585
Hypochlorhydria, which may be present in patients with also required with calcium -channel blockers, which may membranes for I to 4 weeks after the drug is stopped. Small AIDS, can reduce absorption of itraconazole. In this case increase the risk of congestive heart failure if given together, amounts are distributed into breast milk. absorption may be improved by giving itraconazole with an and nisoldipine in particular is considered contra-indicated. Itraconazole is metabolised in the liver mainly by acidic drink, such as a cola beverage. Use with the statins is also best avoided because of the risk of cytochrome P450 isoenzyme CYP3A4. The major metabo muscle damage. lite, hydroxyitraconazole, has antifungal activity compar Breast feeding. Licensed product information does not Reviews of drug interactions vvith azole antifungals. able with that of itraconazole. Itraconazole is also excreted recommend breast feeding while receiving itraconazole Baciewicz FA. Ketoconazole and lluconazole drug as inactive metabolites in the bile or urine; 3 to 18% is although only small amounts of itraconazole are distribu Intern Med 1993; 153: 1970-6. excreted in the faeces as unchanged drug. Small amounts 2. Lomae.;;tro BM, on drug interactions with awle ted into breast milk. are eliminated in the stratum corneum and hair. Itracon antifungal agents. Ann 1998; 32: 915-28. 3. Venkatakrishnan K, et a!. Effects of the antifungal on oxidative azole is not removed by dialysis. Porphyria. The Drug Database for Acute Porphyria, com drug metabolism: clinical relevance. Clin 2000; 38: 111- The elimination half-life after a single 100-mg dose has piled by the Norwegian Porphyria Centre (NAPOS) and 80. been reported as 20 hours, increasing to 30 to 40 hours with the Porphyria Centre Sweden, classifies itraconazole as continued use. probably porphyrinogenic; it should be prescribed only for Immunosuppressants. Fatal hepatitis occurred in a 68- compelling reasons and precautions should be considered year-old woman 1 after 2 months of use of itraconazole P.r�p�r<:Jii<:J':lS. in all patients.1 and leflunomide. The authors suggested that the combined hepatotoxicity of both drugs might have accounted for ProprietaryPreparations (details are given in Volume B) l. The Drug Database for Acute Porphyria. Available at http://www. this. drugs-porphyria.org (accessed 14/10/ll) Single-ingredient Preparations. Arg.: Itrac; Micotenk; Nitridazol; l. A, et al. Fatal hepatitis with leflunomide and itraconazole. Am 1 Panastat; Salimidin; Sporanox; Austral.: Sporanox; Austria: 113: 352-3 . Itrabene; Sporanox; Belg.: Sporanox; Braz.: Estiranox; Fungo Interactions nax; ltraconolt; Itracotan; Itrahexal; Itralex; Itraspor; Itrazol; Enzyme-inducing drugs such as carbamazepine, isoniazid, Metal ions. Didanosine in a formulation containing alu Neo Itrax; Sporanox; Spozol; Traconal; Tracozont; Tratzol; nevirapine, phenobarbital, phenytoin, rifabutin, rifampicin, minium and magnesium ion buffering agents could reduce Traxonol; Canad.: Sporanox; Chile: Itodal; Sporanox; Teramic; or St John's wort may decrease plasma concentrations of the absorption of itraconazole due to the resultant increase China: Mei Fu Sporanox (J!Ji&f=t!i): Yi Qi Kang itraconazole sufficiently to reduce its efficacy. Conversely, in gastric pH. 1 �); Cz. : Cladostad;(9iem): Prokanazol; Sporanox; Denm.: Itrastad; (§Nid;;;; dazol; Sporanox; Sporanox; Sporanox; Itracolt; enzyme inhibitors such as clarithromycin, erythromycin, I. Moreno F, et al. Itraconazole-didanosine excipient interaction. lAMA Fin.: Fr.: Ger.: 269: Itraconbeta; Itradenn; Sempera; Slro:.; Assosept-S; Bevona HIV-protease inhibitors, including ritonavir-boosted HIV 199 3; 1508. Gr.: zole; Brovicton; Deratil; Etrel; Fansidol; Flunol; Fungonazol; protease inhibitors, may increase plasma concentrations of Fungospor; Idranox; Inrozol; Isoflon; Itrabest; Itracon; Itraco itraconazole. Use of drugs that reduce stomach acidity, such Antimicrobial Action nal; Itralfa; Itraproton; Itraspor; Itraviron; Itrazol; Laverio; Lor as antimuscarinics, antacids, proton pump inhibitors, and Itraconazole is a triazole antifungal drug that in sensitive enzo!; Mesmor; Micronazol; Mycodrox; Neo-Candimyk; Promi histamine H -receptor antagonists, may reduce the 2 fungi inhibits cytochrome P450-dependent enzymes nox; Soprazon; Sporanox; Sporizole; Stas; Sterginox; Zetilox; absorption of itraconazole. resulting in impairment of ergosterol synthesis in fungal Hong Kong: Aranox; Inox; Itracon; Itranstad; Quali-itrazole; Like other triazole antifungals, itraconazole is a potent Sporacidt; Sporanox; Cladostad; Itraconep; Itragen; cell membranes. It has a slightly wider spectrum of activity Hung.: inhibitor of the cytochrome P450 isoenzyme CYP3A4, and Omicral; Orungal; India: Biospore; Candistat; Canditral; Ful than ketoconazole. It is active against Aspergillus spp., may increase plasma concentrations of other drugs reliant cover; Fungicap; Itaspor; Itra; Itracan; Itrazen; Itrole; Indon.: Blastomyces dermatitidis, Candidaspp., Coccidioides immitis, upon it for their metabolism. This increases the risk of Forcanox; Fungitrazol; Furolnokt; Itzol; Mycotrazol; Nufatrac; Cryptococcus neoformans, Epidermophytonspp., Histoplasma adverse effects and such combinations should be given with Petrazole; Sporacid; Sporanox; Sporax; Spyrocon; Trachon; Tra capsulatum, Malassezia fu rfu r, Microsporum spp., Paracocci caution and careful monitoring, if at all. Drugs so affected cor; Unitrac; Zitrazolt; Irl.: Sporanox; Israel: Itranol; Sporanox; dioides brasiliensis, Sporothrix schenckii, and Trichophyton spp. may include: Ital. : Sporanox; Tranizolo; Trazer; Triasporin; Jpn: Itrizole; Itraconazole also has son1e antiprotozoal activity against antiarrhythmics such as disopyramide, dofetilide and Malaysia: Canditral; Inox; Itracon; Sporanox; Unitrac; Mex.: • Leishmania spp. Carexant; Conamed; Congox; Derusil; Ergospharmat; Fitocyd; quinidine Acquired resistance to itraconazole is rare but ketocon Fuzoltec; Imazolt; Iqcona; Isoporum; Isox; Itracosid; Itranax; antidepressants such as reboxetine • azole�resistant strains of Candida albicans have been found to Lozartil; Rixtal; Seritral; Silicsan; Sinozol; Solmavin; Sporanox; antiepileptics such as carbamazepine (which in turn • be cross resistant to itraconazole. Steitraz; Trax; Z-Fin; Zitriasol; Zolken; Zotril; Neth.: Trisporal; decreases the concentration of the antifungal, see above) Norw.: Sporanox; NZ: Itcozol; Itrazole; Sporanox; Philipp.: antihistamines such as astemizole, mizolastine, and • Microbiological interactions. Synergistic antifungal effects In ox; Sporanox; Pol. : ItraGen; ItraMerck; Orungal; Trioxal; terfenadine were seen in vitro with terbinafine and itraconazole against Port.: Fungizol; Itracic; Sporanox; Unisens; Rus.: Canditral antimalarials such as halofantrine (KaH,[{JIT}Jarr); Irunine (11pyHHH); Itramicol (UrpaM.llKOJI); Itrazol • strains of Candida albicans1 and Scedosporium prolzficans. 2 antimigraine drugs such as dihydroergotamine, ergo (Urpa3oJI); Miconihol (MHKOHHXOJI); Orungal (OpyHrarr); Orun • For effects on the antifungal activity of azoles when given metrine, ergotamine, methylergometrine, and eletriptan gamin (OpyHraMrrH); Orunit (OpyHHT); Rumycoz (PyMHK03); with amphotericin B, see p. 572.3. Teknazol (TeKHfluconazole and itraconazole against isolates of Candida albkans with Spain: Canadiol; Hongoseril; Oromict; Sporanox; Swed.: antineop/astics such as busulfan, docetaxel, trimetrexate, reduced su�ceptibility to azoles. Antimicrob Agents Chemother 1997; 41: • Sporanox; Gosegyne G; Itraderm; Sporanox; Can and the vinca alkaloids 1812-14. Switz.: Thai.: antipsychotics such as pimozide and sertindole 2. Meletiadis J, et al. In vitro interaction of terhinaline with itrawnawle ditralt; Iconat; Itra; Itracon; Itrasix; Itrazole; Norspor; Spazol; • Sporal; Sporlabt; Spornar; Funit; Itraspor; Sporanox; anxio/ytics and sedatives such as buspirone Antimicrob Agents Turk.: • Sporex; UK: Sporanox; Ukr.: Funit (cisapride • l. Goldman M, et a!. Does long-term itraconazole prophylaxis result in in Ketoconazole (BAN, USAN, r/NN) • HIV-protease inhibitors such as indinavir, ritonavir, and vitro azoic resistance in mucosal Canclida albicans isolates from persons Ketoconazot: Ketdconazoie; Ketoconazoium; Ketokonatsoli; saquinavir (concentrations of the antifungal may be with advanced human immunodeficiency virus infection? Antimicrob increased in turn by indinavir, ritonavir, or co 44: 1585-7. Ketokonazoi; KE'rokonazolas; KeTOKOHi'l30J1. formulated lopinavir-ritonavir, but not by saquinavir) 2. (±i-cis-1 -Acetyl-4-!4-[2·{2,4-dR-4kh14iorophenyi)-00; 2-imidazol- 1 - immunosuppressants such as ciclosporin, sirolimus, and ylQlethyi-: ,3-dioxo!an-4-yimethoxy}pheny!}piperaz!r,e. • Aspergillus i tacrolimus 47: 333-340. C26H28Ci2N,04�531.4 opioids such as alfentanil, fentanyl, and levacetylmetha • -- dol CAS 65277-·12· 1. Pharmacokinetics r; • some oral hypoglycaemics such as repaglinide ATC-D0iACQDO08;iAC GOIAFI0/3; J02A@02. the phosphodiesterase type-5 inhibitors sildenafil and • Itraconazole is absorbed from the gastrointestinal tract ATC Vee - OGO iNi i: QJ02A 802. vardenafil and the phosphodiesterase type- inhibitor when given orally either as capsules containing itraconazole UNII - R9400W9271. cilostazol 3 coated onto sugar spheres or as an oral liquid formulated Pharmacopoeias. In Chin., Bur. (see p. vii), Int., and US. • statins (HMG Co-A reductase inhibitors) such as with hydroxypropylbetadex. Absorption from the capsule Ph. Eur, 8: (Ketoconazole). A white or almost white atorvastatin, lovastatin, and simvastatin formulation is enhanced by an acidic gastric environment powder. Practically insoluble in water; sparingly soluble in • vasopressin receptor antagonists such as conivaptan and and is greatest when doses are taken with food; absorption alcohol; freely soluble in dichloromethane; soluble in tolvaptan from the oral liquid is not dependent on an acid methyl alcohol. Protect from light. Itraconazole is also an inhibitor of p-glycoprotein, and may environment, and absorption is greatest in the fasting increase plasma concentrations of substrates such as state. Peak plasma concentrations occur between 1.5 and 5 digoxin. hours after a dose of either formulation, and steady state is Uses and Administration Where drugs metabolised via CYP3A4 also prolong the reached within 15 days during daily dosing. Peak plasma Ketoconazole is an imidazole antifungal used topically or QT interval, the risk of serious cardiovascular effects such as concentrations at steady state of about 2 micrograms/mL orally. However, the risk of liver damage and adrenal gland torsade de pointes means that the combination should be have been reported after daily doses of 200 mg. problems (see Effects on the Liver p. 587.1 and Effects on avoided; this includes astemizole, bepridil, cisapride, Bioavailability increases with doses of 100 to 400 mg in Endocrine Function, p. 586.3, respectively) with oral use is dofetilide, levacetylmethadol, mizolastine, pimozide, quini such a manner as to suggest that itraconazole undergoes considered by some licensing authorities to outweigh any dine, sertindole, and terfenadine. Other drugs that should saturable metabolism. Itraconazole is highly protein bound; benefits: the EMEA states that oral ketoconazole should not not be used with itraconazole due to the risk of only 0.2% circulates as free drug. Itraconazole is vvidely be used to treat fungal infections, while the FDA states it unacceptable toxicity include eletriptan, the ergotamine distributed but only small amounts diffuse into the CSF. should not be given as first�line treatment but may be derivatives, and the benzodiazepines midazolam and Concentrations attained in the skin, sebum, pus, and many considered for the treatment of life-threatening infections triazolam; additionally, UK licensed product information organs and tissues are several times higher than when other effective antifungal drugs are not available or advises that halofantrine and disopyrarnide be avoided simultaneous plasma concentrations. Therapeutic concen� tolerated. It has been given for the prophylaxis of fungal when oral pulse regimens of itraconazole are used. Care is trations of itraconazole remain in the skin and mucous infections in immunocompromised patients, although
The symbol t denotes a preparation no longer actively marketed 586 Antifun als
fluconazole or itraconazole are usually preferred. It has adverse effects, and lower efficacy. If used as an alterna 3. Nguyen M, et al. Infantile hypercalcemia and hypercalciuria: new been recommended that, because of its erratic absorption tive it is given in doses of 400 to 800 mg daily.1 insights into a vitamin D·dependent mechanism and response to ketoconazole treatment. J Pediatr 2010; 157: 296-302. and slow therapeutic response, ketoconazole should not be 1. Chapman SW, et al. Clinical practice guidelines for the management of used for the treatment of life-threatening fungal infections, blastomycosis: 2008 update by the Infectious Diseases Society of Leishmaniosis. Ketoconazole has been tried as an alterna including fungal meningitis, or for severe infections in America. Clin Infect Dis2008; 46: 1801-12. Also available at: http://www. joumals.uchicago.edu/doi/pdf/ 10.1086/588300 (accessed 03/07/08) tive to conventional first- and second-line therapy for inununocompromised patients. visceral leishmaniasis (p. 923.1),1.2 although reports of The place of ketoconazole in the treatment of fungal treatment have not all been favourable.'·• infections is discussed in the various sections under Choice Endocrine disorders ond molignont neoplosms. Ketocon It has also been tried in cutaneous leishmaniasis of Antifungal, p. 563.1. Ketoconazole has also been used in azole has been reported to impair steroid hormone synth (p. 922.1). A cure rate of 70% was reported in over 100 the treatment of some protozoal infections, including esis1 and to blunt the response of cortisone to adrenocorti patients with Leishmania major infections treated with oral acanthamoeba infections and leishmaniasis. It has also been cotrophic hormone (ACTH)2 and has been tried in the ketoconazole 200 to 400 mg daily for 4 to 6 weeks. used in the management of acute respiratory distress management of some endocrine disorders. Ketoconazole was not considered to be effective in syodrome, hypercalcaemia, and certain endocrine disorders In Cushing's syndrome (p. 2559.1), ketoconazole in infections due to L. tropica, L. aethiopica,' or L. guyanensis.6 and malignancies. For further information see below. doses of up to 1200 mg dally has been used successfully as Ketoconazole 600 mg daily for 28 days has produced similar The usual oral dose for treatment and prophylaxis of an alternative or adjuvant to definitive therapies such as results to sodium stibogluconate intramuscularly for 20 days fungal infections is 200 mg once daily taken with food. This surgery or radiotherapy. 3·6 in patients with cutaneous leishmaniasis due to L. may be increased to 400 mg daily if an adequate response is Treatment of hirsutism is usually with an panamensis 7 A further comparative study" of 96 patients not obtained; in some infections even higher doses have anti-androgen (see under Cyproterone, p. 2262.1), but being treated for cutaneous leishmaniasis, caused mainly by been used. Treatment should usually be continued until ketoconazole has been tried in small numbers of women at a L. major or L. tropica, found ketoconazole given in doses of symptoms have cleared and cultures have become negative. dose of 300mg daily7 or 400 mg daily,8•9 with variable 600 mg in adults or IOmg/kg in children for 30 days to be Some infections may require several months of treatment results. more effective than 6 to 8 bi-weekly intralesional injections and giving ketoconazole for such prolonged periods may Ketoconazole has been reported to produce a beneficial of meglumine antimonate. In another study! ketoconazole increase the risk of hepatotoxicity. response in some forms of precocious puberty (p. 2254.1) was less effective than sodium stibogluconate when It has been suggested that daily doses of 200 mg should that do not generally respond to gonadorelin analogues; cutaneous leishmaniasis was due to L. braziliensis, but not be exceeded when ketoconazole is given with ritonavir cessation of menstruation and regression of pubertal signs in more effective when L. mexicanawas the cause. boosted -protease inhibitors. girlsiO and reduced testosterone secretion and increase in For detailsHIV of doses in children, see below. 1. Wall JP, et al. Ketoconazole in treatment of visceral leishmaniasis. Lancet adult height in boys11·13 has been noted in small numbers of 1990; 330: 81D-1 1. Ketoconazole is applied topically as a 2% cream in the patients studied. 2. Wali JP, et al. Ketoconazole in the treatment of antimony- and treatment of candida! or dermatophyte infections of the pentamidine-resistant Kala-azar. J Infect Dis 1992; 166: 215-16. The anti-androgenic effects of ketoconazole have also skin, or in the treatment of pityriasis versicolor. It is used 3. Sundar S, et al. Ketoconazole in visceral leishmaniasis. Lancet 1990; 336: prostatic cancer 1582-3. once or twice daily and continued for at least a few days been found useful in the management of 4. Rashid JR, et al. The efficacy and safety of ketoconazole in visceral (p. 712.3) in selected patients, !4-ls although there have been after the disappearance of symptoms. A foam containing 2% leishmaniasis. East Afr Med J 1994; 71: 392-5. some concernsabout its tolerability, 17 and it is not generally ketoconazole applied twice daily for 4 weeks may be used in 5. Weinrauch L, et al. Ketoconazole in cutaneous leishmaniasis. Br J the treatment of seborrhoeic dermatitis. A shampoo used as a first-line treatment. Dermatol l987; 117: 666-7. containing 1 or 2% ketoconazole is also used; it is applied Ketoconazole was ineffective in suppressing postoper 6. Dedet J-P, et al. Failure to cure Leishmania brazilieruis guyanensis ative erection in patients undergoing penile reconstructive cutaneous leishmaniasis with oral ketoconazole. Trans R Soc Trop Med twice weekly for 2 to 4 weeks (or occasionally longer) in the Hyg 1986; 80: 176. surgery; 19 it has been tried with prednisone for the treatment of dandruff or seborrhoeic dermatitis. The 2% 7. Saenz RE, etal. Efficacy of ketoconazole against Leishmania braziliensis shampoo is used once daily for up to 5 days in pityriasis management of recurrent ischaemic priapism.20 panamensis cutaneous leishmaniasis. Am J Med 1990; 89: 147-55. versicolor. For prophylaxis of seborrhoeic dermatitis the 2% 1. Pont A, et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern 8. Salmanpour R, et al. Comparative study of the efficacy of oral ketoconazole with intra-lesional meglumine antimoniate (Glucantime) shampoo is used once every 1 to 2 weeks; for prophylaxis of Med 1982; 97: 370-2. 2. White MC, Kendall-Taylor P. Adrenal hypofunction in patients taking for the treatment of cutaneous leishmaniasis. J Dermatol Treat 2001; 12: pityriasis versicolor it may be used once daily for a ketoconazole. Lancet 1985; i: 44-5. 159-62. 9. Navin et al. Placebo-controlled clinical trial of sodium stibogluoonate maximum of 3 days before exposure to sunshine. 3. Winquist EW, et al. Ketoconazole in the management of paraneoplastic TR, (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Cushing's syndrome secondary to ectopic adrenocorticotropin produc Gucitemala. J Infect Dis 1992; 165: 528-34. Administration in children. In infants and children, keto tion. J Clin Oncol 1995; 13: 157-64. 4. Estrada J, et al. The long-term outcome of pituitary irradiation after conazole may be used topically for the treatment of fungal unsuccessful transsphenoidal surgery in Cushing's disease. N Eng!J Med skin infections sintilarly to in adults. Oral use should be 1997; 336: 172-7. Adverse Effects restricted to situations where other antifungals cannot be 5. Berwaerts JJ, et al. Corticotropin-dependent Cushing's syndrome in Nausea and vomiting have been reported in about 3% of recommended for children weighing from 15 to 30 kg; residual or recurrent Cushing's disease. Bndocr J 2000; 47: 401-6. patients, and abdominal pain in about 1%. These adverse children weighing more than 30 kg may be dosed as for 7. Venturoli S, et al. A prospective randomized trial comparing low dose effects are dose-related and may be minimised by giving adults (see p. 585.3). Alternatively, in the USA, the flutamide, finasteride, ketoconazole, and cyproterone acetate�estrogen ketoconazole with food. Asymptomatic, transient elevations American Academy of Pediatrics1 has recommended an oral regimens in the treatment of hirsutism. J Clin Endocrinol Metab 1999; 84: in serum concentrations of liver enzymes may occur in dose of 3.3 to 6.6 mg/kg once daily for children from 2 years 1304-10. 8. Sonino N, et al. Low-dose ketoconazole treatment in hirsute women. J about 10% of patients. Hepatitis has been reported and the of age. Endocrinol Invest !990; 13: 35-40. risk appears to increase if treatment with ketoconazole is 1. American Academy of Pediatrics. Red Book: Report of the Committee 9. Venturoli S, et al. Ketoconazole therapy for women with acne and/or 2012 continued for longer than 2 weeks; it is usually reversible on on Infectious Diseases, 29th ed. Elk Grove Village, illinois, USA: American hirsutism. J Clin Bndocrinol Metab 1990; 71: 335-9. Academy of Pediatrics, 2012. 10. Syed FA, Chalew SA. Ketoconazole treatment of gonadotropin stopping ketoconazole but fatalities have occurred. Keto independent precocious puberty in girls with McCune-Albright conazole interferes with steroid biosyothesis and adverse syndrome: a preliminary report. J Pediatr Endocrinol Metab 1999; Acanthamoeba infections. Although there is currently no 12.: endocrine effects include gyoaecomastia, oligospermia, 81-3. established treatment for granulomatous amoebic menstrual irregularities, and adrenal cortex suppression, 11. Bertelloni S, et al. Long�term outcome of male-limited gonadotropin encephalitis, ketoconazole may have some activity against independent precocious puberty. Horm 1997; 48: 235-9. especially at high doses. Res the Acanthamoeba spp. responsible for this infection and 12. Soriano-Guillen L, et al. Adult height after ketoconazole treatment in Other adverse effects include allergic reactions such as has been applied topically to skin lesions. Ketoconazole patients with familial male�limited precocious puberty. J Clin Endocrinol urticaria and angioedema, and rare cases of anaphylaxis has also been suggested for Acanthamoeba keratitis Metab 2005; 90: 147-5 1. after the first dose have been reported. Pruritus, rash, 13. Almeida MQ, et al. Long-term treatment of familial male-limited alopecia, headache, dizziness, impotence, and somnolence (p. 919.3), when it has been given orally with topical precocious puberty (testotoxicosis) with cyproterone acetate or miconazole. ketoconazole. Clin Endocrinol (Oxf) 2008; 69: 93-98. may also occur. Thrombocytopenia, paraesthesia, raised 14. Lowe FC, Bamberger MH. Indications for use of ketoconazole in intracranial pressure, photophobia, and photosensitivity Acule respirotory distress syndrome. In two small dou management of metastatic prostate cancer. Uroloay 1990; 36: 541-5. have been reported rarely. ble-blind, controlled studies, 1.2 the development of acute 15. Mahler C, etal. Ketoconazole and liarozole in the treatment of advanced After topical use of ketoconazole, irritation, dermatitis, or prostatic cancer. Cancer 1993; 71: 1068-73. respiratory distress syndrome (ARDS-p. 1599.3) and 16. Small EJ, et al. Ketoconazole retains activity in advanced prostate cancer a burning sensation has occurred. mortality rates were lower in high-risk patients given patients with progression despite flutamide withdrawal. J Urol ketoconazole than in those given placebo. An accompany (Baltimore) 1997; 157: 1204-7. Effects on the A case of fatal aplastic anaemia was 17. Bok RA, Small EJ. The treatment of advanced prostate cancer with ing editorial' commented that adequate blood concentra reported1 in a 23-year-old woman who had taken oral ketoconazole: safety issues. Dru9 Safety 1999; 2.0: 451-8. blood. tions appeared to be essential. The mode of action could 18. Pettaway CA, et al. Neoadjuvant chemotherapy and hormonal therapy ketoconazole for 4 days for the treatment of vaginal dis be associated with inhibition of leukotriene and throm followed by radical prostatectomy: feasibility and preliminary results. J charge. boxane syothesis.2•3 Nevertheless, in a study in 234 Clin Oncol 2000; 18: 105Q-7. 1. Duman D, et al. Fatal aplastic anemia during treatment with patients! ketoconazole failed to reduce mortality or 19. DeCastro BJ, et al. Oral ketoconazole for prevention of postoperative ketoconazole. Am J Med 2001; 111: 737. penile erection: a placebo controlled, randomized, double�blind J improve clinical outcomes when given early in the course . Urol (Baltimore) 2008; 179: 193D-2. trial of ARDS. Some centres have developed guidelines for 20. Ahem Levine Ketoconazole and prednisone to prevent Effects on endocrine function. Oral ketoconazole blocks , LA. ketoconazole prophylaxis in patients at risk of ARDS.5 recurrentMR ischemic priapism. J Urol (Baltimore) 2009; 182:: 1401-6. testosterone syothesis and adrenal response to corticotro 1. Slotman GJ, et a!. Ketoconazole prevents acute respiratory failure in pin, resulting in azospermia and oligospermia, gyoaeco critically ill surgical patients. J Trauma 1988; 28: 648-54. mastia, impotence and decreased libido, and adrenal insuf 2. Yu M. Tomasa G. A double-blind, prospective, randomized trial of Ketoconazole has been used1·3 in the Hypercakaemia. ficiency _1·8 As an inhibitor of steroid production, ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of treatment of hypercalcaemia (p. 1778.1). It acts to reduce the adult respiratory distress syndrome. Crit CareMed 1993; 21: 1635-42. ketoconazole is valuable in controlling hypercortisolism 1,25-dihydroxycholecalciferol concentrations by inhibitiog 3. Slotman GJ. Ketoconazole: maybe it isn't the magic potion, but... Crit and is used therapeutically in some endocrine disorders cytochrome P450-dependent !a-hydroxylation of vitamin Care Med 1993; 21: 1642-4. and prostatic cancer. For further discussion see under Uses 4. The ARDS Network Authors. Ketoconazole for early treatment of acute D. For the treatment of infantile hypercalcaemia initial and Administration, above. lung injury and acute respiratory distress syndrome: a randomized doses have ranged from 3 to 9 mg/kg daily, depending on controlled trial. JAMA 2000; 2.83: 1995-2002. I. DeFelice R, et al. Gynecomastia with ketoconazole. Antimicrob Agents 5. Sinuff T, et al. Development implementation, and evaluation of a the severity of the disease; the dose has then been pro Chemother 1981; 19: 1073-4. ketoconazole practice guideline for ARDS prophylaxis. J Crit Care 1999; gressively decreased, and finally stopped when the urinary 2. Pont A. et al. High·dose ketoconazole therapy and adrenal and testicular 14: 1-6. calcium/creatinine ratio decreased below the upper limits function in humans. Arch Intern Med 1984; 144: 2150-3. 3. White MC, Kendall-Taylor P. Adrenal hypofunction in patients taking of normal.' ketoconazole. Lancet 1985; i: 44-5. Blastomycosis. Ketoconazole has largely been replaced by I. Yavuz H. Familiar drugs for the treatment of hypercalcemia. J Pediatr 4. Dandona P, et al. Non-suppression of cortisol secretion by long term itraconazole as the azole of choice in the treatment of blas 1998; 133: 311. treatment with ketoconazole in patients with acute leukaemia. J Clin tomycosis (p. 564.1) because of its higher incidence of 2. Young C, et a!. Hypercalcaemia in sarcoidosis. Lancet 1999; 353: 374. Pathol 1985; 38: 677-8.
All cross-references refer to entries in Volume A 587
5. Pillans PI, et al. Hyponatraemia and confusion in a patient taking trations of isoniazid and rifampicin may also be reduced by zole; Fulkit; Funazolet; Fungicide; Funginoc; Fungizole; ketoconazole. Lancet 1985; 821-2. i: ketoconazole. Hyphoral; Jacanzole; Jcanzole; K to Z; Ke-Toza; Kenazol; Keta 6. McCance DR et al. Acute hypoadrenalism and hepatotoxicity after fung; Keto; Ketocare; Ketoco; Ketocure; Ketonex; Ketopil; treatment with ketoconazole. Lancet 1987; 573. Ketoconazole inhibits certain hepatic oxidase enzymes, i: Ketovate; Ketoz; Ketozoe; Ketozole; Kezole; Kiton; Koiz; KZ; 7. Best TR, et al. Persistent adrenal insufficiency secondary to low-dose especially the cytochrome P450 isoenzyme CYP3A4, in a ketoconazole therapy. Am J Med 1987; 82: 676-80. similar way to itraconazole (p. 585.1) and similar care KZL; Nizol; Nizral; Novale; Ocana; Indon.: Anfuhext; Dermar 8. Khosla S, et al. Adrenal crisis in the setting of high-dose ketoconazole al; Dexazol; Dysfungalt; Fexazol; Formyco; Funet; Fungasol; should be taken to avoid adverse effects due to increased therapy. Arch InternMed 1989; 149: 802-4. Fungoral; Grazol; Interzol; Ketomed; Lusanoc; Micoticumt; plasma concentrations of the interacting drugs. Muzoral; Mycodenn; Mycoral; Mycozid; Nizol; Nizoral; Nofung; A disulfiram-like reaction may occur in patients taking Effects onthe liver. Hepatic adverse reactions to oral keto Picamic; Profungal; Solinfec; Sporex; Thicazol; Wizol; Zoloral; ketoconazole after drinking alcohol. The efficacy of oral Zoralin; Zumazolt; Ketopine; Ketozol; Nizoral; conazole are well known.'· 4 Transient minor elevations of Irl.: Israel: liver enzymes without clinical signs or symptoms of contraceptives may be reduced. Ketozol; Nizoral; Ital.: Asquam; Nizoral; Triatop; Malaysia: For reviews of drug interactions with azole antifungals, hepatic disease occur in about 10% of patients and may Dezor; Diazon; Fungazol; Funginox; Ketozotan; Kezoral; Larry; occur at any stage of treatment. Although this reaction is see Itraconazole, p. 585.2. Nizoral; Pristine; Pristinex; Yucomy; Mex. : Akorazolt; Biozoral; not usually clinically important it may signal the onset of Conazol; Cremosan; Ergomicon; Eurolat; Fomiral; Fungipar; Fungoral; Fungosinet; Hispazzont; Honzil; Ketofar; Ketomed; more serious hepatic injury and indicates the need for Antimicrobial Action Ketomizol; Ketoril; Konaderm; Konaturil; Lizovag; Messelzol; close monitoring of liver function. Symptomatic hepatic Ketoconazole is an imidazole antifungal that interferes with Mi-Ke�Sons; Micoser; Micozol; Mycocil; Mycodib; Nastil; reactions are much rarer (less than 0.1% of patients) but ergosterol synthesis and therefore alters the permeability of Nazolfarm; Nazoltec; Nizoral; Onofin-K; Prenalon; Remecon; are potentially fatal. There is usually a hepatocellular pat the cell membrane of sensitive fungi. It is reported to be Strizolet; Termizol; Tiniasil; Tiniazol; Toconal; Tolcrem; Tomi tern of damage and sometimes cholestasis. Patients at fungistatic at concentrations achieved clinically. Ketocon ko; Triatop; Neth.: Nizoral; Norw.: Fungoral; Konazalt; NZ: increased risk of hepatic injury include those with a his azole has a wide spectrum of antimicrobial activity Daktagold; Ketopine; Nizoral; Sebizole; Philipp.: Conatabt; tory of liver disease, those aged over 50, especially including activity against Blastomyces dennatitidis, Candida Dezor; Donaxene; Fungizol; Ketovid; Konazole; Kazee; Nizoral; women, and those requiring prolonged treatment. It is spp., Coccidioides immitis, Epidennophyton floccosum, Histoplas Reduff; Pol.: Fungorest; Nizoral; Noell; Zoxinat; Port.: Farmor important to monitor liver function during treatment as ma capsulatum, Malassezia spp., Microsporum canis, Para ol; Nizale; Nizoral; Tedol; Rus.: Fungistab (United Kingdom. BMJ 1987; 294: 419-21. Microbiological interactions. For the effect of imidazoles zolin; Thai.: AC-FA; Chintaral; Chintoral; Dandril; D"ezor; Dia 4. Garcia Rodriguez LA, et al. A cohort study onthe risk ofacute liver injury and amphotericin B on each other's antimicrobial activity, zon; Fungazol; Fungiderm-K; Funginox; Fungizin; Kandex; among users of ketoconazole and other antifungal drugs. Br J Clin Kara; Katsin; Kazinal; Kenalynt; Kenazol; Kenoral; Ketazon; Pharmacol 1999; 48: 847-52. see Amphotericin B, p. 572.3. Ketocine; Ketolan; Ketomed; Ketonazole; Ketopac; Ketoral; Resistance. For a discussion of increasing resistance of Ketosilt; Ketozal; Kezole; Kezon; Konaz; Konazol; Lamat; Precautions Candida spp. to azoles see Fluconazole, Antimicrobial Larry; Liquimed; Manoketo; Masarol; Mizoco; Mizoron; Mycel Ia; Myco-shampoo; Myco; Mycoral; Nazole; Ninazol; Nizoral; Since ketoconazole has been reported to cause hepatotoxi Action, p. 580.2. Nora; Pasalen; SP-Keto; Sporaxyl; Sporoxyl; Fungoral; city it should not be given to patients with pre-existing liver Turk.: Keto; Ketoderrn; Ketoral; Konazol; Nizoral; UK: Daktarin Gold; disease. Patients given ketoconazole should be monitored Pharmacokinetics Dandrazol; Dandrid; Nizoral; Ukr.: Kenazole (KeH33on); Ketodin for symptoms of hepatitis; also, liver function tests should be The absorption of ketoconazole from the gastrointestinal (Kero.rum); Ketozoral (Ker03oparr); Livarol (J1Hsapon); Nizoral performed before starting oral treatment with ketoconazole tract is variable and increases with decreasing stomach pH. (HH3oparr); USA: Extina; Ketodan; Nizoral; Xolegel; Venez.: lasting for more than 14 days and then at least monthly Mean peak plasma concentrations of about 3.5 micro Arcolane; Freetop; Kenazol; Ketazol; Ketomed; Nizoral. throughout therapy. Adrenal function should be monitored grams/mL occur about 2 hours after an oral dose of 200 mg. in patients with actual or borderline adrenal insufficiency, Systemic absorption after topical or vaginal application in Multi-ingredient Preparations. Arg.: Bactisonat; Butimerin Com those under prolonged periods of physiological stress, or healthy subjects is minimal. Ketoconazole is more than 90% plex; Ciprocon; Colposan; Dercotex; Dermoperative; Gentacler; those on prolonged therapy showing signs or symptoms bound to plasma proteins, mainly albumin. It is widely Gynerium; Linfol Dermico; Magicrem; Microsona C; Ovogin; suggestive of adrenal insufficiency. Torgyn Duo; Tricur; Tridermal; Betacortazol; Betazol distributed and appears in breast milk. Penetration into the Braz.: Ketoconazole has been shown to be teratogenic in animal Cortt; Betricort; Candicort; Capel; Celocort; Cetobeta; Cetocort; CSF is poor. The elimination of ketoconazole is reported to studies and its use is generally not recommended during Cetocorten; Cimecort; Conacort; Cortifungin; Dermocorte; be biphasic, with an initial half-life of 2 hours and a terminal pregnancy. For a discussion of the caution needed when Emscort; Naderm; Novacort; Trok-N; Trok; China: Baolongkang half-life of about 8 hours. using azole antifungals during pregnancy, see under Bi Liang (�'�); Compound Ketoconazole Ketoconazole is metabolised in the liver to inactive Pregnancy in Precautions of Fluconazole, p. 579.3. d'itft;•India:i!l1); Apodruff; Clinhair; Cotar-K; Danclear; (:!l::!JI!I'I!JtDancure; metabolites. It is excreted as metabolites and unchanged Hypochlorhydria, which may be present in patients with Emvate;li!f:); Everzple; Flakefree; Fungicide; Hyphoral; Kekona; drug chiefly in the faeces; some is excreted in the urine. AIDS, can reduce absorption of ketoconazole. In this case Ketosis; Ketotar; Ketz; Koiz; Konaz; KTC; Nazcare; Nazz; Nuforce Shampoo; Ocona-CT; Ocona-Z; Scalpe; Keto Z; absorption may be improved by giving ketoconazole with an References. Ital.: Daneshmend Warnock DW. Clinical pharmacokinetics of ketocon Ketomousse; Ketoplus; Femisan; Loffymixt; acidic drink, such as a cola beverage. L TK, Malaysia: Mex.: azole. Clin Phannacokinet 1988; 14: 13-34. Trexen Duo; Philipp.: Scalpex; Rus.: Keto Plus (Kero Ilmoc); 2. Lelawongs P, et al. Effect of food and gastric acidity on absorption of Thai.: Nizoral Cool; Ukr.: Keto Plus (Kero Ilmoc); USA: Xolegel Breast feeding. Ketoconazole is excreted in breast milk orally administered ketoconazole. Clin Pharm 1988; 7: 228-35. CorePak; Xolegel Duo. and licensed product information states that oral use 3. Lakc�Bakaar G, et al. Gastropathy and ketoconazole malabsorption in should be avoided during breast feeding. However, no the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988; 109: 471-3. adverse effects were seen in a breast-fed infant whose Pharmacopoeial Prepara�ons 4. Daneshmend TK. Diseases and drugs but not food decrease ketoconazole USP 36: Ketoconazole Oral Suspension; Ketoconazole Tablets. mother was receiving ketoconazole;1 it was calculated that 'bioavailability'. Br J Clin Pharmaco/ 1990; 29: 783-4. the infant was exposed to about 0.4% of the usual thera 5. Hurwitz A, et al. Gastric function in the elderly: effects on absorption of ketoconazole. J Clin Pharmacol 2003; 43: 996-1002. peutic dose of ketoconazole for this age group. The Ameri 6. Fitch WL, et al. Revisiting the metabolism of ketoconazole using accurate can Academy of Pediatrics considers2 that use of ketocon mass. Drug Metab Lett 2009; 3: 191-8. Lanoconazole (r!NNJ azole is therefore usually compatible with breast feeding. ,Lanoconazol; Lanoconatolum; latoconatole; I. Moretti ME, et at. Disposition of maternal ketoconazole in breast milk. r ti Am J Obstet Gynecol 1995; 173: 1625-6. P.r.�P.�. c:l c:ln.� llitJ ill, 2. American Academy of Pediatrics. The transfer of drugs and other ProprietaryPreparations (details are given in Volume B) (±t;a·!(fJliJ; JlaHOKOHd'!Qfl,)�-(o-Chto;ophe ny!)-1,3,dithiolan-2-ytldene]it)""lid: chemicals into human milk. Pediatrics 2001; 108: 776-89. [Retired May azole-c1 -acetonitriJe: 2010] Correction. ibid.; 1029. Also available at: http:f/aappolicy. Single-ingredient Prepara�ons. Arg.: C-86; Cetonil; Eumicel; aappublications.org/cgi/content/full/pediatrics%3b108/3/776 (accessed Faction; Fangan; Fitonal; Grenfung; Keduo; Ketogeno; Ketolef; C,4H,o0!113$r319.8 28/06/05) Ketonazol; Micoespec; Micoral; Orifungal; Perative; Pitylis; CAS � Quadion; Sinamida Accion Caspa; Socosep; Tiki; Triatop; Aus 10153(}.10-3. Porphyria. The Drug Database for Acute Porphyria, com tral.: Hexal Konazol Shampoot; Nizoral; Sebizole; Austria: UN!! .� 4£785831 1 F. piled by the Norwegian Porphyria Centre (NAPOS) and Fungoral; Nizoral; Belg.: Docketoralt; Nizoral; Pelikairt; Braz.: the Porphyria Centre Sweden, classifies ketoconazole for Acidermt; Arcolan; Candiderm; Candoral; Cetoconalab; Ceto systemic use as porphyrinogenic; it should be prescribed derm; Cetohexal; Cetomed; Cetornizol; Cetonax; Cetoneo; Profile only for compelling reasons and precautions should be Cetonil; Cetonin; Cetozan; Cetozol; Cleartop; Conazol; Dermi Lanoconazole is an imidazole antifungal used topically in taken in all patients. Dermatological preparations are clas trat; Ketonazol; Lozan; Miconan; Micoral; Nizonazol; Nizoral; the treatment of fungal skin infections as a l% cream, Nizoretict; Noriderm; Noronal; Zanoc; Zolmicol; Keto sified as possibly porphyrinogenic; they should be used Canad.: ointment, or solution, applied once daily. For a discussion of denn; Nizoral; Nu-Ketocont; Arcolane; Biogel; Fungar only when no safer alternative is available and precautions Chile: the caution needed when using azole antifungals during est; Fungium; Soridennal; TKC; 999 Xuanling (999 China: pregnancy, see under Pregnancy in Precautions of Flucon should be considered in vulnerable patients 1 Gold Daktarin (""l:SJ'I:'T): Jing Yu Kexin l. ;& azole, p. 579.3. The Drug Database for Acute Porphyria. Available at: http://www. Nizoral Pikangwang Triatop Xian Ke drugs-porphyria.org (accessed 24/10/11) !ll.); (!li:'t'); ("jjJfu(); Xin (!IL�9i');Zhuolixin (!it!Jt.:E);Cz. : Asquamt;(;llHJ'); Nizoral; Denm.:(lidJ'/:fiJ(); Nizoral; Samkol; Fin.:(lj!il:I[J(); Konact; Nizoral; Fr.: Ketoderm; Hypersensitivity. For reports of cross-sensitivity between Interactions Ketoliumt; Nizoralt; Ger.: Nizoral; Terzolin; Gr.: Abba; Adena lanoconazole and luliconazole, see p. 588.1. san; Aquarius; Botaderm; Cezolin; Ebersept; Flidaphen; Fun Use of drugs that reduce stomach acidity, such as goral; Ilgem; Libroman; Lovegin; Mycofebrin; Neo-egmol; antimuscarinics, antacids, histamine Hrantagonists, and Nyoxep; Reprol; Scalpin; Sostatin; Tonsil; Vafluson; Zemidral; r ti proton pump inhibitors, may reduce the absorption of Hong Kong: CP-Ketot; Dezor; Diazon; Fluzoralt; Fungazolt; P.r.�P.�. �_ c:>.n.� ketoconazole. Absorption of ketoconazole may also be Funginoxt; Ketocon; Ketovid; Ketozol; Ketozole; Larry; Proprietary Preparations (details are given in Volume B) reduced by sucralfate. Enzyme-inducing drugs such as Nizoral; Pristine; Pristinex; Stada K t; Synizoralt; Ziconalt; rifampicin, isoniazid, efavirenz, nevirapine, or phenytoin Hung.: Ketospor; Nizoral; India: Arclone; Arcolane; Dandoff; Single-ingredient Prepara�ons. Jpn: Astat. may reduce plasma-ketoconazole concentrations. Concen- Dandrex; Danfree; Danruf; Denfast; Derm-Keta; Emcon; Fina-
The symbol denotes a preparation no longer actively marketed t