Ketoconazole

Pronunciation

(kee toe KOE na zole)

U.S. Brand Names

Nizoral®; Nizoral® A-D [OTC]

Generic Available

Yes

Canadian Brand Names

Apo-Ketoconazole®; Ketoderm®; Nizoral®; Novo-Ketoconazole

Use

Treatment of susceptible fungal infections, including candidiasis, oral thrush, blastomycosis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, chromomycosis, candiduria, chronic mucocutaneous candidiasis, as well as certain recalcitrant cutaneous dermatophytoses; used topically for treatment of tinea corporis, tinea cruris, tinea versicolor, and cutaneous candidiasis, seborrheic dermatitis

Use - Dental

Treatment of susceptible fungal infections in the oral cavity including candidiasis, oral thrush, and chronic mucocutaneous candidiasis

Use - Unlabeled/Investigational

Treatment of prostate cancer (androgen synthesis inhibitor)

Pregnancy Risk Factor

Lactation

Enters breast milk/not recommended

Contraindications

Hypersensitivity to ketoconazole or any component of the formulation; CNS fungal infections (due to poor CNS penetration); coadministration with ergot derivatives or cisapride is contraindicated due to risk of potentially fatal cardiac arrhythmias

Warnings/Precautions

Use with caution in patients with impaired hepatic function; has been associated with hepatotoxicity, including some fatalities; perform periodic liver function tests; high doses of ketoconazole may depress adrenocortical function.

Adverse Reactions

Oral:

1% to 10%:

Dermatologic: Pruritus (2%)

Gastrointestinal: Nausea/vomiting (3% to 10%), abdominal pain (1%)

<1%: Headache, dizziness, somnolence, fever, chills, bulging fontanelles, depression, gynecomastia, diarrhea, impotence, thrombocytopenia, leukopenia, hemolytic anemia, hepatotoxicity, photophobia

Cream: Severe irritation, pruritus, stinging (~5%)

Shampoo: Increases in normal hair loss, irritation (<1%), abnormal hair texture, scalp pustules, mild dryness of skin, itching, oiliness/dryness of hair

Overdosage/Toxicology

Oral: Symptoms of overdose include dizziness, headache, nausea, vomiting, diarrhea. Overdoses are well tolerated. Treatment includes supportive measures and gastric decontamination.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP1A2 (strong), 2A6 (moderate), 2B6 (weak), 2C8/9 (strong), 2C19 (moderate), 2D6 (moderate), 3A4 (strong)

Benzodiazepines: Alprazolam, diazepam, temazepam, triazolam, and midazolam serum concentrations may be increased; consider a benzodiazepine not metabolized by CYP3A4 (such as lorazepam) or another antifungal that is metabolized by CYP3A4. Concurrent use is contraindicated.

Buspirone: Serum concentrations may be increased; monitor for sedation

Busulfan: Serum concentrations may be increased; avoid concurrent use

Calcium channel blockers: Serum concentrations may be increased (applies to those agents metabolized by CYP3A4, including felodipine, nifedipine, and verapamil); consider another agent instead of a calcium channel blocker, another antifungal, or reduce the dose of the calcium channel blocker; monitor blood pressure

Cisapride: Serum concentration is increased which may lead to malignant arrhythmias; concurrent use is contraindicated

CYP1A2 substrates: Ketoconazole may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine.

CYP2A6 substrates: Ketoconazole may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.

CYP2C8/9 substrates: Ketoconazole may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

CYP2C19 substrates: Ketoconazole may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline.

CYP2D6 substrates: Ketoconazole may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Ketoconazole may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of ketoconazole. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Ketoconazole may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Didanosine: May decrease absorption of ketoconazole (due to buffering capacity of oral solution); applies only to oral solution formulation of didanosine

Docetaxel: Serum concentrations may be increased; avoid concurrent use

Erythromycin (and clarithromycin): May increase serum concentrations of ketoconazole.

H2 blockers: May decrease ketoconazole absorption. Ketoconazole depends on gastric acidity for absorption. Avoid concurrent use.

HMG-CoA reductase inhibitors (except pravastatin and fluvastatin): Serum concentrations may be increased. The risk of myopathy/rhabdomyolysis may be increased. Switch to pravastatin/fluvastatin or suspend treatment during course of ketoconazole therapy.

Immunosuppressants: Cyclosporine, sirolimus, and tacrolimus: Serum concentrations may be increased; monitor serum concentrations and renal function

Methylprednisolone: Serum concentrations may be increased; monitor

Nevirapine: May decrease serum concentrations of ketoconazole; monitor

Oral contraceptives: Efficacy may be reduced by ketoconazole (limited data); use barrier birth control method during concurrent use

Phenytoin: Serum concentrations may be increased; monitor phenytoin levels and adjust dose as needed

Protease inhibitors: May increase serum concentrations of ketoconazole. Includes amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir; monitor

Proton pump inhibitors: May decrease ketoconazole absorption. Ketoconazole depends on gastric acidity for absorption. Avoid concurrent use (includes omeprazole, lansoprazole).

Quinidine: Serum levels may be increased; monitor

Rifampin: Rifampin decreases ketoconazole's serum concentration to levels which are no longer effective; avoid concurrent use.

Sildenafil: Serum concentrations may be increased by ketoconazole; consider dosage reduction. A maximum sildenafil dose of 25 mg in 48 hours is recommended with other strong CYP3A4 inhibitors.

Tadalafil: Serum concentrations may be increased by ketoconazole. A maximum tadalafil dose of 10 mg in 72 hours is recommended with strong CYP3A4 inhibitors.

Trimetrexate: Serum concentrations may be increased; monitor

Vardenafil: Serum concentrations may be increased by ketoconazole. If ketoconazole dose is 200 mg/day, limit vardenafil to a maximum of 5 mg/24 hours. If ketoconazole dose is 400 mg/day, limit vardenafil dose to a maximum of 2.5 mg/24 hours.

Warfarin: Anticoagulant effects may be increased; monitor INR and adjust warfarin's dose as needed

Vinca alkaloids: Serum concentrations may be increased; avoid concurrent use

Zolpidem: Serum levels may be increased; monitor

Ethanol/Nutrition/Herb Interactions

Food: Ketoconazole peak serum levels may be prolonged if taken with food.

Herb/Nutraceutical: St John's wort may decrease ketoconazole levels.

Mechanism of Action

Alters the permeability of the cell wall by blocking fungal cytochrome P450; inhibits biosynthesis of triglycerides and phospholipids by fungi; inhibits several fungal enzymes that results in a build-up of toxic concentrations of hydrogen peroxide; also inhibits androgen synthesis

Pharmacodynamics/Kinetics

Absorption: Oral: Rapid (~75%); Shampoo: None

Distribution: Well into inflamed joint fluid, saliva, bile, urine, breast milk, sebum, cerumen, feces, tendons, skin and soft tissues, and testes; crosses blood-brain barrier poorly; only negligible amounts reach CSF

Protein binding: 93% to 96%

Metabolism: Partially hepatic via CYP3A4 to inactive compounds

Bioavailability: Decreases as gastric pH increases

Half-life elimination: Biphasic: Initial: 2 hours; Terminal: 8 hours

Time to peak, serum: 1-2 hours

Excretion: Feces (57%); urine (13%)

Dosage

Fungal infections:

Oral:

Children 2 years: 3.3-6.6 mg/kg/day as a single dose for 1-2 weeks for candidiasis, for at least 4 weeks in recalcitrant dermatophyte infections, and for up to 6 months for other systemic mycoses

Adults: 200-400 mg/day as a single daily dose for durations as stated above

Shampoo: Apply twice weekly for 4 weeks with at least 3 days between each shampoo

Topical: Rub gently into the affected area once daily to twice daily

Prostate cancer (unlabeled use): Oral: Adults: 400 mg 3 times/day

Dosing adjustment in hepatic impairment: Dose reductions should be considered in patients with severe liver disease

Hemodialysis: Not dialyzable (0% to 5%)

Administration

Administer tablets 2 hours prior to antacids to prevent decreased absorption due to the high pH of gastric contents.

Monitoring Parameters

Liver function tests

Dietary Considerations

May be taken with food or milk to decrease GI adverse effects.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. Oral formulation may be taken with food, at least 2 hours before any antacids. Take full course of medication as directed; some infections may require long periods of therapy. If you have diabetes, test serum glucose regularly; may impact effectiveness of oral hypoglycemics. May cause nausea and vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); headache (mild analgesic may be necessary); or dizziness (use caution when driving). Report unresolved headache, rash or itching, yellowing of eyes or skin, changes in color of urine or stool, chest pain or palpitations, or sense of fullness or ringing in ears. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Topical: Wash and dry area before applying medication thinly. Do not cover with occlusive dressing. Report severe skin irritation or if condition does not improve.

Shampoo: Allow 3 days between shampoos. You may experience some hair loss, scalp irritations, itching change in hair texture, or scalp pustules. Report severe side effects or if infestation persists.

Cardiovascular Considerations

Ketoconazole may increase cyclosporine levels by up to 50% at high doses. It may also potentiate the anticoagulant effect of warfarin and can increase lovastatin and simvastatin levels. Concomitant administration with cisapride is contraindicated.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause drowsiness, dizziness, or depression

Mental Health: Effects on Psychiatric Treatment

May cause leukopenia; use caution with clozapine and carbamazepine

Dosage Forms

Cream, topical: 2% (15 g, 30 g, 60 g)

Shampoo, topical (Nizoral® A-D): 1% (6 mL, 120 mL, 210 mL)

Tablet (Nizoral®): 200 mg

Extemporaneously Prepared

A 20 mg/mL suspension may be made by pulverizing twelve 200 mg ketoconazole tablets to a fine powder; add 40 mL Ora-Plus® in small portions with thorough mixing; incorporate Ora-Sweet® to make a final volume of 120 mL and mix thoroughly; refrigerate (no stability information is available)

Allen LV, "Ketoconazole Oral Suspension," US Pharm , 1993, 18(2):98-9, 101.

References

Como JA and Dismukes WE, "Oral Azole Drugs as Systemic Antifungal Therapy," N Engl J Med , 1994, 330(4):263-72.

Ginsburg AM, McCracken GH Jr, and Olsen K, "Pharmacology of Ketoconazole Suspension in Infants and Children," Antimicrob Agents Chemother , 1983, 23(5):787-9.

Gorman SE, Dela Cruz F, and Paloucek F, "Ketoconazole and Zidovudine Overdose," Am J Emerg Med , 1995, 13(1):115-6.

Greenblatt DJ, von Moltke LL, Harmatz JS, et al, "Interaction of Triazolam and Ketoconazole," Lancet , 1995, 345(8943):191.

Herrod HG, "Chronic Mucocutaneous Candidiasis in Childhood and Complications of non- Candida Infection: A Report of the Pediatric Immunodeficiency Collaborative Study Group," J Pediatr , 1990, 116(3):377-82.

Hwang WL, Gau JP, Young JH, et al, "Ketoconazole and High-Dose Methylprednisolone Predisposing to Cyclosporine-Induced Seizures: A Report of Three Cases," Acta Haematol , 1992, 88(2-3):139-41.

Janssen PA and Symoens JE, "Hepatic Reactions During Ketoconazole Treatment," Am J Med , 1983, 74(1B):80-5.

Lyman CA and Walsh TJ, "Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications," Drugs , 1992, 44(1):9-35.

Small EJ, Halabi S, Dawson NA, et al, "Antiandrogen Withdrawal Alone or in Combination With Ketoconazole in Androgen-Independent Prostate Cancer Patients: A Phase III Trial (CALGB 9583)," J Clin Oncol , 2004, 22(6):1025-33.

Terrell CL, "Antifungal Agents. Part II. The Azoles," Mayo Clin Proc , 1999, 74(1):78-100.

Trachtenberg J and Pont A, "Ketoconazole Therapy for Advanced Prostate Cancer," Lancet , 1984, (8400):433-5.

Varhe A, Olkkola KT, and Neuvonen PJ, "Oral Triazolam is Potentially Hazardous to Patients Receiving Systemic Antimycotics Ketoconazole or Itraconazole," Clin Pharmacol Ther , 1994, 56(6 Pt 1):601-7.

Wynn RL, "Erythromycin and Ketoconazole (Nizoral®) Associated With Terfenadine (Seldane®)-Induced Ventricular Arrhythmias," Gen Dent , 1993, 41(1):27-9.

International Brand Names

AC-FA® (TH); Adco-Dermed® (ZA); Akorazol® (MX); Anfuhex® (ID); Antanazol® (SG); Apo-Ketoconazole® (CA); Aquarius® (YU); Arcolan® (BR); Beatoconazole® (SG); C-86 Crema® (AR); Candiderm® (BR); Candoral® (BR); Cetoconazol® (BR); Cetonax® (BR); Cetonil® (AR, BR); Chemicon® (EC); Chintaral® (TH); Conazol® (DO, MX); Cremosan® (MX); DaktaGold® (AU); Daktarin® (GB); Daktarin Gold® (GB); Danruf Shampoo® (IN); Dermaral® (ID); Dezoral® (SG); Diazon® (SG, TH); Dikoven® (DO); Eprofil® (CL); Eumicel® (AR); Faction® (AR); Fangan® (AR); Fitonal® (AR); Forat® (DO); Formyco® (ID); Funazole® (IN); Fundan® (SE); Funet® (ID); Fungarest® (CL, ES); Fungarest Crema® (CL); Fungarest Vaginal® (ES); Fungasol® (ID); Fungazol® (TH); Fungicide® (IN); Fungicil® (AR); Fungiderm-K® (TH); Funginox® (TH); Fungium® (CL, EC); Fungo Hubber® (ES); Fungoral® (AT, BR, MX, NO, SE, TR); Fungores® (PL); Grenfung® (AR); H-Ketoconazol® (RO); Interzol® (ID); Katsin® (TH); Kazinal® (TH); Keduo® (AR); Kenalyn® (TH); Kenazole® (TH); Kenazol® (TH); Kenoral® (TH); Ketacon® (BR); Ketazol® (JO, LB, TH, ZA); Ketazon® (TH); Ketocine® (TH); Ketoconazol® (CL, EC, ID, RO); Ketoconazol Ecar® (CO); Ketoconazole Hovid® (SG); Ketoconazole® (ID); Ketoconazol Fabra® (AR); Ketoconazol Genfar® (EC); Ketoconazol Korhispana® (ES); Ketoconazol L.CH.® (CL); Ketoconazol MK® (CO, CR, DO, GT, HN, PA, SV); Ketoconazol Ratiopharm® (ES); Ketocon® (BD, EC); Ketoderm® (CA); Kétoderm® (FR); Ketoderm® (TR); Ketofun® (BD); Ketogel® (AR); Ketoisdin® (ES); Ketoisdin Vaginal® (ES); Ketokonazol® (CR, PL); Ketolam® (DO); Ketolan® (TH); Ketomed® (CO, ID, TH); Ketonan® (BR); Ketonazole (TH); Ketonil® (CL); Ketopine® (NZ); Ketoral® (BD, TH, TR); Ketosil® (TH); Ketoson® (SE); Ketospor® (CR, GT, PA); Ketozal® (TH); Ketozol® (AR); Ketozole® (SG); Ketozol-Mepha® (CH); Ketrozol® (CY); Kezon® (TH); Kezoral® (DK); Kez® (ZA); Konaderm® (CR, GT, HN, MX, PA, SV); Konazol® (TH, TR); Krefin® (HN); Lama® (TH); Larry® (TH); Lusanoc® (ID); Manoketo® (TH); Masarol® (TH); Miconan® (BR); Micoral® (AR, BR); Micosin® (EC); Micoticum® (ES, ID); Mi-Ke-Son's® (MX); Mizoron® (TH); Muzoral® (ID); Mycella® (TH); Mycodib® (MX); Mycoral® (ID); Mycoseb® (YU); Mycozid® (ID); Ninazol® (TH); Nizale® (PT); Nizcrème® (ZA); Nizol® (ID); Nizoral® (AT, AU, BE, BG, BR, CA, CH, CO, CR, CY, CZ, DE, DK, DO, EC, EG, FI, FR, GB, GT, HK, HN, HU, ID, IE, IL, IT, JO, LB, LK, LU, MT, MX, NL, NZ, PA, PL, PT, RO, RU, SG, SV, TH, TR, YU, ZA); Nizorelle® (ZA); Nizovules® (ZA); Nizshampoo® (ZA); N-Ketoconazol® (RO); Nofung® (ID); Nora® (TH); Novo-Ketoconazole (CA); Onofin-K® (MX); Orifungal® (AR); Oronazol® (CZ, HR, RU, SI); Panfungol® (ES); Panfungol Vaginal® (ES); Pasalen® (TH); Perative® (AR); Picamic® (ID); Pristine® (SG); Pristinex® (SG); Profungal® (ID, SG); Quadion® (AR); Rapamic® (PT); Rekonazol® (YU); Sebizole® (AU, NZ, SG); Socosep® (AR); Sostatin® (RO); Sporoxyl® (TH); Sporum® (CO); Termizol® (MX); Terzolin® (CH, DE); Thicazol® (ID); Tikl® (AR); Tiniazol® (MX); Tiracaspa® (BR); TKC® (CL); Transderm® (CL); Triatop® (AT, IT, TH); Triatop Intensivo® (AR); Tructum® (CL); Wizol® (ID); Yucomy YSP® (SG); Zoloral® (ID); Zoralin® (ID); Zumazol® (ID)

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