th or without fingernail involvement, due to dermatophytes (tinea unguium), and onychomycosis of the fingernail due to dermatophytes (tinea unguium). prior to initiating treatment, appropriate nail specimens for laboratory testing (koh preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (see clinical pharmacology: special populations, contraindications, warnings, and adverse reactions: post-marketing experience for more information.) description of clinical studies: blastomycosis: analyses were conducted on data from two open-label, non-concurrently controlled studies (n=73 combined) in patients with normal or abnormal immune status. the median dose was 200 mg/day. a response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. histoplasmosis: analyses were conducted on data from two open-label, non-concurrently controlled studies (n=34 combined) in patients with normal or abnormal immune status (not including hiv-infected patients). the median dose was 200 mg/day. a response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. histoplasmosis in hiv-infected patients: data from a small number of hiv-infected patients suggested that the response rate of histoplasmosis in hiv-infected patients is similar to that of non-hiv-infected patients. the clinical course of histoplasmosis in hiv-infected patients is more severe and usually requires maintenance therapy to prevent relapse. aspergillosis: analyses were conducted on data from an open-label, "single-patient-use" protocol designed to make itraconazole available in the u.s. for patients who either failed or were intolerant of amphotericin b therapy (n=190). the findings were corroborated by two smaller open-label studies (n=31 combined) in the same patient population. most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin b therapy. onychomycosis of the toenail: analyses were conducted on data from three double-blind, placebo-controlled studies (n=214 total; 110 given itraconazole capsules) in which patients with onychomycosis of the toenails received 200 mg of itraconazole capsules once daily for 12 consecutive weeks. results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative koh plus negative culture, in 54% of patients. thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). the mean time to overall success was approximately 10 months. twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of koh or culture from negative to positive). onychomycosis of the fingernail: analyses were conducted on data from a double-blind, placebo-controlled study (n=73 total; 37 given itraconazole capsules) in which patients with onychomycosis of the fingernails received a 1-week course of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole, which was followed by a second 1-week course of 200 mg of itraconazole capsules b.i.d. results demonstrated mycologic cure in 61% of patients. fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. the mean time to overall success was approximately 5 months. none of the patients who achieved overall success relapsed.

gs with itraconazole is contraindicated. (see boxed warning, contraindications, and precautions: drug interactions.) cardiac disease: itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (chf) or a history of chf. itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. for patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. these risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. such patients should be informed of the signs and symptoms of chf, should be treated with caution, and should be monitored for signs and symptoms of chf during treatment. if signs or symptoms of chf appear during administration of itraconazolecapsules, discontinue administration. itraconazole has been shown to have a negative inotropic effect. when itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. in a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated spect imaging; these resolved before the next infusion, 12 hours later. itraconazole has been associated with reports of congestive heart failure. in post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. in addition, itraconazole can inhibit the metabolism of calcium channel blockers. therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of chf. concomitant administration of itraconazoleand felodipine or nisoldipine is contraindicated. cases of chf, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (see clinical pharmacology: special populations, contraindications, precautions: drug interactions, and adverse reactions: post-marketing experience for more information.) interaction potential: itraconazole has a potential for clinically important drug interactions. coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in precautions: drug interactions. interchangeability: itraconazole capsules and itraconazoleoral solution should not be used interchangeably. this is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given. in addition, the topical effects of mucosal exposure may be different between the two formulations. only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

first 3 days of treatment. treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. an inadequate period of treatment may lead to recurrence of active infection. itraconazole capsules and itraconazole oral solution should not be used interchangeably. only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. treatment of onychomycosis: toenails with or without fingernail involvement: the recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. treatment of onychomycosis: fingernails only: the recommended dosing regimen is 2 treatment courses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. the courses are separated by a 3-week period without itraconazole capsules. use in patients with renal impairment: limited data are available on the use of oral itraconazole in patients with renal impairment. caution should be exercised when this drug is administered in this patient population. (see clinical pharmacology: special populations and precautions.) use in patients with hepatic impairment: limited data are available on the use of oral itraconazole in patients with hepatic impairment. caution should be exercised when this drug is administered in this patient population. (see clinical pharmacology: special populations, warnings, and precautions.)

compromised or receiving multiple concomitant medications. treatment was discontinued in 10.5% of patients due to adverse events. the median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). the table lists adverse events reported by at least 1% of patients. table 3: clinical trials of systemic fungal infections: adverse events occurring with an incidence of greater than or equal to 1% *rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. body system/adverse event incidence (%) (n=602) gastrointestinal nausea vomiting diarrhea abdominal pain anorexia 11 5 3 2 1 body as a whole edema fatigue fever malaise 4 3 3 1 skin and appendages rash* pruritus 9 3 central/peripheral nervous system headache dizziness 4 2 psychiatric libido decreased somnolence 1 1 cardiovascular hypertension 3 metabolic/nutritional hypokalemia 2 urinary system albuminuria 1 liver and biliary system hepatic function abnormal 3 reproductive system, male impotence 1 adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. adverse events reported in toenail onychomycosis clinical trials patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. the following adverse events led to temporary or permanent discontinuation of therapy. table 4: clinical trials of onychomycosis of the toenail: adverse events leading to temporary or permanent discontinuation of therapy adverse event incidence (%) itraconazole (n=112) elevated liver enzymes (greater than twice the upper limit of normal) 4 gastrointestinal disorders 4 rash 3 hypertension 2 orthostatic hypotension 1 headache 1 malaise 1 myalgia 1 vasculitis 1 vertigo 1 the following adverse events occurred with an incidence of greater than or equal to 1% (n=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. adverse events reported in fingernail onychomycosis clinical trials patients in these trials were on a dosing regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. the following adverse events led to temporary or permanent discontinuation of therapy. table 5: clinical trials of onychomycosis of the fingernail: adverse events leading to temporary or permanent discontinuation of therapy adverse event incidence (%) itraconazole (n=37) rash/ pruritus 3 hypertriglyceridemia 3 the following adverse events occurred with an incidence of greater than or equal to 1% (n=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. adverse events reported from other clinical trials in addition, the following adverse drug reaction was reported in patients who participated in itraconazole capsules clinical trials: hepatobiliary disorders: hyperbilirubinemia. the following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole oral solution and itraconazole iv excluding the adverse reaction term "injection site inflammation" which is specific to the injection route of administration: cardiac disorders: cardiac failure, left ventricular failure, tachycardia; general disorders and administration site conditions: face edema, chest pain, chills; hepatobiliary disorders: hepatic failure, jaundice; investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, urine analysis abnormal; metabolism and nutrition disorders: hyperglycemia, hyperkalemia, hypomagnesemia; psychiatric disorders: confusional state; renal and urinary disorders: renal impairment; respiratory, thoracic and mediastinal disorders: dysphonia, cough; skin and subcutaneous tissue disorders: rash erythematous, hyperhidrosis; vascular disorders: hypotension post-marketing experience adverse drug reactions that have been first identified during post-marketing experience with itraconazole (all formulations) are listed in the table below. because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. table 6: postmarketing reports of adverse drug reactions blood and lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia immune system disorders: anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema nervous system disorders: peripheral neuropathy, paresthesia, hypoesthesia, tremor eye disorders: visual disturbances, including vision blurred and diplopia ear and labyrinth disorders: transient or permanent hearing loss cardiac disorders: congestive heart failure respiratory, thoracic and mediastinal disorders: pulmonary edema, dyspnea gastrointestinal disorders: pancreatitis, dysgeusia hepatobiliary disorders: serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis skin and subcutaneous tissue disorders: toxic epidermal necrolysis, stevens-johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria musculoskeletal and connective tissue disorders: arthralgia renal and urinary disorders: urinary incontinence, pollakiuria reproductive system and breast disorders: erectile dysfunction general disorders and administration site conditions: peripheral edema investigations: blood creatine phosphokinase increased there is limited information on the use of itraconazole during pregnancy. cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. a causal relationship with itraconazole has not been established. (see clinical pharmacology: special populations, contraindications, warnings, and precautions: drug interactions for more information.)

at higher doses due to saturable hepatic metabolism. absorption itraconazole is rapidly absorbed after oral administration. peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. the observed absolute oral bioavailability of itraconazole is about 55%. the oral bioavailability of itraconazole is maximal when itraconazole capsules are taken immediately after a full meal. absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., h 2 -receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (see precautions: drug interactions.) absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole capsules are administered with an acidic beverage (such as a non-diet cola). when itraconazole capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a h 2 -receptor antagonist, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone. (see precautions: drug interactions.) itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of drug is given. (see warnings) distribution most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). it has also a marked affinity for lipids. only 0.2% of the itraconazole in plasma is present as free drug. itraconazole is distributed in a large apparent volume in the body (>700 l), suggesting extensive distribution into tissues. concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. concentrations in the cerebrospinal fluid are much lower than in plasma. metabolism itraconazole is extensively metabolized by the liver into a large number of metabolites. in vitro studies have shown that cyp3a4 is the major enzyme involved in the metabolism of itraconazole. the main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole. excretion itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. as re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period. special populations: renal impairment: limited data are available on the use of oral itraconazole in patients with renal impairment. a pharmacokinetic study using a single 200-mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). in uremic subjects with a mean creatinine clearance of 13 ml/min. × 1.73 m 2 , the exposure, based on auc, was slightly reduced compared with normal population parameters. this study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (t max , c max , and auc 0 to 8h ). plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. after a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as crcl 50 to 79 ml/min), moderate (defined in this study as crcl 20 to 49 ml/min), and severe renal impairment (defined in this study as crcl <20 ml/min) were similar to that in healthy subjects (range of means 42 to 49 hours vs. 48 hours in renally impaired patients and healthy subjects, respectively). overall exposure to itraconazole, based on auc, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. data are not available in renally impaired patients during long-term use of itraconazole. dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (see precautions and dosage and administration.) hepatic impairment: itraconazole is predominantly metabolized in the liver. a pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as capsule. a statistically significant reduction in mean c max (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. however, overall exposure to itraconazole, based on auc, was similar in cirrhotic patients and in healthy subjects. data are not available in cirrhotic patients during long-term use of itraconazole. (see contraindications, precautions: drug interactions and dosage and administration.) decreased cardiac contractility: when itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. in a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated spect imaging; these resolved before the next infusion, 12 hours later. if signs or symptoms of congestive heart failure appear during administration of itraconazole capsules, itraconazole should be discontinued. (see boxed warning, contraindications, warnings, precautions: drug interactions and adverse reactions: post-marketing experience for more information.) microbiology mechanism of action: in vitro studies have demonstrated that itraconazole inhibits the cytochrome p450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. antimicrobial activity: itraconazole exhibits in vitro activity against blastomyces dermatitidis, histoplasma capsulatum, histoplasma duboisii, aspergillus flavus, aspergillus fumigatus, and trichophyton species (see indications and usage, description of clinical studies). susceptibility testing for specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by fda for this drug, please see: https://www.fda.gov/stic. resistance: isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. itraconazole is not active against zygomycetes (e.g., rhizopus spp., rhizomucor spp., mucor spp. and absidia spp.), fusarium spp., scedosporium spp. and scopulariopsis spp. cross-resistance: several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. the finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. studies (both in vitro and in vivo ) suggest that the activity of amphotericin b may be suppressed by prior azole antifungal therapy. as with other azoles, itraconazole inhibits the 14 c-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. ergosterol is the active site for amphotericin b. in one study the antifungal activity of amphotericin b against aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. the clinical significance of test results obtained in this study is unknown.