amples.) this increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. for example, increased plasma concentrations of some of these drugs can lead to qt prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. specific examples are listed in precautions: drug interactions . itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole. there is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.

ugs with itraconazole oral solution is contraindicated. (see boxed warning, contraindications, and precautions: drug interactions .) cardiac disease: itraconazole oral solution should not be used 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 itraconazole oral solution, monitor carefully and consider other treatment alternatives which may include discontinuation of itraconazole oral solution 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 oral solution 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 itraconazole and 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 contraindications , clinical pharmacology: special populations , precautions: drug interactions , and adverse reactions: postmarketing 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 oral solution and itraconazole capsules 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. only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis. hydroxypropyl-β-cyclodextrin: itraconazole oral solution contains the excipient hydroxypropyl-β-cyclodextrin which produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a rat carcinogenicity study. these findings were not observed in a similar mouse carcinogenicity study. the clinical relevance of these adenocarcinomas is unknown. (see precautions: carcinogenesis, mutagenesis, and impairment of fertility .) treatment of severely neutropenic patients: itraconazole oral solution as treatment for oropharyngeal and/or esophageal candidiasis was not investigated in severely neutropenic patients. due to its pharmacokinetic properties, itraconazole oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidiasis.

e for 2 weeks following resolution of symptoms. doses up to 200 mg (20 ml) per day may be used based on medical judgment of the patient's response to therapy. itraconazole oral solution and itraconazole capsules should not be used interchangeably. patients should be instructed to take itraconazole oral solution without food, if possible. only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis. 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 .)

for oropharyngeal or esophageal candidiasis. table 3 below lists adverse events reported by at least 2% of patients treated with itraconazole oral solution in u.s. clinical trials. data on patients receiving comparator agents in these trials are included for comparison. table 3: summary of adverse events reported by ³2% of itraconazole treated patients in u.s. clinical trials (total) * of the 350 patients, 209 were treated for oropharyngeal candidiasis in controlled studies, 63 were treated for esophageal candidiasis in controlled studies and 78 were treated for oropharyngeal candidiasis in an open study. † of the 125 patients, 62 were treated for oropharyngeal candidiasis and 63 were treated for esophageal candidiasis. ‡ all 81 patients were treated for oropharyngeal candidiasis. body system/adverse event itraconazole total (n = 350*) % all controlled studies (n = 272) % fluconazole (n = 125 † ) % clotrimazole (n = 81 ‡ ) % gastrointestinal disorders nausea diarrhea vomiting abdominal pain constipation 11 11 7 6 2 10 10 6 4 2 11 10 8 7 1 5 4 1 7 0 body as a whole fever chest pain pain fatigue 7 3 2 2 6 3 2 1 8 2 4 2 5 0 0 0 respiratory disorders coughing dyspnea pneumonia sinusitis sputum increased 4 2 2 2 2 4 3 2 2 3 10 5 0 4 3 0 1 0 0 1 skin and appendages disorders rash increased sweating skin disorder unspecified 4 3 2 5 4 2 4 6 2 6 1 1 central/peripheral nervous system headache dizziness 4 2 4 2 6 4 6 1 resistance mechanism disorders pneumocystis carinii infection 2 2 2 0 psychiatric disorders depression 2 1 0 1 adverse events reported by less than 2% of patients in u.s. clinical trials with itraconazole included: adrenal insufficiency, asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence, gynecomastia, hematuria, hemorrhoids, hot flushes, implantation complication, infection unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus, rhinitis, rigors, stomatitis ulcerative, taste perversion, tinnitus, upper respiratory tract infection, vision abnormal, and weight decrease. edema, hypokalemia and menstrual disorders have been reported in clinical trials with itraconazole capsules. adverse events reported from other clinical trials a comparative clinical trial in patients who received intravenous itraconazole followed by itraconazole oral solution or received amphotericin b reported the following adverse events in the itraconazole intravenous/itraconazole oral solution treatment arm which are not listed above in the subsection “adverse events reported in oropharnyngeal or esophageal candidiasis trials” or listed below as postmarketing reports of adverse drug reactions: serum creatinine increased, blood urea nitrogen increased, renal function abnormal, hypocalcemia, hypomagnesemia, hypophosphatemia, hypotension, tachycardia and pulmonary infiltration. in addition, the following adverse drug reactions were reported in patients who participated in itraconazole oral solution clinical trials: cardiac disorders: cardiac failure; general disorders and administration site conditions: edema; hepatobiliary disorders: hepatic failure, hyperbilirubinemia; metabolism and nutrition disorders: hypokalemia; reproductive system and breast disorders: menstrual disorder the following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole capsules and itraconazole iv excluding the adverse reaction term “injection site inflammation” which is specific to the injection route of administration: cardiac disorders: left ventricular failure; gastrointestinal disorders: gastrointestinal disorder; general disorders and administration site conditions: face edema; hepatobiliary disorders: jaundice, hepatic function abnormal; investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, urine analysis abnormal; metabolism and nutrition disorders: hyperglycemia, hyperkalemia; nervous system disorders: somnolence; psychiatric disorders: confusional state; renal and urinary disorders: renal impairment; respiratory, thoracic and mediastinal disorders: dysphonia; skin and subcutaneous tissue disorders: rash erythematous; vascular disorders: hypertension in addition, the following adverse drug reaction was reported in children only who participated in itraconazole oral solution clinical trials: mucosal inflammation. post-marketing experience adverse drug reactions that have been first identified during post-marketing experience with itraconazole (all formulations) are listed in table 4 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 4: 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 metabolism and nutrition disorders: hypertriglyceridemia 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 gastrointestinal disorders: pancreatitis hepatobiliary disorders: serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes 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: renal and urinary 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.)

amples.) this increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. for example, increased plasma concentrations of some of these drugs can lead to qt prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. specific examples are listed in precautions: drug interactions . itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole. there is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.

been reported. (see adverse reactions: post-marketing experience .)

raconazole clearance decreases at higher doses due to saturable hepatic metabolism. absorption itraconazole is rapidly absorbed after administration of the oral solution. peak plasma concentrations of itraconazole are reached within 2.5 hours following administration of the oral solution under fasting conditions. the observed absolute bioavailability of itraconazole under fed conditions is about 55% and increases by 30% when the oral solution is taken in fasting conditions. itraconazole exposure is greater with the oral solution than with the capsule formulation 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.

ecreases at higher doses due to saturable hepatic metabolism. absorption itraconazole is rapidly absorbed after administration of the oral solution. peak plasma concentrations of itraconazole are reached within 2.5 hours following administration of the oral solution under fasting conditions. the observed absolute bioavailability of itraconazole under fed conditions is about 55% and increases by 30% when the oral solution is taken in fasting conditions. itraconazole exposure is greater with the oral solution than with the capsule formulation 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.

at hepatocytes, in ames tests with salmonella typhimurium (6 strains) and escherichia coli , in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation ( drosophila melanogaster ) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with c3h/10t½ c18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5 times the mrhd), even though parental toxicity was present at this dosage level. more severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20 times the mrhd). hydroxypropyl-β-cyclodextrin (hp-β-cd) hydroxypropyl-β-cyclodextrin (hp-β-cd) is the solubilizing excipient used in itraconazole oral solution. hydroxypropyl-β-cyclodextrin (hp-β-cd) was found to produce neoplasms in the large intestine at 5,000 mg/kg/day in rat carcinogenicity study. this dose was about 6 times amount contained in the recommended clinical dose of itraconazole oral solution based on body surface area comparisons. the clinical relevance of this finding is unknown. the slightly higher incidence of adenocarcinomas in the large intestines was linked to the hypertrophic/hyperplastic and inflammatory changes in the colonic mucosa brought about by hp-β-cd-induced increased osmotic forces. in addition, hp-β-cd was found to produce pancreatic exocrine hyperplasia and neoplasia when administered orally to rats at doses of 500, 2,000 or 5,000 mg/kg/day for 25 months. adenocarcinomas of the exocrine pancreas produced in the treated animals were not seen in the untreated group and are not reported in the historical controls. the recommended clinical dose of itraconazole oral solution contains approximately 1.7 times the amount of hp-β-cd as was in the 500 mg/kg/day dose, based on body surface area comparisons. this finding was not observed in the mouse carcinogenicity study at doses of 500, 2,000 or 5,000 mg/kg/day for 22 to 23 months. this finding was also not observed in a 12-month toxicity study in dogs or in a 2-year toxicity study in female cynomolgus monkeys. since the development of the pancreatic tumors may be related to a mitogenic action of cholecystokinin and since there is no evidence that cholecystokinin has a mitogenic action in man, the clinical relevance of these findings is unknown. hp-β-cd has no antifertile effect, and is not mutagenic.

tients in these studies were hiv seropositive. in an uncontrolled, open-label study of selected patients clinically unresponsive to fluconazole tablets (n = 74, all patients hiv seropositive), patients were treated with itraconazole oral solution 100 mg b.i.d. (clinically unresponsive to fluconazole in this study was defined as having received a dose of fluconazole tablets at least 200 mg/day for a minimum of 14 days.) treatment duration was 14 to 28 days based on response. approximately 55% of patients had complete resolution of oral lesions. of patients who responded and then entered a followup phase (n = 22), all relapsed within 1 month (median 14 days) when treatment was discontinued. although baseline endoscopies had not been performed, several patients in this study developed symptoms of esophageal candidiasis while receiving therapy with itraconazole oral solution. itraconazole oral solution has not been directly compared to other agents in a controlled trial of similar patients. esophageal candidiasis: a double-blind randomized study (n = 119, 111 of whom were hiv seropositive) compared itraconazole oral solution (100 mg/day) to fluconazole tablets (100 mg/day). the dose of each was increased to 200 mg/day for patients not responding initially. treatment continued for 2 weeks following resolution of symptoms, for a total duration of treatment of 3 to 8 weeks. clinical response (a global assessment of cured or improved) was not significantly different between the two study arms, and averaged approximately 86% with 8% lost to follow-up. six of 53 (11%) itraconazole-treated patients and 12/57 (21%) fluconazole-treated patients were escalated to the 200 mg dose in this trial. of the subgroup of patients who responded and entered a follow-up phase (n = 88), approximately 23% relapsed across both arms within 4 weeks.

ole and contact their healthcare provider immediately. instruct patients to stop itraconazole treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. instruct patients that hearing loss can occur with the use of itraconazole. the hearing loss usually resolves when treatment is stopped, but can persist in some patients. advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. advise patients that if they experience these events, they should not drive or use machines.