, nail discoloration, facial swelling. Post-marketing Experience Adverse events identified during post approval use with XOLEGEL include burning sensation, pain, skin irritation, and erythema. Because these events 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. DRUG INTERACTIONS Formal drug interaction studies with XOLEGEL have not been performed. Coadministration of oral ketoconazole with CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, lovastatin and atorvastatin, may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. These effects have not been observed with topically administered ketoconazole.

SIDE EFFECTS 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 practice. The following adverse reactions were reported in clinical trials: Immune System Disorders: anaphylactoid reaction Endocrine Disorders: gynecomastia Metabolism and Nutrition Disorders: alcohol intolerance, anorexia, hyperlipidemia, increased appetite Psychiatric Disorders: insomnia, nervousness Nervous System Disorders: headache, dizziness, paresthesia, somnolence Eye Disorders: photophobia Vascular Disorders: orthostatic hypotension Respiratory, Thoracic and Mediastinal Disorders: epistaxis Gastrointestinal Disorders: vomiting, diarrhea, nausea, constipation, abdominal pain, abdominal pain upper, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration Hepatobiliary Disorders: hepatitis, jaundice, hepatic function abnormal Skin and Subcutaneous Tissues Disorders: erythema multiforme, rash, dermatitis, erythema, urticaria, pruritus, alopecia, xeroderma Musculoskeletal and Connective Tissue Disorders: myalgia Reproductive System and Breast Disorders: menstrual disorder General Disorders and Administration Site Conditions: asthenia, fatigue, hot flush, malaise, edema peripheral, pyrexia, chills Investigations: platelet count decreased. Post-Marketing Experience The following adverse reactions have been identified during postapproval use of Nizoral tablets. Because these 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. The following adverse reactions were reported during post-marketing experience: Blood and Lymphatic System Disorders: thrombocytopenia Immune System Disorders: allergic conditions including anaphylactic shock, anaphylactic reaction, angioneurotic edema Endocrine Disorders: adrenocortical insufficiency Nervous System Disorders: reversible intracranial pressure increased (e.g. papilloedema, fontanelle bulging in infants) Hepatobiliary Disorders: serious hepatotoxicity including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis, photosensitivity Musculoskeletal and Connective Tissue Disorders: arthralgia Reproductive System and Breast Disorders: erectile dysfunction; with doses higher than the recommended therapeutic dose of 200 or 400mg daily, azoospermia. DRUG INTERACTIONS Drugs that affect the absorption, distribution, metabolism, and excretion of ketoconazole may alter the plasma concentrations of ketoconazole. For example, gastric acid suppressants (e.g., antacids, histamine H2-blockers, proton pump inhibitors) have been shown to reduce plasma concentrations of ketoconazole. Ketoconazole is a substrate and potent inhibitor of CYP3A4. Therefore, the following drug interactions may occur when NIZORAL® is co-administered with other drugs that interact with CYP3A4. (See Table 1 and Table 2 for an overview of these drug interactions; details are provided in the text that follows these tables.) NIZORAL® may decrease the elimination of drugs metabolized by CYP3A4, thereby increasing their plasma concentrations. Increased exposure to these drugs may cause an increase or prolongation of their therapeutic and/or adverse effects. Concomitant use with NIZORAL® Tablets is contraindicated for drugs known to present a risk of serious side effects with increased exposure (see BOXED WARNING, CONTRAINDICATIONS section, and, Table 1). For others, monitoring of plasma concentrations is advised when possible. Clinical signs and symptoms associated with these drugs should be monitored, with dosage adjusted as needed. Inducers of CYP3A4 may decrease the plasma concentrations of ketoconazole (see Table 2). NIZORAL® may not be effective in patients concomitantly taking one of these drugs. Therefore, administration of these drugs with NIZORAL® is not recommended. Other inhibitors of CYP3A4 may increase the plasma concentrations of ketoconazole (see Table 2). Patients who must take NIZORAL® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of NIZORAL® . Table 1: Selected Drugs That Have Been Shown To or Are Predicted To Have Their Plasma Concentrations Altered By NIZORAL®* Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is contraindicated. Alprazolam, midazolam, triazolam HMG-CoA reductase inhibitors (lovastatin, simvastatin) Cisapride Nisoldipine Dofetilide Pimozide Eplerenone Quinidine Ergot alkaloids (ergotamine, dihydroergotamine) Systemic exposure to these drugs is increased by ketoconazole: Careful monitoring, with possible adjustment in dosage, is recommended. Alfentanil, fentanyl, sulfentanil Indinavir, saquinavir Amlodipine, felodipine, nicardipine, nifedipine Methylprednisolone Bosentan Rifabutin Buspirone Sildenafil Busulfan Sirolimus (co-administration not recommended) Carbamazepine Tacrolimus Cilostazol Telithromycin Cyclosporine Tolterodine Digoxin Trimetrexate Docetaxel, paclitaxel Verapamil Oral anti-coagulants Vinca alkaloids (vincristine, - vinblastine, vinorelbine) * This list is not all-inclusive. Table 2: Selected Drugs That Have Been Shown To or Are Predicted To Alter The Plasma Concentration Of NIZORAL® Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended. Carbamazepine Phenytoin Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate) Rifampin, rifabutin, isoniazid Nevirapine Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered Ritonavir * This list is not all-inclusive. Effects of ketoconazole on other drugs Systemic exposure to the following drugs is significantly increased by co­administration of ketoconazole. Concomitant use of these drugs with NIZORAL® Tablets is contraindicated: Alprazolam, midazolam, triazolam Co-administration of NIZORAL® Tablets with alprazolam, midazolam, or triazolam has resulted in elevated plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated or chronic administration of these agents. Concomitant administration of NIZORAL® Tablets with alprazolam, oral midazolam, and oral triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.) Special precaution and patient monitoring are required with concomitant parenteral midazolam, because the sedative effect may be prolonged. Cisapride Oral ketoconazole potently inhibits the metabolism of cisapride resulting in a mean eight-fold increase in AUC of cisapride, which can lead to prolongation of QT interval. Therefore concomitant administration of NIZORAL® Tablets with cisapride is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Dofetilide The class III antiarrhythmic dofetilide is known to prolong the QT interval. The potential increase in dofetilide plasma concentrations when administered concomitantly with ketoconazole could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes. Therefore, concomitant administration of NIZORAL® Tablets with dofetilide is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Eplerenone Ketoconazole increases the eplerenone AUC by roughly 5-fold, thereby increasing the risk for hyperkalemia and hypotension. Co-administration of NIZORAL® and eplerenone is contraindicated. (See CONTRAINDICATIONS section.) Ergot Alkaloids Elevated concentrations of ergot alkaloids can cause ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine and ergotamine with NIZORAL® Tablets is contraindicated. (See CONTRAINDICATIONS section.) HMG-CoA Enzyme Inhibitors (lovastatin, simvastatin) Co-administration of ketoconazole with CYP3A4-metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin, may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of NIZORAL® Tablets with these HMG-CoA reductase inhibitors is contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.) Nisoldipine Pre-treatment with and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold increase in mean AUC and Cmax of nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone. Concomitant administration of ketoconazole with nisoldipine is contraindicated. (See CONTRAINDICATIONS section.) Pimozide Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of NIZORAL® and pimozide could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes, and is therefore contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Quinidine The class IA antiarhythmic quinidine is known to prolong the QT interval. The potential increase in quinidine plasma concentrations when administered concomitantly with ketoconazole could result in serious cardiovascular events including QTc prolongation and rare occurrences of torsades de pointes. Therefore, concomitant administration of NIZORAL® Tablets with quinidine is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Co-administration of ketoconazole with the following agents was shown or is expected to result in increased exposure to these drugs. Therefore, careful monitoring of plasma concentrations or adverse events of these drugs is recommended. Adjustment of dosage of these drugs may be needed. Alfentanil, sufentanil, fentanyl In vitro data suggest that alfentanil, sufentanil and fentanyl are metabolized by CYP3A4. Concomitant administration of NIZORAL® Tablets and alfentanil, sufentanil, or fentanyl may increase plasma concentrations of the latter drugs. Amlodipine, felodipine, nicardipine, nifedipine CYP3A4 metabolized calcium channel blockers such as amlodipine, felodipine, nicardipine, and nifedipine should be used cautiously with NIZORAL® Tablets as ketoconazole may cause several-fold increases in plasma concentrations of these calcium channel blockers. Bosentan Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1- and 2.3 – fold, respectively. No dosage adjustment of bosentan is needed but close monitoring for increased bosentan-associated adverse effects is recommended. Buspirone Concomitant administration of buspirone with ketoconazole may result in significant increases in plasma concentrations of buspirone. When administered with NIZORAL® Tablets, a low initial dose of buspirone with subsequent dosage adjustment based on clinical assessment is recommended. Busulfan NIZORAL® Tablets may decrease the clearance and thus increase the systemic exposure to busulfan. Carbamazepine In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Close monitoring of plasma carbamazepine concentrations is recommended whenever ketoconazole is given to patients stabilized on carbamazepine therapy. Cilostazol Ketoconazole had been shown to increase both cilostazol AUC and Cmax by about two-fold when administered concurrently. Co-administration of ketoconazole with cilostazol resulted in increased incidences of adverse effects, such as headache. When NIZORAL® Tablets is administered concomitantly with cilostazol, the prescriber should consider up to a 50% reduction in cilostazol dosage. Cyclosporine Ketoconazole tablets may alter the metabolism of cyclosporine, thereby resulting in elevated cyclosporine plasma concentrations. Dosage adjustment may be required if cyclosporine or tacrolimus is given concomitantly with NIZORAL® Tablets. Digoxin 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 ketoconazole. Docetaxel In the presence of ketoconazole, the clearance of docetaxel in cancer patients was shown to decrease by 50%. When docetaxel and NIZORAL® are administered together, dosage reduction in docetaxel may be necessary in order to minimize the incidence of toxicities associated with docetaxel. Indinavir, saquinavir Concomitant administration of NIZORAL® and protease inhibitors metabolized by CYP3A4, such as indinavir and saquinavir, may increase plasma concentrations of these protease inhibitors. Dosage reduction of indinavir is recommended when administering ketoconazole concomitantly. No dosage adjustments are recommended when saquinavir and ketoconazole are coadministered for a short period of time. Methylprednisolone NIZORAL® Tablets may alter the metabolism of methylprednisolone, resulting in elevated plasma concentrations of methylprednisolone. Dose adjustments may be required if methylprednisolone is given concomitantly with NIZORAL® Tablets. Oral anti-coagulants Oral imidazole compounds such as ketoconazole may enhance the anticoagulant effect of coumarin-like drugs, thus the anticoagulant effect should be carefully titrated and monitored. Oral hypoglycemic agents 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 ketoconazole tablets (an imidazole) cannot be ruled out. Rifabutin Ketoconazole was shown to inhibit the CYP-mediated metabolism of rifabutin in vitro. Co-administration with NIZORAL® Tablets may result in elevated plasma concentrations of rifabutin. Sildenafil Ketoconazole had been shown to increase sildenafil plasma concentrations. When used concomitantly with NIZORAL® Tablets, a 50% reduction in sildenafil starting dose should be considered. Sirolimus Multiple-dose ketoconazole had been shown to increase sirolimus Cmax and AUC by 4.3-fold and 10.9-fold, respectively. The concomitant use of NIZORAL® Tablets and sirolimus is not recommended. Tacrolimus Ketoconazole had been shown to decrease the oral clearance of tacrolimus thereby leading to a 2-fold increase in tacrolimus oral bioavailability. Adjustment in tacrolimus dosage may be required if tacrolimus is given concomitantly with NIZORAL® Tablets. Telithromycin Ketoconazole increased the AUC of telithromycin by 1.5 to 2-fold. Use caution when administering telithromycin concurrently with NIZORAL® Tablets since this may result in an increased risk for telithromycin associated adverse events. Tolterodine In the presence of ketoconazole, the apparent oral clearance of tolterodine decreased resulting in at least a two-fold increase in tolterodine. For patients receiving ketoconazole, a 50% reduction in the initial tolterodine dosage is recommended. Trimetrexate In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Patients treated concomitantly with trimetrexate and NIZORAL® Tablets should be carefully monitored for trimetrexate-associated toxicities. Verapamil Findings of in vitro metabolic studies indicate that verapamil is metabolized by enzymes including CYP3A4. Ketoconazole may increase verapamil serum concentrations. Caution should be taken when co-administering verapamil with NIZORAL® Tablets. Vinca Alkaloids (vincristine, vinblastine, vinorelbine) NIZORAL® may inhibit the metabolism of vinca alkaloids metabolized by CYP3A4. Close monitoring for toxicities associated with vincristine, vinblastine, or vinorelbine is recommended when co-administered with NIZORAL® Tablets. Effects of other drugs on ketoconazole Drugs affecting the absorption of ketoconazole Gastric Acid Suppressors/Neutralizers Studies have shown that absorption of ketoconazole is impaired when gastric acid production is decreased. Reduced plasma concentrations of ketoconazole were reported when NIZORAL® Tablets were administered with antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors (omeprazole, lansoprazole) and sucralfate. (See DRUG INTERACTIONS (General) section.) Drugs that were shown or are expected to significantly reduce the systemic exposure to ketoconazole Co-administration of ketoconazole with potent CYP3A4 enzyme inducers is not recommended. Carbamazepine Concomitant administration of ketoconazole tablets with carbamazepine may alter the metabolism of one or both of the drugs. Close monitoring for both plasma concentrations of carbamazepine and reduced ketoconazole efficacy is recommended. Nevirapine Ketoconazole AUC and Cmax decreased by a median of 63% and 40%, respectively, in HIV-infected patients who were given nevirapine 200 mg once daily for two weeks along with ketoconazole 400 mg daily. Concomitant administration of NIZORAL® Tablets and nevirapine is not recommended. Phenytoin Concomitant administration of ketoconazole with phenytoin may alter the metabolism of one or both of the drugs. Close monitoring for both plasma concentrations of phenytoin and reduced efficacy of NIZORAL® Tablets is recommended. Rifampin, rifabutin, isoniazid Concomitant administration of rifampin and rifabutin with ketoconazole tablets reduces the blood concentrations of the latter. INH (Isoniazid) was also reported to affect ketoconazole concentrations adversely. These antitubercular drugs should not be given concomitantly with NIZORAL® Tablets. Drugs that significantly increase the systemic exposure to ketoconazole Ritonavir Concomitant administration of ritonavir with ketoconazole tablets increases was shown to increase the oral bioavailability of ketoconazole. Therefore, when ritonavir is to be given concomitantly, higher doses ( > 200 mg/day) of NIZORAL® Tablets should not be used. Other drug interactions Alcohol Rare cases of a 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. Loratadine After the co-administration of 200 mg oral ketoconazole twice daily and one 20 mg dose of loratadine to 11 subjects, the AUC and Cmax of loratadine averaged 302% (±142 S.D.) and 251% (± 68 S.D.), respectively, of those obtained after cotreatment with placebo. The AUC and Cmax of descarboethoxyloratadine, an active metabolite, averaged 155% (± 27 S.D.) and 141% (± 35 S.D.), respectively. However, no related changes were noted in the QTc 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 ketoconazole.

SIDE EFFECTS During clinical trials 45 (5.0%) of 905 patients treated with Ketoconazole Cream 2% and 5 (2.4%) of 208 patients treated with placebo reported side effects consisting mainly of severe irritation, pruritus and stinging. One of the patients treated with Ketoconazole Cream developed a painful allergic reaction. In worldwide postmarketing experience, rare reports of contact dermatitis have been associated with Ketoconazole Cream or one of its excipients, namely sodium sulfite or propylene glycol. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Flammable Contents XOLEGEL is flammable. Avoid being near fire, flame, or smoking during and immediately following application of XOLEGEL. Systemic Effects Hepatitis and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topically administered ketoconazole. Local Effects XOLEGEL can cause local irritation at the application site. If irritation occurs or if the disease worsens, use of the medication should be discontinued and the health care provider should be contacted [see ADVERSE REACTIONS]. Patient Counseling Information [See FDA-Approved Patient Labeling (PATIENT INFORMATION)] This medication is to be used as directed by the health care provider. It is for external use only. XOLEGEL may be irritating to mucus membranes. Contact with the eyes, nostrils, and mouth should be avoided. As with any topical medication, patients should wash their hands after application. This medication should not be used for any disorder other than that for which it has been prescribed. Patients should report any signs of adverse reactions to their health care provider. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ketoconazole gel has been evaluated in a 2-year dermal carcinogenicity study in CD-1 mice. Ketoconazole gel applied topically at doses up to 80 mg ketoconazole/kg/day (76 times the human dose) exhibited no evidence of dermal or systemic tumorigenic effects attributable to ketoconazole or the gel vehicle. A long-term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. Ketoconazole gel at a dosage up to 5 mg/kg/dose is not photocarcinogenic when topically applied to hairless mice five days per week for a period of 40 weeks. Ketoconazole produced no evidence of mutagenicity in the dominant lethal mutation test in male and female mice at single oral doses up to 80 mg/kg. When tested in the Ames assay, ketoconazole was found to be non-mutagenic to Salmonella typhimurium in the presence and absence of metabolic activation. Ketoconazole, in combination with another drug, gave equivocal results in the mouse micronucleus test. At oral doses of 75 to 80 mg/kg/day (71 to 76 times the human dose) ketoconazole impaired the reproductive performance in female (decreased pregnancy and implantation rates) and male (increased abnormal sperm and decreased sperm motility) rats. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well controlled trials in pregnant women. XOLEGEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive toxicity studies have not been performed with XOLEGEL. Ketoconazole was tested for its effects on offspring in the rat at oral doses of 10, 20, 40, 80, and 160 mg/kg. Ketoconazole was teratogenic (syndactylia and oligodactylia) at 80 mg/kg/day and embryotoxic at 160 mg/kg/day (76 and 152 times the human dose, respectively). However, these effects may be related to maternal toxicity, which was also seen at these dose levels. Oral doses of 10, 20, 40, 80, and 160 mg/kg were studied in pre- and postnatal development studies in rats. Doses of 40 mg/kg (38 times the human dose) and above were associated with maternal toxicity, an increase in the length of gestation, and an increase in the number of stillborn fetuses. These doses of ketoconazole were also toxic to the offspring, resulting in a decrease in fetal/pup weights and viability. Nursing Mothers It is not known whether XOLEGEL is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XOLEGEL is administered to a nursing woman. If used during lactation and XOLEGEL is applied to the chest, care should be taken to avoid accidental ingestion by the infant. Pediatric Use Safety and effectiveness in pediatric subjects below the age of 12 have not been established. Geriatric Use Of the 933 subjects in the three safety and efficacy trials, 193 (20.7%) were 65 and older, while 61 (6.5%) were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS NIZORAL® Tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks. Hepatotoxicity Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity was reported both by patients receiving high doses for short treatment durations and by patients receiving low doses for long durations. The hepatic injury has usually, but not always, been reversible upon discontinuation of NIZORAL® Tablets treatment. Cases of hepatitis have been reported in children. At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST, total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR), and testing for viral hepatitides). Patients should be advised against alcohol consumption while on treatment. If possible, use of other potentially hepatotoxic drugs should be avoided in patients receiving NIZORAL® Tablets. Prompt recognition of liver injury is essential. During the course of treatment, serum ALT should be monitored weekly for the duration of treatment. If ALT values increase to a level above the upper limit of normal or 30 percent above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained. Liver tests should be repeated to ensure normalization of values. Hepatotoxicity has been reported with restarting oral ketoconazole (rechallenge). If it is decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring liver injury from the drug. QT Prolongation and Drug Interactions Leading to QT Prolongation Ketoconazole can prolong the QT interval. Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, and cisapride. Ketoconazole can cause elevated plasma concentrations of these drugs which may prolong the QT interval, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. Adrenal Insufficiency NIZORAL® Tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. This effect is not shared with other azoles. The recommended dose of 200 mg - 400 mg daily should not be exceeded. Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.). Adverse Reactions Associated with Unapproved Uses Ketoconazole has been used in high doses for the treatment of advanced prostate cancer and for Cushing's syndrome when other treatment options have failed. The safety and effectiveness of ketoconazole have not been established in these settings and the use of ketoconazole for these indications is not approved by FDA. In a clinical trial involving 350 patients with metastatic prostatic cancer, eleven deaths were reported within two weeks of starting treatment with high doses of ketoconazole tablets (1200 mg/day). It is not possible to ascertain from the information available whether death was related to ketoconazole therapy or adrenal insufficiency in these patients with serious underlying disease. Hypersensitivity Anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported. Enhanced Sedation Co-administration of NIZORAL® Tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Concomitant administration of NIZORAL® Tablets with oral triazolam, oral midazolam, or alprazolam is contraindicated. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS sections.) Myopathy Co-administration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin is contraindicated with NIZORAL® Tablets. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS sections.) PRECAUTIONS General NIZORAL® Tablets have been demonstrated to lower serum testosterone. Once therapy with NIZORAL® Tablets 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. Clinical manifestations of decreased testosterone concentrations may include gynecomastia, impotence and oligospermia. 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, abdominal pain, jaundice, dark urine or pale stools (see WARNINGS section). Carcinogenesis, Mutagenesis, Impairment of Fertility Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. Ketoconazole was not carcinogenic in an 18-month, oral study in Swiss albino mice or a 24-month oral carcinogenicity study in Wistar rats at dose levels of 5, 20 and 80 mg/kg/day. The high dose in these studies was approximately 1x (mouse) or 2x (rat) the clinical dose in humans based on a mg/m² comparison. Pregnancy Teratogenic effects Pregnancy Category C: Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given in the diet at 80 mg/kg/day (2 times the maximum recommended human dose, based on body surface area comparisons). 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. NIZORAL® Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects 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 ketoconazole during the third trimester of gestation. This occurred when ketoconazole was administered at doses higher than 10 mg/kg (about one fourth the maximum human dose, based on body surface area comparison). Nursing Mothers Ketoconazole has been shown to be excreted in the milk. Mothers who are under treatment with NIZORAL® Tablets should not breast feed. Pediatric Use NIZORAL® Tablets have not been systematically studied in children of any age, and essentially no information is available on children under 2 years. NIZORAL® Tablets should not be used in pediatric patients unless the potential benefit outweighs the risks.

WARNINGS Kuric™ is not for ophthalmic use. Kuric™ contains sodium sulfite anhydrous, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. PRECAUTIONS General If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. Hepatitis (1:10,000 reported incidence) and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topical ketoconazole. Carcinogenesis, Mutagenesis, Impairment of Fertility A long-term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. The dominant lethal mutation test in male and female mice revealed that single oral doses of 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. Pregnancy Teratogenic effects Pregnancy Category C:Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given orally in the diet at 80 mg/kg/day, (10 times the maximum recommended human oral dose). However, these effects may be related to maternal toxicity, which was seen at this and higher dose levels. There are no adequate and well-controlled studies in pregnant women. Ketoconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether Kuric™ (ketoconazole) 2% cream administered topically could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established.