Itraconazole

Pharmacokinetics

The systemic availability of itraconazole and the bioequivalence of single 200 mg doses of itraconazole solution and two capsule formulations have been evaluated in a crossover study in 30 male volunteers [ ]. Itraconazole and hydroxyitraconazole were 30–37% more available from the solution and greater than from either capsule formulation. However, the values of C _max , t _max , and half-lives were comparable. There were no differences in safety and tolerance. The normal t _max of itraconazole is 1.5–4 hours and serum concentrations are dose-related. Steady-state concentrations are reached after about 10–14 days and are high in comparison with those attained after single doses. With single daily dose treatment the half-life is 20–30 hours. Itraconazole is highly protein bound. The tissue concentrations in lung, kidney, liver, bone, spleen, and muscle are 2–3 times higher than the corresponding serum concentrations. Concentrations in omentum and adipose tissue are particularly high, and higher concentrations are also found in various parts of the genital tract. Itraconazole is markedly keratinophilic; after withdrawal it will take 1–2 weeks before concentrations in the skin start to fall. Itraconazole concentrations in urine, saliva, eye fluids, and cerebrospinal fluid are low. Penetration of itraconazole into ocular tissues is low compared with those of ketoconazole and fluconazole [ , ]. Itraconazole is degraded in the liver and excreted via the bile and to some extent in the urine. Its metabolism is not altered by renal dysfunction [ , ].

General adverse effects and adverse reactions

Most reported adverse reactions to itraconazole are transient. Gastrointestinal reactions, mild dyspepsia, pyrosis, nausea, vomiting, diarrhea, and epigastric pain are not uncommon. In many published reports mention is made of increases in serum liver enzyme activities and hypertriglyceridemia, and symptomatic liver toxicity has been reported. Itraconazole does not induce drug-metabolizing enzymes and is a weaker inhibitor of microsomal enzymes than ketoconazole [ ]. In rats given doses of up to 160 mg/kg, there was no induction or inhibition of the metabolism of xenobiotics [ ]. Hypokalemia has often been reported, without an explanation of the mechanism. The use of higher doses (400 or even 600 mg/day) causes an increased incidence of adverse effects; among those documented at these dosages are severe hypokalemia, reversible adrenal insufficiency, and (in one published case) dysrhythmias, the latter being connected with an interaction with terfenadine [ ]. Rashes and pruritus have been reported. Tumor-inducing effects have not been described.

In patients taking itraconazole capsules for prolonged periods the common adverse reactions were nausea and vomiting (in under 10%), hypertriglyceridemia (9%), hypokalemia (6%), raised aminotransferase activities (5%), rashes and/or pruritus (2%), headache or dizziness (under 2%), and foot edema (1%) [ ].

In a study using the UK General Practice Research Database to determine rates of rare, serious drug-induced, adverse effects on the liver, kidneys, skin, or blood, occurring within 45 days of completing a prescription or refill in 54 803 users of either fluconazole or itraconazole, one patient had an abnormal liver function test while taking itraconazole in whom a drug-induced etiology could not be ruled out, a rate of 3.2 per 100 000 prescriptions (95% CI = 0.6, 18) for serious adverse liver effects [ ]. Thus, itraconazole does not commonly have serious adverse effects on the liver, kidneys, skin, or blood.

Observational studies

The pharmacokinetics, safety, and antifungal efficacy of intravenous itraconazole (400 mg for 2 days then 200 mg/day for 12 days), followed by 12 weeks of oral capsules (400 mg/day) have been investigated in 31 immunocompromised patients with invasive pulmonary aspergillosis [ ]. All received intravenous itraconazole and 26 then took oral itraconazole for a median of 79 days. Potentially therapeutic trough plasma itraconazole concentrations of 0.5 microgram/ml or more were achieved in 64% of the patients by day 2 and were generally maintained after switching to oral therapy. There was a complete or partial response in 15 patients. There were adverse events during intravenous therapy in 28 patients, and 13 had adverse events that were possibly related to the drug. The main events (at least 10% incidence) were fever, diarrhea, increased blood urea nitrogen, and nausea. Two of these 13 patients had intravenous therapy withdrawn. There were no consistent clinically relevant changes in laboratory parameters. During oral therapy, nine patients had similar adverse events that were possibly related to itraconazole. Treatment was withdrawn in seven patients because of adverse events during this phase. There were no deaths related to itraconazole.

Intravenous itraconazole for 7 days (200 mg bd for 2 days, then 200 mg od for 5 days), followed by itraconazole oral solution 200 mg od or bd for 14 days, has been assessed in 17 patients with hematological malignancies requiring antifungal prophylaxis [ ]. The mean trough plasma concentration at the end of the intravenous period was 0.54 micrograms/ml. This concentration was not maintained during once-daily oral treatment but increased further during twice-daily treatment, with a trough itraconazole concentration of 1.12 micrograms/ml at the end of oral treatment. All patients had some adverse events, mainly gastrointestinal. The two patients who were withdrawn from the study during intravenous treatment both reported fever; one also had pneumonitis and died from pneumonia 2 weeks after withdrawal, but this was unrelated to the drug. Patients were withdrawn during oral treatment because of fever (n = 3), pneumonitis (n = 2), colitis (n = 1), and abdominal pain and diarrhea (n = 1). Biochemical and hematological abnormalities were frequent, but there were no consistent changes.

The efficacy and safety of intermittent itraconazole therapy have been investigated in 635 patients with onychomycosis [ ]. Intermittent itraconazole (400 mg/day for 1 week per month for 2 months) was effective and safe. Most adverse events were minor and occurred infrequently; there were no major changes in liver function tests.

Two dosages of itraconazole have been compared in the treatment of tinea corporis or tinea cruris in a multicenter, randomized, double-blind, parallel-group study, which showed that itraconazole 200 mg for 1 week (54 patients) is similarly effective, equally well tolerated, and at least as safe as the established regimen of itraconazole 100 mg for 2 weeks (60 patients) [ ]. In a similar study in tinea pedis or tinea manuum, itraconazole 400 mg once a week (66 patients) and itraconazole 100 mg once every 4 weeks (69 patients) were both effective; the two schedules were equally well tolerated and safe [ ].

In an open multicenter study in 156 Chinese patients who were given intravenous itraconazole for 2 weeks followed by 200 mg bd orally for 28 day, the most common adverse events were hypokalemia (14%), gastrointestinal disorders (13%), raised liver enzymes (11%), and raised bilirubin (8.3%) [ ].

Comparative studies

Placebo-controlled studies

In a double blind, randomized, placebo-controlled, multicenter trial in plantar or moccasin-type tinea pedis in 72 patients, itraconazole 200 mg bd was significantly more effective than placebo; its safety and tolerability were comparable with placebo [ ].

In a double-blind, randomized trial in 71 adults undergoing orthotopic liver transplantation to investigate the role of itraconazole for prevention of invasive fungal infections, the patients were randomly assigned to either oral itraconazole (5.0 mg/kg preoperatively and 2.5 mg/kg bd postoperatively) or placebo [ ]. Therapy continued for a maximum of 56 days or until the patient was discharged from hospital or met a predefined end-point. Nine patients in the placebo group and one patient in the itraconazole group developed fungal end-points requiring therapy with amphotericin. Adverse events were reported by 97% and 100% of the patients given itraconazole and placebo respectively, and there were one and six deaths respectively.

The efficacy of itraconazole as prophylaxis against serious fungal infections has been investigated in a randomized, double-blind, placebo-controlled study in 39 patients (mean age 15 years) with chronic granulomatous disease, a rare disorder in which the phagocytes fail to produce hydrogen peroxide [ ]. After the initial treatment, each patient alternated between itraconazole and placebo annually. Patients aged 13 years or older and all patients weighing at least 50 kg took itraconazole 200 mg/day; those under 13 years or weighing less than 50 kg took 100 mg/day. One patient (who had not adhered properly to treatment) had a serious fungal infection while taking itraconazole, compared with seven who had a serious fungal infection while taking placebo. There were no serious adverse reactions, although one patient had a rash and another had abnormal liver function tests, both of which resolved after withdrawal of itraconazole. Itraconazole prophylaxis appears to be effective and well-tolerated in chronic granulomatous disease, but monitoring for long-term adverse reactions is warranted.

Cardiovascular

QT interval prolongation and ventricular extra beats have been attributed to itraconazole [ ].

• An otherwise healthy 30-year-old man who took itraconazole for onychomycosis developed palpitation and frequent ventricular extra beats. A 12-lead electrocardiogram was normal, but Holter recording showed 17 484 (18%) monomorphic extra beats and four runs among 96 930 beats/day. Another Holter recording after withdrawal of itraconazole showed 1032 atrial extra beats but no ventricular extra beats. The QT _c interval was 0.39 seconds without itraconazole, 0.41 seconds with itraconazole, and 0.43 seconds when multiple ventricular extra beats were documented.

Ventricular fibrillation has been attributed to itraconazole-induced hypokalemia [ ].

• Pleural and subsequent pericardial effusion developed in a woman treated with itraconazole 200 mg bd for a localized pulmonary infection with Aspergillus fumigatus [ ]. After more than 9 weeks of treatment she developed a pericardial effusion, which necessitated drainage. Itraconazole was withdrawn. Six weeks later, and 2 weeks after the resumption of itraconazole, she developed signs of pulmonary edema and cardiac enlargement. These signs disappeared rapidly on discontinuation of itraconazole.

Studies in dogs and healthy human volunteers have suggested that itraconazole has a negative inotropic effect; the mechanism is unknown. A systematic analysis of data from the FDA’s Adverse Event Reporting System (AERS) identified 58 cases suggestive of congestive heart failure in patients taking itraconazole [ ]. A simultaneous search did not identify any cases of congestive heart failure in patients taking fluconazole and ketoconazole, ruling out the possibility of a class effect. In consequence, the labeling of itraconazole has been revised. Itraconazole is now contraindicated for the treatment of onychomycosis in patients with evidence of ventricular dysfunction. For systemic fungal infections, the risks and benefits of itraconazole should be reassessed if signs or symptoms of congestive heart failure develop.

Nervous system

Headache due to itraconazole has been mentioned in some reports [ ]. Dizziness is an uncommon complaint, as are mood disturbances.

• A 74-year-old man without a previous psychiatric history developed delirium 1 day after starting to take itraconazole 200 mg bd for disseminated histoplasmosis [ ]. Extensive diagnostic work-up for potential causes was negative, and he continued to take itraconazole because of clinical improvement. Four days later, his delirium worsened and the dose of itraconazole was reduced to 200 mg/day. Despite the lower dosage, his delirium continued to worsen, and itraconazole was withdrawn, after which his mental status improved rapidly. However, the fungal infection recurred, and itraconazole 200 mg/day was restarted. One day later, the delirium recurred.

The mechanism of this adverse reaction is unclear; hypothetically, release of prostaglandins and cytokines after successful therapy could have resulted in delirium, although it could simply have been due to the patient’s inherent risk of delirium secondary to age, anemia, and disseminated histoplasmosis.

Painful neuropathy associated with itraconazole has been reported in a man with type 1 diabetes [ ].

Psychiatric

Visual hallucinations with confusion have been reported in a 75-year-old woman, occurring on three separate occasions, each time about 2 hours after a 200 mg dose of itraconazole. Her symptoms abated spontaneously over about 8 hours [ ].

Electrolyte balance

Hypokalemia, either in isolation or with hypertension, occurs in about 6% of patients taking long-term itraconazole [ , ]; the mechanism is unknown.

• Severe hypokalemia followed by rhabdomyolysis occurred in a 19-year-old man with chronic granulomatous disease 20 days after he started to take oral itraconazole (200 mg bd) for a cutaneous abscess caused by Aspergillus fumigatus ; hypokalemia may have been aggravated by concomitant treatment with intravenous amphotericin B during the first seven days of antifungal therapy [ ].

Hypokalemia and edema have also been observed in a number of patients taking high-dose therapy (600 mg/day) [ , ], associated with mildly depressed aldosterone concentrations. Marked ankle edema with weight gain was seen in a patient taking itraconazole 400 mg/day, in whom there was no explanation other than the use of the drug; after withdrawal of the itraconazole the symptoms disappeared [ ].

Hematologic

Leukopenia has been attributed to itraconazole [ ].

• A 14-year-old patient received itraconazole 1 mg/kg/day for dermatophytosis and had a fall in white blood cell count from 5 × 10 ⁹ /l at baseline (53% neutrophils) to 2.1 × 10 ⁹ /l (41% neutrophils) after 16 weeks of therapy with itraconazole. The white blood cell count returned to normal 9 weeks after drug withdrawal.

The joint database of the German Arzneimittelkomission der Deutschen Ärzteschaft (AkDÄ) and the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), based on voluntary reports, lists 683 reports of untoward drug effects of itraconazole, of which 4% are reduced erythrocyte counts, 3.2% reduced leukocyte counts, and 9.2 % reduced platelet counts [ ]. Although compared with fluconazole and voriconazole, hematological adverse events associated with itraconazole were less frequent in absolute and relative terms, monitoring of blood counts is recommended when itraconazole is prescribed for prolonged periods of time.

Gastrointestinal

Dyspepsia, pyrosis, nausea, vomiting, mild epigastric discomfort, and diarrhea can occur in patients taking itraconazole [ ]. These gastrointestinal complaints are generally mild, but they seem to be the most frequent adverse reactions during treatment. The total incidence of adverse effects was 3–5% in patients treated for superficial mycosis and 8% in 99 patients treated for deep mycosis [ ]. An incidence closer to 15% was reported in a multicenter trial [ ].

Of 216 patients who were treated with itraconazole for at least 3 weeks for prophylaxis or treatment of Aspergillus infection, 99 had adverse reactions, of whom 73 had one symptom, 23 had two, and three had three [ ]. The most common adverse events were fluid retention (n = 46, 21%) and gastrointestinal symptoms (n = 45, 21%). Nausea and/or vomiting affected 32 patients (15%) and abdominal pain, flatulence, and diarrhea affected 13 (6%).

Of 1108 patients with HIV treated for mucosal candidiasis, 239 reported gastrointestinal symptoms [ ].

Pseudomembranous colitis has been reported in association with exposure to itraconazole [ ].

• A 54-year-old man developed new abdominal pain and non-bloody diarrhea 1 month after exposure to a 7-day course of oral itraconazole 200 mg/day. He was taking stable chronic sertraline, valproic acid, and perphenazine, and had not taken antimicrobial drugs for 6 months. Flexible sigmoidoscopy after clinical progression showed pseudomembranes, and subsequent evaluation excluded other causes of diarrhea. Although Clostridium difficile culture and toxin assay were eventually negative, possibly because of delayed stool sampling, he responded to a 10-day course of anti-anaerobic drug therapy and was discharged with completely resolved symptoms.

The authors proposed that itraconazole had disrupted the resident fungal flora of the colon.

Liver

In most clinical reports, there were some cases of raised liver enzyme activities; the changes were transient or disappeared after withdrawal of itraconazole [ ]. More serious hepatotoxicity was not reported.

• Focal nodular hyperplasia of the liver has been reported in a 38-year-old woman who had taken itraconazole 200 mg/day for 4 months for a fungal infection of the fingernails [ ]. She had taken no other drugs in the year during which focal nodular hyperplasia developed.

• Of three patients, two women aged 62 and 57 and a man aged 75 years, who developed symptomatic hepatic injury 5–6 weeks after starting to take itraconazole, two had the biochemical pattern of cholestatic liver damage [ ].

All itraconazole clinical trials sponsored by Janssen Research Foundation for the treatment of onychomycosis, in which there was an assessment of laboratory safety, have been analysed [ ]. There were no significant differences in the number of code 4 abnormalities (baseline value is in the reference range and at least two values, or the last testing in the observation period, exceed twice the upper limit of the reference range) in liver function tests (alanine transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin). The incidence of all the code 4 abnormalities was under 2%. Itraconazole pulse therapy for onychomycosis appears to be safe, especially from the perspective of potential liver damage. In the itraconazole package insert, liver function tests are recommended in patients receiving continuous itraconazole for over 1 month. There is no such monitoring requirement for the pulse regimen, unless the patient has a history of underlying hepatic disease, the liver function tests are abnormal at baseline, or signs or symptoms suggestive of liver dysfunction develop at any time.

In 49 patients with invasive fungal infections who were given intravenous itraconazole for 2–42 days, liver function tests were abnormal in 20 [ ]. Those with liver enzyme abnormalities before treatment were more likely to have liver damage during treatment. However, hepatic damage was associated with itraconazole in only two patients with mild liver function test abnormalities.

Liver failure requiring liver transplantation after itraconazole treatment for 3 weeks for toenail onychomycosis has been reported in a 25-year-old woman [ ].

In 54 studies of the frequency of adverse effects of antifungal agents in 9228 patients, itraconazole was the most hepatotoxic (32%) [ ]. However, lack of standard definitions, heterogeneous patient pools, and differing protocols make large-scale comparisons between studies and agents difficult.

Skin

Different types of rash, including a case of acneiform rash, have been reported in patients taking itraconazole; in one case there were bloody bullae [ ].

• A 29-year-old man developed an infiltrative maculopapular eruption after 1 week of itraconazole 100 mg bd for tinea corporis [ ]. Itraconazole was withdrawn, and the lesions disappeared within 7 days. Scratch tests, patch tests, scratch-patch tests, and drug induced lymphocyte stimulation tests for itraconazole were negative; however, rechallenge with systemic itraconazole induced a maculopapular eruption on the face, hands, and the dorsa of the feet. Empty itraconazole capsules had no cutaneous effects, suggesting an allergic reaction to a metabolite of the compound.

Photosensitivity has been attributed to itraconazole 200 mg qds for 5 days, with a reduced minimal erythema dose for both UVB (0.12 J/cm ² ) and UVA (20.1 J/cm ² ), negative photopatch testing, and a positive photochallenge [ ]. The authors proposed a photoallergic mechanism because earlier exposure to itraconazole had been uneventful. However, details about sun exposure during the first exposure and about the intensity of sun exposure during the oral photochallenge procedure were not given. The eruption responded to oral glucocorticoids, which is more typical of photoallergic than phototoxic reactions.

The risk of serious skin disorders has been estimated in 61 858 users of oral antifungal drugs, aged 20–79 years, identified in the UK General Practice Research Database [ ]. They had received at least one prescription for oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. The background rate of serious cutaneous adverse reactions (corresponding to non-use of oral antifungal drugs) was 3.9 per 10 000 person-years (95% CI = 2.9, 5.2). Incidence rates for current use were 15 per 10 000 person-years (1.9, 56) for itraconazole, 11.1 (3.0, 29) for terbinafine, 10 (1.3, 38) for fluconazole, and 4.6 (0.1, 26) for griseofulvin. Cutaneous disorders associated with the use of oral antifungal drugs in this study were all mild.

• A 45-year-old woman with autoimmune polyglandular syndrome type I taking long-term betamethasone developed fatal toxic epidermal necrolysis when she was given itraconazole [ ]. It was unclear, however, whether the polyglandular syndrome or any of the other drugs used in her care (canrenoate, co-amoxiclav, furosemide, levofloxacin, and pantoprazole) were causally involved.

A fixed drug eruption has been attributed to itraconazole [ ].

Sexual function

There are inconsistent reports about the effects of itraconazole on sex steroids. Concentrations of testosterone, corticosterone, and progesterone were unchanged in rats and in six dogs in which possible endocrine effects were studied [ ]. On the other hand, the administration of itraconazole to seven male volunteers for 2 weeks did not produce detectable changes in plasma testosterone or cortisol concentrations. There was a slightly reduced cortisol response to ACTH stimulation 2 weeks after the start of high-dose itraconazole therapy (600 mg/day) in one of eight patients with severe mycosis [ ].

Erectile impotence, with normal steroid concentrations, has been reported, as has a reduction in libido [ ].

Immunologic

Itraconazole 200 mg bd for 2 weeks caused a serum sickness-like reaction in a 53-year-old woman with Ménière’s disease [ ].

Immediate hypersensitivity reactions to itraconazole are extremely rare, but urticaria and angioedema have been reported [ ].

• Angioedema of the face and generalized urticaria occurred in a 65-year-old man on day 3 of oral treatment with itraconazole 100 mg bd for prophylaxis of candidiasis [ ]. The symptoms responded promptly to parenteral glucocorticoids. Oral rechallenge with itraconazole resulted in a maculopapular rash and angioedema within 2 hours after ingestion. The patient had no personal or family history of allergy.

Pregnancy

Since embryotoxicity and teratogenicity have been found in rats, albeit after the administration of high doses, it has been recommended that itraconazole should be avoided during pregnancy [ ].

In a prospective cohort study of 229 pregnant women who had been exposed to oral itraconazole, 198 during the first trimester, and control subjects who had not been exposed to any known teratogens, the rates of major were 3.2% and 4.8% (RR = 0.67; 95% CI = 0.23, 1.95); the rate of any pregnancy loss was higher in the exposed group (RR = 1.75; 95% CI = 1.47, 2.09) [ ].

In a prospective cohort study in 206 pregnant women who had been exposed to itraconazole during the first trimester and 207 pregnant women who had had a non-teratogenic drug exposure during the first trimester, there were no significant differences in major congenital anomalies or in the rates of vaginal deliveries, premature births, or high or low birth weights; however, the rates of live births, spontaneous abortions, and terminations of pregnancy were significantly increased [ ].

Age

In a prospective study of itraconazole prophylaxis, in which dosages were adjusted to target plasma trough concentrations of 0.5 mg/l or more in 44 prophylactic cycles in 39 children with cancer, a median dosage of 8 (3.5–16.0) mg/kg/day was required to achieve the dosing target [ ]. Adverse reactions (gastrointestinal, raised aminotransferase activities, and one case of hemolysis) that required drug withdrawal were reported in 11% of courses. There were no breakthrough infections.

The safety, tolerability, and pharmacokinetics of itraconazole and its active metabolite hydroxyitraconazole after administration of itraconazole solution in hydroxypropyl-β-cyclodextrin have been investigated in a multicenter study in 26 infants and children aged 6 months to 12 years with mucosal candidiasis or at risk of invasive fungal disease [ ]. There was a trend to lower minimum plasma concentrations in children aged 6 months to 2 years. The systemic absorption of the solubilizer hydroxypropyl-β-cyclodextrin was less than 1%. Given at 5 mg/kg/day, this formulation provided potentially therapeutic concentrations in plasma, somewhat lower than those attained in adults, and it was well tolerated and safe.

Itraconazole 100 mg/day has been studied in 24 children with Trichophyton tonsurans tinea capitis [ ]. Itraconazole was well tolerated, but 15 children required re-treatment due to persistent infection.

The safety, pharmacokinetics, and pharmacodynamics of an oral suspension of cyclodextrin itraconazole (2.5 mg/kg od or bd for 15 days) have been investigated in an open, sequential, dose-escalation study in 26 children and adolescents, 5–18 years old, infected with HIV (mean CD4 count 128 × 10 ⁶ /l) with oropharyngeal candidiasis [ ]. Apart from mild to moderate gastrointestinal disturbances in three patients, cyclodextrin itraconazole was well tolerated. Two patients withdrew prematurely because of adverse events. The oropharyngeal candidiasis score fell significantly from a mean of 7.5 at baseline to 2.8 at the end of therapy, demonstrating antifungal efficacy in this setting. Based on these results, a dosage of 2.5 mg/kg bd was recommended for the treatment of oropharyngeal candidiasis in children aged 5 years and over.

The safety and efficacy of oral cyclodextrin itraconazole (5 mg/kg/day) as antifungal prophylaxis has been assessed in an open trial in 103 neutropenic children (median age 5 years; range 0–15 years) [ ]. Prophylaxis was started at least 7 days before the onset of neutropenia and continued until neutrophil recovery. Of the 103 patients, only 47 completed the course of prophylaxis; 27 withdrew because of poor compliance, 19 because of adverse events, and 10 for other reasons. Serious adverse events (other than death) occurred in 21 patients, including convulsions (n = 7), suspected drug interactions (n = 6), abdominal pain (n = 4), and constipation (n = 4). The most common adverse events considered definitely or possibly related to itraconazole were vomiting (n = 12), abnormal liver function (n = 5), and abdominal pain (n = 3). Tolerability of the study medication at end-point was rated as good (55%), moderate (11%), poor (17%), or unacceptable (17%). There were no unexpected problems of safety or tolerability.