Generic Name: Ketoconazole
Class: Azoles
VA Class: AM700
CAS Number: 65277-42-1
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
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 carcinoma†106 108 180 181 182 183 285 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 hep
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