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Generic Name: Ketoconazole
Class: Azoles
VA Class: AM700
CAS Number: 65277-42-1

Warning(s)

Special Alerts:

[Posted 07/26/2013] ISSUE: FDA is taking several actions related to Nizoral (ketoconazole) oral tablets, including limiting the drug’s use, warning that it can cause severe liver injuries and adrenal gland problems, and advising that it can lead to harmful drug interactions with other medications. FDA has approved label changes and added a new Medication Guide to address these safety issues. As a result, Nizoral oral tablets should not be a first-line treatment for any fungal infection. Nizoral should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated.

Liver Injury (Hepatotoxicity): Nizoral tablets can cause liver injury, which may potentially result in liver transplantation or death. FDA has revised the Boxed Warning, added a strong recommendation against its use (contraindication) in patients with liver disease, and included new recommendations for assessing and monitoring patients for liver toxicity.

Adrenal Insufficiency: Nizoral tablets may cause adrenal insufficiency by decreasing the body’s production of corticosteroids.

Drug Interactions: Nizoral tablets may interact with other drugs a patient is taking and can result in serious and potentially life-threatening outcomes, such as heart rhythm problems.

See the FDA Drug Safety Communication for additional information, including a Data Summary.

BACKGROUND: Nizoral (ketoconazole) is indicated for the treatment of fungal infections when alternatives are not available or not tolerated. The topical formulations of Nizoral have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the Nizoral tablets, which are taken by mouth.

RECOMMENDATION: Nizoral tablets should be used only for the treatment of certain life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or tolerated. Healthcare professionals should assess the liver status of the patient before starting oral ketoconazole, and monitor serum ALT levels during treatment. 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.). Review all concomitant medications for the potential for drug interactions with Nizoral tablets.

For more information visit the FDA website at: and .

Warning(s)

  • Oral ketoconazole has been associated with hepatoxicity, including some fatalities.263 Inform patients of the risk and monitor closely.263

  • Concomitant use with cisapride or with astemizole or terfenadine (drugs no longer commercially available in the US) is contraindicated.263 Pharmacokinetic interactions can occur and serious cardiovascular events have been reported with concomitant use.263 VT, VF, and torsades de pointes have been reported in patients receiving concomitant cisapride; death, VT, and torsades de pointes have been reported in patients receiving concomitant terfenadine.263 (See Interactions.)

Introduction

Antifungal; azole (imidazole derivative).127 222

Uses for Nizoral

Blastomycosis

Treatment of North American blastomycosis caused by Blastomyces dermatitidis.213 220 234 238 263 264 288 290 291 292 299 300

Drugs of choice are IV amphotericin B (especially for severe infections and those involving the CNS) or oral itraconazole;234 238 264 288 290 292 296 297 298 299 332 333 fluconazole and ketoconazole are considered alternatives.238 264 288 290 292 296 297 299

Oral ketoconazole usually has been effective when used in immunocompetent individuals with mild to moderate pulmonary or extrapulmonary blastomycosis.213 220 290 291 292 297 Consider that treatment failures have been reported when ketoconazole was used for treatment of cutaneous or pulmonary blastomycosis in individuals who had asymptomatic or subclinical CNS involvement at the time of the initial diagnosis.211 295 296 (See Meningitis and Other CNS Infections under Cautions.)

Candida Infections

Treatment of candidiasis, candiduria, chronic mucocutaneous candidiasis, or oropharyngeal and esophageal candidiasis.212 238 263 279 291 292 320 322 323 326 328 329 331 334 341

Has been used for treatment of uncomplicated vulvovaginal candidiasis.340 343 344 Not a drug of choice for initial treatment; single-dose fluconazole is the only oral regimen included in current CDC recommendations for treatment of uncomplicated vulvovaginal candidiasis.270 272 Recommended by CDC and others as one of several alternatives for maintenance treatment of recurrent vulvovaginal candidiasis in women with a history of recurrent infections.270 271 340 343 344 346

Chromomycosis

Treatment of chromomycosis (chromoblastomycosis) caused by Phialophora.263 288 335 A response may not be attained in those with more extensive disease.335

Optimum regimens for chromomycosis have not been identified.288 335 Flucytosine may be a drug of choice used alone or in conjunction with another antifungal (e.g., IV amphotericin B, oral itraconazole, oral ketoconazole).288 335

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Coccidioidomycosis

Treatment of mild to moderate coccidioidomycosis caused by Coccidioides immitis.238 263 280 290 291 292 293 303 304 305 327

Drugs of choice are IV amphotericin B (especially for severe infections and those in immunocompromised patients including HIV-infected individuals) or oral fluconazole; itraconazole and ketoconazole are considered alternatives.234 238 279 280 288 290 292 293

Dermatophytoses

Treatment of certain dermatophytoses of the skin, scalp, and nails, including tinea capitis (scalp ringworm), tinea corporis (ringworm of the body), tinea cruris (jock itch; groin ringworm), tinea pedis (athlete’s foot, foot ringworm), tinea manuum (hand ringworm), and tinea unguium (onychomycosis; nail ringworm) caused by Epidermophyton, Microsporum, or Trichophyton.263 291 324 325

Used for severe recalcitrant cutaneous dermatophyte infections in patients who have not responded to topical therapy or have not responded to or are unable to take other oral antifungals (e.g., griseofulvin).263

Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal; an oral antifungal may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection does not respond to topical therapy, or the patient is immunocompromised or has a coexisting disease.352 353 356 357 358 360 Tinea capitis and tinea barbae generally are treated using an oral antifungal.325 353 359

While topical antifungals usually are effective for treatment of uncomplicated tinea manuum and tinea pedis,353 356 358 360 an oral antifungal usually is necessary for treatment of severe, chronic, or recalcitrant tinea pedis, for treatment of chronic moccasin-type (dry-type) tinea pedis, and for treatment of tinea unguium (onychomycosis).353 357 358 360

Histoplasmosis

Treatment of histoplasmosis caused by Histoplasma capsulatum.213 238 263 288 290 291 292 293 375

Drugs of choice are IV amphotericin B (especially for life-threatening infections including those in HIV-infected individuals) or oral itraconazole; ketoconazole and fluconazole are considered alternatives.238 279 280 290 291 292 375

Paracoccidioidomycosis

Treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis.238 263 288 291 311 335

Drug of choice for initial treatment of severe infections is IV amphotericin B;238 288 291 293 310 311 335 oral azole antifungals (e.g., ketoconazole, itraconazole) can be used in patients with less severe infections.238 288 291 335

Pityriasis (Tinea) Versicolor

Has been effective for treatment of pityriasis (tinea) versicolor, a superficial infection caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale).234 354 355

Pityriasis (tinea) versicolor generally can be treated topically with an imidazole-derivative azole antifungal (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), an allylamine antifungal (e.g., terbinafine), ciclopirox olamine, or certain other topical therapies (e.g., selenium sulfide 2.5%).234 324 352 354 355 357 An oral antifungal (e.g., itraconazole, ketoconazole) may be indicated, with or without a topical agent, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.324 354 355 357

Acanthamoeba Infections

Has been used in conjunction with a topical anti-infective (e.g., miconazole, neomycin, metronidazole, propamidine isethionate) in the treatment of >Acanthamoeba keratitis.134 135 136 137 138 139 140 226 Optimum therapy for Acanthamoeba keratitis remains to be clearly established, but prolonged local and systemic therapy with multiple anti-infectives and often surgical treatment (e.g., penetrating keratoplasty) usually required.134 135 136 137 138 139 140

A regimen of oral ketoconazole, rifampin, and co-trimoxazole has been used for treatment of chronic Acanthamoeba meningitis in several immunocompetent children.187 225 (See Meningitis and Other CNS Infections under Cautions.)

Leishmaniasis

Has been used for treatment of cutaneous or mucocutaneous leishmaniasis caused by various Leishmania spp. (e.g., Leishmania major, L. mexicana, L. panamensis, L. braziliensis, L. tropica).203 204 205 206 207 208 209 234 250 314 316 317 Usual drugs of choice are pentavalent antimony compounds (e.g., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US]).225 234 317 319 Preferred alternatives or additional drugs of choice are IV amphotericin B (conventional or liposomal formulations) and parenteral pentamidine; other alternatives include oral azole antifungals (e.g., itraconazole, ketoconazole) or topical paromomycin (for cutaneous leishmaniasis when there is a low potential for mucosal spread).225 234 319

Has been used in a limited number of patients for treatment of antimony-resistant visceral leishmaniasis (kala-azar) caused by L. donovani,261 262 315 317 318 but may be less effective in these infections than in the treatment of cutaneous leishmaniasis.261 262 317 Usual drugs of choice for initial treatment of visceral leishmaniasis are pentavalent antimony compounds, but resistance and treatment failures are becoming increasingly common;288 317 IV amphotericin B and pentamidine are considered alternatives.288 317 319

Prostate Cancer

Because of ketoconazole’s ability to inhibit testicular and adrenal steroid synthesis, the drug has been used in the treatment of advanced prostatic carcinoma.106 107 108 151 179 180 181 182 183 184 284 285 286 368 369

Cushing’s Syndrome

Has been used effectively for palliative treatment of Cushing’s syndrome (hypercortisolism), including adrenocortical hyperfunction associated with adrenal or pituitary adenoma or ectopic corticotropin-secreting tumors.112 113 114 151 154 224 342

Has been used in a limited number of geriatric patients ≥75 years of age for treatment of corticotropin-dependent Cushing’s syndrome; may provide an effective alternative in patients who cannot tolerate surgical treatment.342

Hirsutism and Precocious Puberty

Has been used with some success in a limited number of patients for treatment of dysfunctional hirsutism.115 370

Has been used in a limited number of boys for treatment of precocious puberty.116 185 186

Hypercalcemia

Has been used with some success for treatment of hypercalcemia in adults with sarcoidosis.363 364 365 366 Has reduced serum calcium concentrations in some, but not all, patients with sarcoidosis-associated hypercalcemia;364 365 366 hypercalcemia and increased serum 1,25-dihydroxyvitamin D concentrations may recur when ketoconazole dosage is decreased or the drug discontinued.365 366

Has been effective in a few adolescents for treatment of tuberculosis-associated hypercalcemia.367

Nizoral Dosage and Administration

Administration

Oral Administration

Administer orally.263

To ensure absorption in patients with achlorhydria, each 200-mg ketoconazole tablet should be dissolved in 4 mL of 0.2N hydrochloric acid solution263 or taken with 200 mL of 0.1N hydrochloric acid.a The resultant solution should be administered via a plastic or glass straw to avoid contact with the teeth, and a glass of water should be administered immediately after the solution.263 Alternatively, some clinicians recommend that each 200 mg of ketoconazole be given with ≥680 mg of glutamic acid hydrochloride.198 199 Other clinicians suggest that each 200 mg of ketoconazole be administered with an acidic beverage (e.g., Coca-Cola, Pepsi)273 or the dose dissolved in 60 mL of citrus juice to ensure absorption; however, this strategy may not be adequate in all patients with achlorhydria and patients should be monitored closely for therapeutic failure.273

Dosage

Pediatric Patients

General Pediatric Dosage
Treatment of Fungal Infections
Oral

Children >2 years of age: 3.3–6.6 mg/kg once daily has been used.234 263

Adults

General Adult Dosage
Treatment of Fungal Infections
Oral

200 mg once daily.263 Dosage may be increased to 400 mg once daily for severe infections or if the expected clinical response is not achieved.263

Blastomycosis
Oral

Some clinicians suggest 400 mg once or twice daily.213 220 238 288 290 292 296 299 301 327 375 Treatment usually continued for 6–12 months.a

Candidiasis
Oropharyngeal and Esophageal Candidiasis
Oral

200–400 mg daily.238 279

Vulvovaginal Candidiasis
Oral

Treatment of uncomplicated vulvovaginal candidiasis in nonpregnant women: 200–400 mg twice daily for 5 days.340 343 344

When used as a maintenance regimen to reduce the frequency of recurrent episodes of vulvovaginal candidiasis in women who have received an initial intensive antifungal regimen (i.e., 7–14 days of an intravaginal azole antifungal or a 2-dose fluconazole regimen), ketoconazole has been given in a dosage of 100 mg once daily for up to 6 months.270 340 341 343 344 346

Chromomycosis
Oral

200–400 mg daily.335 Treatment usually continued for 6–12 months.

Coccidioidomycosis
Oral

400 mg once or twice daily.213 220 238 288 290 292 296 299 301 327 375 Treatment usually continued for 6–12 months.

Dermatophytoses
Oral

200–400 mg daily has been given for 1–2 months.a Infections involving glabrous skin require a minimum of 4 weeks of treatment; palmar and plantar infections may respond more slowly.263 Tinea unguium (onychomycosis) may require ≥6–12 months of treatment.a

Histoplasmosis
Oral

400 mg once or twice daily.213 220 238 288 290 292 296 299 301 327 375 A dosage of 200 mg once or twice daily also has been used.375

A minimum of 6 months of therapy usually required, but 2–6 months has been effective in some patients.a

Paracocciodioidomycosis
Oral

200–400 mg daily.335

A minimum of 6 months of therapy usually required, but 2–6 months has been effective in some patients.a

Leishmaniasis
Cutaneous and Mucocutaneous Leishmaniasis
Oral

400–600 mg daily for 4–8 weeks has been used.203 204 207 208 317

Visceral Leishmaniasis (Kala-Azar)
Oral

400–600 mg daily for 4–8 weeks has been used.315 317 318

Prostate Cancer
Oral

400 mg every 8 hours has been used for treatment of prostatic carcinoma106 108 180 181 182 183 285 or as an adjunct in the management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma.152 178 Risk of depressed adrenocortical function at this high dosage should be considered.263 (See Endocrine and Metabolic Effects under Cautions.)

Cautions for Nizoral

Contraindications

  • Hypersensitivity to ketoconazole.263

  • Concomitant use with certain drugs metabolized by CYP3A4 isoenzymes (e.g., astemizole [no longer commercially available in the US], cisapride, midazolam, terfenadine [no longer commercially available in the US], triazolam).263 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Hepatic Effects

Hepatotoxicity (usually the hepatocellular type) has been reported.164 165 166 167 168 169 170 191 192 193 263

Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy (median 28 days),50 61 164 167 168 169 170 188 189 190 191 192 263 but occasionally may be apparent within 3–7 days of initiation of therapy.164 166 167 191 192 263 Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug,50 164 165 166 167 188 189 190 191 192 263 recovery may take several months;164 165 167 188 190 263 rarely, death has occurred.164 165 167 168 169 170 191 192 193 263

Most cases of hepatotoxicity have been reported in patients receiving the drug for tinea unguium (onychomycosis);50 167 168 169 188 189 190 191 192 193 263 many others were receiving the drug for chronic, refractory dermatophytoses.167 191 192 Several cases of ketoconazole-induced hepatitis have been reported in children.165 167 189 191 192 263

Monitor closely for clinical and biochemical signs of hepatotoxicity.164 166 167 169 170 192 263 Perform liver function tests (e.g., serum AST, ALT, alkaline phosphatase, γ-glutamyltransferase [γ-glutamyltranspeptidase, GGT, GGTP], bilirubin) prior to and frequently (e.g., biweekly during the first 2 months of therapy and monthly or bimonthly thereafter) during therapy, particularly in those receiving prolonged therapy, those receiving other potentially hepatotoxic drugs, and those with a history of hepatic disease.164 166 167 169 170 188 189 190 193 263

Minor, asymptomatic elevations in liver function test results may return to pretreatment concentrations during continued ketoconazole therapy.164 167 191 192 193 If liver function test results are substantially elevated or if such abnormalities persist, worsen, or are accompanied by other manifestations of hepatic dysfunction, ketoconazole should be discontinued.164 167 168 169 170 189 190 191 192

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis and urticaria reported rarely.102 263

General Precautions

Endocrine and Metabolic Effects

Ketoconazole can inhibit testosterone synthesis and transient decreases in serum testosterone may occur;109 110 151 174 263 concentrations usually return to baseline values after the drug is discontinued.263 Testosterone concentrations are impaired with ketoconazole dosage of 800 mg daily and abolished with dosage of 1.6 g daily.263

Ketoconazole may inhibit cortisol synthesis, particularly in patients receiving relatively high daily dosage or divided daily dosing.109 112 113 114 151 154 156 157 158 159 166 173 192 229 230 The adrenocortical response to corticotropin (ACTH) may be at least transiently diminished and a reduction in urinary free and serum cortisol concentrations may occur.109 110 112 113 114 151 154 156 157 158 159 166 173 192 Adrenocortical insufficiency has been reported only rarely.109 159 160 166 173 192 229 Adrenocortical hypofunction generally is reversible following discontinuance of the drug,154 156 157 166 but rarely may be persistent.159

To minimize the risk of possible endocrine and metabolic effects, dosages greater than those usually recommended should not be used.263

Meningitis and Other CNS Infections

Because CSF concentrations of ketoconazole are unpredictable following oral administration, the drug should not be used alone to treat CNS fungal infections, including candidal, coccidioidal, or cryptococcal meningitis.263 291 302 330

Specific Populations

Pregnancy

Category C.263

Lactation

Probably distributed into human milk.263 Discontinue nursing or the drug.263

Pediatric Use

Use in pediatric patients only when potential benefits justify possible risks.263 Has not been systematically studied in children of any age,263 but has been used in a limited number of children >2 years of age.263 There is essentially no information available to date on use in children <2 years of age.263

Common Adverse Effects

GI effects (nausea, vomiting), hepatic effects, pruritus.263

Interactions for Nizoral

Inhibits CYP3A4.263

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are substrates of CYP3A4.263

Hepatotoxic Drugs

Monitor closely if used concomitantly with other potentially hepatotoxic drugs, especially in patients requiring prolonged therapy or with a history of liver disease.263 (See Hepatic Effects under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Alcohol

Disulfiram reactions (flushing, rash, peripheral edema, nausea, headache) have occurred rarely in patients who ingested alcohol while receiving ketoconazole;263 267 268 usually resolved within a few hours263

Some clinicians recommend that alcohol be avoided during and for 48 hours after discontinuance of ketoconazole therapy267

Antacids

Because gastric acidity is necessary for dissolution and absorption of ketoconazole, concomitant administration of antacids may decrease absorption of the antifungal263

Administer antacids at least 2 hours after ketoconazole263

Anticoagulants, oral (warfarin)

Possible enhanced anticoagulant effects263

Monitor PT or other appropriate tests closely; adjust anticoagulant dosage if necessary263

Anticonvulsants (phenytoin)

Possible pharmacokinetic interaction with changes in metabolism of one or both drugs263

Monitor serum concentrations if used concomitantly263

Antidiabetic agents, sulfonylureas

Increased plasma concentrations of the antidiabetic agent and symptoms of hypoglycemia reported with other azoles (e.g., itraconazole)263 b

Consider the possibility that hypoglycemia may occur when ketoconazole used concomitantly with antidiabetic agents263

Antihistamines (astemizole, loratadine, terfenadine)

Aztemizole and terfenadine (drugs no longer commercially available in the US): Pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias, prolonged QT interval)252 253 254 255 256 257 259 260 263 287

Loratadine: Increased plasma concentrations and AUCs of loratadine and its active metabolite, but no evidence of changes in QT interval or incidence of adverse effects263

Aztemizole and terfenadine: Concomitant use contraindicated252 254 263 265

Antimycobacterials (rifampin, isoniazid)

Rifampin: Decreased serum concentrations of ketoconazole111 141 221 263

Isoniazid: May affect ketoconazole serum concentrations111 263

Do not use concomitantly with rifampin or isoniazid263

Benzodiazepines (midazolam, triazolam)

Increased plasma concentrations of midazolam or triazolam; possible prolonged sedative and hypnotic effects of the drugs263

Ketoconazole should not be used concomitantly with midazolam or triazolam263

Special precaution is required if parenteral midazolam is used in patients receiving ketoconazole because the sedative effects of midazolam may be prolonged263

Cisapride

Increased cisapride plasma concentrations and increased risk of adverse effects (e.g., cardiovascular effects)263 276

Concomitant use contraindicated263

Digoxin

Increased plasma concentrations of digoxin reported; causative relationship unclear263

Closely monitor digoxin concentrations in patients receiving ketoconazole263

Histamine H2-receptor antagonists (e.g., cimetidine, ranitidine)

Because gastric acidity is necessary for dissolution and absorption of ketoconazole, concomitant administration of histamine H2-receptor antagonists may decrease absorption of the antifungal 263

Administer H2-receptor antagonist at least 2 hours after ketoconazole263

Immunosuppressive agents (cyclosporine, methylprednisolone, prednisone, tacrolimus)

Cyclosporine or tacrolimus: Increased concentrations of the immunosuppressive agent142 143 144 263 372

Methylprednisolone or prednisone: Increased concentrations of the corticosteroid and possible enhanced adrenal suppression227 228 232 233

Cyclosporine or tacrolimus: Use with caution and monitor concentrations of the immunosuppressive agent if possible; adjust cyclosporine or tacrolimus dosage if needed when ketoconazole is initiated or discontinued146 263

Methylprednisolone or prednisolone: Adjust dosage of the corticosteroid as needed227 228 263

Paclitaxel

In vitro evidence that ketoconazole can inhibit metabolism of paclitaxel269

Clinical importance unclear; use concomitantly with caution269

Sucralfate

Possible decreased absorption of ketoconazole362

Administer sucralfate at least 2 hours after ketoconazole362

Theophylline

Conflicting data;147 150 possible decreased theophylline concentrations147

Pending further accumulation of data, monitor serum theophylline concentrations and adjust theophylline dosage if necessary when ketoconazole is initiated or discontinued in patients receiving theophylline147

Nizoral Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract;162 163 peak plasma concentrations attained within 1–2 hours.149 162 263

Ketoconazole must be dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach.a Bioavailability depends on the pH of the gastric contents in the stomach; an increase in pH results in decreased absorption of the drug.a (See Absorption: Special Populations.)

Food

Effect of food on rate and extent of GI absorption of ketoconazole has not been clearly determined.162

Plasma Concentrations

Considerable interindividual variations in peak plasma concentrations and AUCs have been reported.a

Special Populations

Oral bioavailability may be decreased in patients with achlorhydria,a including those with HIV-associated gastric hypochlorhydria.198 200 Concomitant administration of dilute hydrochloric acid solution usually normalizes absorption of the drug in these patients.198 Concomitant administration of an acidic beverage may increase bioavailability in some individuals.273 (See Oral Administration under Dosage and Administration.)

Distribution

Extent

Distributed into urine, bile, saliva, sebum, cerumen, and synovial fluid.a

May be distributed into CSF following oral administration, but CNS penetration is unpredictable and has generally been considered to be minimal.a

Not known whether crosses the placenta in humans; crosses the placenta in rats.a Distributed into milk of dogs; probably distributed into human milk.a

Plasma Protein Binding

84–99% bound to plasma proteins, primarily albumin.263 a

Elimination

Metabolism

Partially metabolized in the liver to several inactive metabolites by oxidation and degradation of the imidazole and piperazine rings, by oxidative O-dealkylation, and by aromatic hydroxylation.a

Elimination Route

Major route of elimination of ketoconazole and its metabolites appears to be excretion into the feces via the bile.a

In fasting adults with normal renal function, approximately 57% of a single 200-mg oral dose is excreted in feces within 4 days (20–65% of this is unchanged drug); approximately 13% of the dose is excreted in urine within 4 days (2–4% of this is unchanged drug).a

Half-life

Plasma concentrations appear to decline in a biphasic manner with a half-life of approximately 2 hours in the initial phase and 8 hours in the terminal phase.263

Special Populations

Plasma concentrations and half-life not substantially affected by renal or hepatic impairment.a

Stability

Storage

Oral

Tablets

Well-closed container at 15–25°C; protect from moisture.263

Actions and Spectrum

  • Imidazole-derivative azole antifungal.127 222

  • Usually fungistatic in action.119 121 127 129 130 131 132 133

  • Presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA).127 128 130 131 Inhibits cytochrome P-450 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.128 129 130 151

  • Spectrum of antifungal activity includes many fungi, including yeasts and dermatophytes.263 a Has some in vitro activity against some gram-positive bacteria (e.g., staphylococci, Nocardia) and some protozoa (e.g., Acanthamoeba, Leishmania).134 135 136 a

  • Candida: Active in vitro and in vivo against C. albicans,120 121 122 123 124 373 C. dubliniensis,283 and some strains of C. glabrata,120 122 123 124 373 C. lusitaniae,289 C. parapsilosis,373 and C. tropicalis.373

  • Dermatophytes: Active against Epidermophyton floccosum,263 a Microsporum canis,a M. gypseum,120 a Trichophyton mentagrophytes,a T. rubrum,a and T. tonsurans.a

  • Other fungi: Active against Blastomyces dermatitidis,263 371 Coccidioides immitis,263 Cryptococcus neoformans,263 373 Histoplasma capsulatum,263 Paracoccidioides brasiliensis,263 and Phialophoa.263 Also active against Actinomadura madurae, Aspergillus flavus,120 122 124 A. fumigatus,122 124 Malassezia furfur (Pityrosporum orbiculare),a Petriellidium boydii,120 122 and Sporothrix schenckii.120 122 124 May be active against some strains of Exophiala castellanii275 and Scopulariopsis, including some strains of S. acremonium and S. brevicaulis.374

  • Strains of Candida albicans resistant to ketoconazole have been isolated from patients who received the drug.125 126

  • Ketoconazole-resistant Candida may be cross-resistant to other azole antifungals (e.g., fluconazole, itraconazole).337

  • In vitro and in vivo studies indicate ketoconazole can directly inhibit synthesis of adrenal steroids and testosterone.109 110 112 113 114 115 116 117 148 151 154 156 157 158 159 160 161 171 172 173 174 175 176 Appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (e.g., 11β-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme).112 114 117 151 152 154 155 157 158 159 171 172 173 174 175 176 192 201

  • Inhibits cortisol synthesis in a dose-dependent manner in individuals with normal adrenocortical function and in patients with Cushing’s syndrome (hypercortisolism).109 112 113 114 151 154 156 157 158 159 166 173 192

Advice to Patients

  • Importance of taking drugs that may affect gastric acidity, including antacids, histamine H2-receptor antagonists (e.g., cimetidine, ranitidine), and sucralfate, at least 2 hours after ketoconazole.263

  • Advise patients with achlorhydria to dissolve each 200-mg ketoconazole tablet in 4 mL of 0.2N hydrochloric acid solution.263 Importance of ingesting the solution via a plastic or glass straw to avoid contact with the teeth and importance of drinking a glass of water immediately after the solution.263

  • Inform patients of the risk of hepatotoxicity and instruct them to report any signs or symptoms of possible hepatic dysfunction (e.g., unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, pale feces) to their clinician.167 168 188 189 263

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.263

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.263

  • Importance of advising patients of other important precautionary information.263 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ketoconazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg

Ketoconazole Tablets (scored)

aaiPharma, Mutual, Mylan, Pliva, Stada, Taro, Teva, Torpharm

Nizoral (with povidone; scored)

Janssen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ketoconazole 200MG Tablets (TARO): 14/$30.99 or 42/$88.99

Nizoral 200MG Tablets (JANSSEN): 30/$129.99 or 90/$369.95

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

50. Heiberg JK, Svejgaard E. Toxic hepatitis during ketoconazole treatment. BMJ. 1981; 283:825-6. [IDIS 138588] [PubMed 6271328]

61. Firebrace DAJ. Hepatitis and ketoconazole therapy. BMJ. 1981; 283:1058-9. [IDIS 139321] [PubMed 6271330]

101. Craven PC, Graybill JR, Jorgensen JH et al. High-dose ketoconazole for treatment of fungal infections of the central nervous system. Ann Intern Med. 1983; 98:160-7. [IDIS 164926] [PubMed 6297345]

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