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Itraconazole: Side Effects

Itraconazole: Side Effects

Itraconazole is a triazole antifungal drug. It is used orally to treat oropharyngeal and vulvovaginal candidiasis, pityriasis versicolor, dermatophytoses unresponsive to topical treatment, and systemic infections, including aspergillosis, blastomycosis, chromoblastomycosis, cocci-dioidomycosis, cryptococcosis, histoplasmosis, paracocci-dioidomycosis, and sporotrichosis. It is also used to prevent fungal infections in immunocompromised patients.

Pharmacokinetics

The systemic availability of itraconazole and the bioequi-valence 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 were greater than from either capsule formulation. However, the values of Cmax, fmax, and half-lives were comparable.

There were no differences in safety and tolerance. The normal fmax 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.

Observational studies

The pharmacokinetics, safety, and antifungal efficacy of intravenous itraconazole (400 mg for 2 days then 200 mg for 12 days), followed by 12 weeks of oral capsules (400 mg/day) have been investigated in 31 immunocom-promised 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.

The pharmacokinetics and safety of 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, have 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 microgram/ 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, pneumonitis, colitis, and abdominal pain and diarrhea. 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 multi-center, 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 manum, 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.

Comparative studies

Amphotericin

Data on the safety of itraconazole have been collected in an open, randomized, multicenter study in 277 adults with cancer and neutropenia. Itraconazole oral solution (100 mg bd, was compared with a combination of amphotericin capsules and nystatin oral suspension. Adverse events were reported in about 45% of patients in each group. The most frequent were vomiting (14 versus 12 patients), diarrhea (12 versus, nausea (5 versus, and rash (2 versus 13 patients). There were no differences in liver function test abnormalities. Treatment had to be withdrawn because of adverse events (including death) in 34 patients who took itraconazole and 33 of those who took amphotericin plus nystatin; there were 17 deaths in each group and death was recorded as adverse event in 13 and 9 patients, respectively.

Itraconazole (400 mg intravenously for 2 days, 200 mg intravenously for up to 12 days, then 400 mg/day orally) and intravenous amphotericin deoxycholate (0.7-1.0 mg/kg) have been compared in 384 granulocytopenic patients with persistent fever in a randomized, multicenter trial. The median duration of therapy was 8.5 days. The incidence of drug-related adverse events (5 versus 54%) and the rate of withdrawal due to toxicity (19 versus 38%) were significantly lower with itraconazole. The most frequent reasons for withdrawal in patients taking itraconazole were nausea and vomiting (5%), rash (3%), and abnormal liver function tests (3%). Significantly fewer of the patients who received itraconazole had nephrotoxicity (5 versus 24%); however, more had hyper-bilirubinemia (10 versus 5%). There was no difference in gastrointestinal adverse events between the two groups.

Itraconazole elixir 2.5 mg/kg bd has been compared with amphotericin capsules 500 mg qds for the prophylaxis of systemic and superficial fungal infections in a double-blind, randomized, placebo-controlled, multicenter trial for 1-59 days. While itraconazole significantly reduced the frequency of superficial fungal infections, it was not superior in reducing invasive fungal infections or in improving mortality.

Adverse events were reported in 222 patients taking itraconazole (79%) and in 205 patients taking amphotericin (74%). The commonest adverse events were gastrointestinal, followed by rash and hypokalemia, with no differences between the two regimens. In both groups, 5% of the adverse events were considered to be definitely drug-related. Comparable numbers of patients in the two groups permanently stopped treatment because of adverse events (including death), 75 (27%) in the itraconazole group and 78 (28%) in the amphotericin group. Nausea (9 and 11%) and vomiting (8 and 7%) were the most frequently reported adverse events that led to withdrawal. Biochemical changes were comparable in the two groups.

Other antifungal azoles

The safety of continuous itraconazole (50-200 mg/day for up to 3 months) in the treatment of onychomycosis and dermatomycosis has been reviewed, using published and unpublished data from clinical trials. The overall incidence of adverse events in patients who took continuous itraconazole (21%) differed little from that in patients who took either topical miconazole or oral placebo (18%). The most frequently reported adverse events were gastrointestinal disorders (6.7%), headache (4.2%), and skin disorders (2.7%). No data were given on the incidence of serious adverse events attributed to itraconazole.

Among laboratory abnormalities, clinically significant rises in liver function tests occurred in 3.4% of 527 patients treated with itraconazole (2.6% in patients treated with 50-200 mg/day for dermatomycosis versus 6.6% in patients treated with 200 mg/day for 3 months for onychomycosis).

Oral fluconazole 400 mg qds and oral itraconazole 200 mg bd have been compared in a randomized, double blind, placebo-controlled trial in 198 patients with progressive non-meningeal coccidioidomycosis. Overall, 57% and 72% of patients responded to 12 months of therapy with fluconazole and itraconazole, respectively. Relapse rates after withdrawal did not differ significantly. Both drugs were well tolerated.

Serious adverse events occurred in eight of 97 fluconazole-treated patients and six of 101 itraconazole-treated patients. They included raised liver enzymes, gastrointestinal disturbances, hypokalemia, and skin rash. Alopecia was reported in 15 of 97 patients taking fluconazole and in only four of 101 patients taking itraconazole. Similarly, dry lips were reported in 11 of 97 patients taking fluconazole and in none of 101 patients taking itraconazole. Both adverse events have previously been reported with fluconazole.

In a double-blind comparison in oropharyngeal candi-diasis in 244 patients with AIDS, itraconazole oral solution and fluconazole capsules (each 100 mg/day for 14 days) were equally efficacious; there were no significant differences in adverse effects.

Itraconazole oral solution and fluconazole tablets have been compared in oropharyngeal candidiasis in HIV/ AIDS patients in a prospective randomized, blind, multi-center trial. Both regimens of itraconazole oral solution (100 mg bd for 7 days or 100 mg od for 14 days) were equivalent to fluconazole (100 mg od for 14 days). Itraconazole oral solution was well tolerated.

Oral itraconazole solution has been compared with intravenous/oral fluconazole for the prevention of fungal infections in a randomized, controlled trial in adult liver transplant recipients, who were randomized to receive either oral itraconazole solution (200 mg bd) or intravenous/oral fluconazole (400 mg/day). Prophylaxis was started immediately before transplant surgery and continued for 10 weeks after transplantation.

Proven fungal infection developed in nine of 97 patients given itraconazole and in four of 91 patients given fluconazole. Mortality from fungal infection was very low and occurred in only one of the 188 patients. Except for more frequent gastrointestinal adverse effects (nausea, vomiting, diarrhea) with itraconazole, both drugs were well tolerated and neither was associated with hepatotoxicity. Mean trough plasma concentrations of itraconazole were over 250 µg/ml throughout the study and were not affected by H2 histamine receptor antagonists or antacids.

Terbinafine

Itraconazole (28 patients) and terbinafine (27 patients) have been compared in a double-blind, randomized study in tinea capitis. The cure rates at week 12 were 86% and 78% respectively. Adverse events were mild and did not warrant discontinuation of therapy.

Placebo-controlled studies

In a double blind, randomized, placebo-controlled, multi-center 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.

General adverse effects

Most of the reported adverse effects of itraconazole are transient. Gastrointestinal reactions, mild dyspepsia, pyrosis, nausea, vomiting, diarrhea, and epigastric pain are not uncommon. In many of the 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) arrhythmias, the latter being connected with an interaction with terfenadine. Skin rashes and pruritus have been reported. Tumor-inducing effects have not been described.

In patients taking itraconazole capsules for prolonged periods the common adverse effects were nausea and vomiting (in under 10%), hypertriglyceridemia (9%), hypokalemia (6%), raised transaminases (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 for serious adverse liver effects. Thus, itraconazole does not commonly have serious adverse effects on the liver, kidneys, skin, or blood.

Itraconazole: Organs and Systems

Itraconazole: Second-Generation Effects

Drug Administration

Drug formulations

Itraconazole is poorly soluble in water and highly lipophilic. It is available as capsules, as oral and parenteral solutions that both contain hydroxypropyl-P-cyclodextrin as a solubilizer.

Absorption of itraconazole from capsules depends on a low gastric pH and is reduced by fasting and improved by the presence of food and acidic beverages; it is unpredictable in patients with hypochlorhydria. The fmax occurs at 1.5-2 hours. When polyethylene glycol is used as a solvent, the absorption is not as good. Inadequate plasma concentrations are often found in patients receiving cytotoxic drug therapy, which predisposes them to mucositis, poor food intake, and vomiting. The absorption of oral itraconazole seems to be reduced in patients with AIDS.

Systemic absorption of the cyclodextrin carrier after oral administration is negligible. After intravenous administration the cyclodextrin is not metabolized and is almost completely eliminated by glomerular filtration within 24 hours. Although the cyclodextrin enhances the systemic availability of itraconazole, it can have gastrointestinal adverse effects when used in escalating dosages exceeding 400 mg/day.

A dose-ranging study of itraconazole in antifungal prophylaxis in 123 neutropenic patients with hematological malignancies has been reported. The dosing regimens included itraconazole capsules 400, 600, or 800 mg/day and itraconazole cyclodextrin solution 400 and 800 mg/day (with an additional loading with 800 mg of the capsule formulation for 7 days). Ten of twenty-eight patients taking 800 mg/day as a solution withdrew after 1-6 days with severe nausea and vomiting in temporal relation to ingestion of the drug. All the patients who discontinued the solution continued medication with itraconazole capsules in the same dosage without gastrointestinal adverse effects.

Itraconazole: Statins

Itraconazole increases the risk of skeletal muscle toxicity of some statins by increasing their serum concentrations, but not all statins are equally affected. Concomitant use of atorvastatin, lovastatin, and simvastatin with itraconazole should be avoided or the doses should be reduced; fluvastatin and pravastatin have much less potential than other statins for clinically significant interactions with itraconazole and other CYP3A4 inhibitors; the effects of cerivastatin are intermediate.

In a randomized, open, three-way, crossover study, 18 healthy subjects took single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without or with itraconazole 200 mg. Concomitant cerivastatin + itraconazole and pravastatin + itraconazole produced small increases in AUC, Cmax, and half-life (up to 51%, 25%, and 23% respectively). However, itraconazole markedly increased atorvastatin AUC (150%), Cmax (38%), and half-life (30%). Thus, itraconazole markedly increases systemic exposure to atorvastatin, but results in only modest increases in the plasma concentrations of cerivastatin and pravastatin.

Atorvastatin

Itraconazole increases serum concentrations of atorvastatin by inhibiting CYP3A4. In a randomized, double-blind, crossover study in 10 healthy volunteers,itraconazole 200 mg increased the AUC and half-life of atorvastatin 40 mg about three-fold, with a change in Cmax. The AUC of atorvastatin lactone was increased about 4-fold, and the Cmax and half-life were increased more than 2-fold. Itraconazole significantly reduced the Cmax and AUC of 2-hydroxyatorvastatin acid and 2-hydroxyatorvastatin lactone and increased the half-life of 2-hydroxyatorvastatin lactone. The concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should therefore be avoided, or the dose of atorvastatin should be reduced accordingly.

Cerivastatin

Cerivastatin uses a secondary CYP2C8-mediated metabolic pathway, which is unaffected by itraconazole. The effects of itraconazole on the pharmacokinetics of cerivastatin and its major metabolites have been investigated in a randomized, double-blind, crossover study. Inhibition of the CYP3A4-mediated M-l pathway led to raised serum concentrations of cerivastatin, cerivastatin lactone, and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors. However, the effect was modest.

Fluvastatin

The effects of itraconazole 100 mg on the pharmacokinetics of fluvastatin 40 mg have been studied in a randomized, placebo-controlled, crossover study in 10 healthy volunteers. Itraconazole had no significant effect on the Cmax or total AUC of fluvastatin, but slightly prolonged its half-life.

Lovastatin

The effects of itraconazole 100 mg on the pharmacokinetics of lovastatin 40 mg have been studied in a randomized, placebo-controlled, crossover study in 10 healthy volunteers. Itraconazole, even in this low dosage, greatly increased plasma concentrations of lovastatin and its active metabolite, lovastatin acid, and increased the Cmax of lovastatin about 15-fold and the total AUC by more than 15-fold; similarly, the Cmax and total AUC of lovastatin acid were increased about 12-fold and 15-fold respectively.

Pravastatin

The effects of itraconazole 200 mg on the pharmacokinetics of pravastatin have been studied in a randomized, double-blind, crossover study in 10 healthy volunteers. Itraconazole slightly increased the AUC and Cmax of pravastatin, but the changes were not statistically significant; the half-life was not altered.

Simvastatin

The effects of itraconazole 200 mg on the pharmacokinetics of simvastatin have been studied in a randomized, double-blind, crossover study in 10 healthy volunteers. Itraconazole increased the Cmax and AUC of simvastatin and simvastatin acid at least 10-fold. The Cmax and AUC of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold respectively, and the half-life was increased by 25%.

In two cases, rhabdomyolysis was caused by itraconazole in heart transplant recipients taking long-term ciclosporin and simvastatin. To avoid severe myo-pathy, ciclosporin concentrations should be monitored frequently and statins should be withdrawn or the dosage should be reduced, as long as azoles need to be prescribed in transplant recipients. Patients need to be educated about signs and symptoms that require immediate physician intervention.

Itraconazole: Glucocorticoids

Itraconazole can inhibit the metabolic clearance of glucocorticoids by interfering with CYP3A4 and can directly inhibit steroidogenesis, thereby causing serious adverse effects. The effects on different glucocorticoids differ.

Budesonide

Two patients with cystic fibrosis developed profound adrenal failure and impairment of inhaled steroid clearance, resulting in paradoxical Cushing's syndrome, after long-term treatment with itraconazole and inhaled budenoside. Pituitary-adrenal axis and gonadal function was then assessed in 37 patients treated with itraconazole with or without budesonide.

An adrenocorticotropic hormone (ACTH) test (tetracosactide 250 micrograms) was performed in 25 patients with cystic fibrosis taking itraconazole and budesonide and in 12 patients taking itraconazole alone (6 with cystic fibrosis and 6 with chronic granulomatous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma renin activity and follicle-stimulating hormone, luteinizing hormone, progesterone, estradiol, testosterone, and serum inhibin A and B concentrations. ACTH tests performed as part of a pretransplantation program in a further 30 patients with cystic fibrosis were used as controls. Eleven of the twenty-five patients who took both itraconazole and budesonide had adrenal insufficiency.

None of the patients taking itraconazole alone and none of the control patients with cystic fibrosis had an abnormal ACTH test. Mineralocorticoid or gonadal insufficiency was not observed in any patient. Only one patient with an initial pathological ACTH test subsequently normalized; the other 10 patients improved but had not achieved normal adrenal function 2-10 months after itraconazole had been withdrawn.

The effects of itraconazole on the pharmacokinetics and cortisol-suppressing activity of budesonide by inhalation were further investigated in a randomized, double-blind, two-phase, crossover study in 10 healthy subjects who took oral itraconazole 200 mg/day or placebo for 5 days. On day 5, 1 hour after the last dose of itraconazole or placebo, they took budesonide 1000 micrograms by inhalation.

Plasma budesonide and cortisol concentrations were measured up to 23 hours. Itraconazole increased the mean total AUC of inhaled budesonide 4.2-fold (range 1.7-9 and the peak plasma concentration 1.6-fold compared with placebo. The mean half-life of budesonide was prolonged from 1.6 to 6.2 hours. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole compared with placebo, with a 43% reduction in the AUC of plasma cortisol from 0.5 to 10 hours and a 12% reduction in the cortisol concentration measured 23 hours after budesonide, at 8 a.m. Thus, itraconazole markedly increased the systemic exposure to inhaled budesonide. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production.

Dexamethasone

Itraconazole markedly increases both systemic exposure to dexamethasone and its effects. This interaction has been investigated in a randomized, double-blind, placebo-controlled, crossover study. Eight healthy volunteers took either oral itraconazole 200 mg od or placebo for 4 days. On day 4, each subject was given oral dexamethasone 4.5 mg or intravenous dexamethasone sodium phosphate 5.0 mg. Itraconazole reduced the systemic clearance of intravenous dexamethasone by 68%, and increased its AUC and prolonged its half-life more than three-fold; the AUC of oral dexamethasone was increased nearly four-fold and its half-life nearly three-fold. Morning plasma cortisol concentrations at 47 and 71 hours after dexamethasone were significantly lower after itraconazole than placebo.

Methylprednisolone

The interaction of itraconazole with oral methylprednisolone has been examined in a randomized, double-blind, crossover study in 10 healthy volunteers taking either oral itraconazole 200 mg/day or placebo for 4 days. On day 4 each subject took methylprednisolone 16 mg. Itraconazole increased the total AUC of methylprednisolone 3.9-fold compared with placebo, the peak plasma methylprednisolone concentration 1.9-fold, and the half-life 2.4-fold. This effect was probably through inhibition of CYP3A4.

Similar effects were found in a study of the effects of itraconazole on the kinetics of intravenous methylprednisolone in a double-blind, randomized, crossover study in nine healthy volunteers. Itraconazole (200 mg for 4 days) increased the AUC of methylprednisolone (16 mg on day 2.6-fold, and the AUCi2-24 12-fold. The systemic clearance of methylprednisolone was reduced to 40% by itraconazole and the half-life was increased from 2.1 to 4.8 hours. The mean morning plasma cortisol concentration was only 9% of that during the placebo phase. Thus, concomitant itraconazole greatly increased exposure to methylprednisolone during the night-time and led to enhanced adrenal suppression.

The effects of oral itraconazole (400 mg on the first day, then 200 mg/day for 3 days) on the pharmacokinetics of a single oral dose of methylprednisolone 48 mg have been studied in 14 healthy men in a two-period, crossover study. Plasma cortisol concentrations were determined as a pharmacodynamic index. Itraconazole significantly increased the mean AUC of methylprednisolone from 2773 to 7011 hours.µg/ml and the half-life from 3.2 to 5.5 hours. Cortisol concentrations at 24 hours were significantly lower after the administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 versus 109 µg/ml).

Prednisolone

The effects of oral itraconazole (400 mg on the first day then 200 mg/day for 3 days) on the pharmacokinetics of a single oral dose of prednisolone 60 mg or methylprednisolone 48 mg have been studied in 14 healthy men in a two-period, crossover study. Plasma cortisol concentrations were determined as a pharmacodynamic index. The disposition of prednisolone was unchanged.

The effects of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone have been investigated in a double-blind, randomized, crossover study. Ten healthy subjects took either oral itraconazole 200 mg od or placebo for 4 days. On day 4 they took oral prednisolone 20 mg. Itraconazole increased the plasma AUC of prednisolone by 24% and its half-life by 29% compared with placebo. The peak plasma concentration and time to the peak of prednisolone were not affected. Itraconazole reduced the mean morning plasma cortisol concentration, measured 23 hours after prednisolone, by 27%.

The minor interaction of itraconazole with oral prednisolone is probably of limited clinical significance. The susceptibility of prednisolone to interact with CYP3A4 inhibitors is considerably smaller than that of methylprednisolone, and itraconazole and probably also other inhibitors of CYP3A4 can be used concomitantly with prednisolone without marked interaction.

Itraconazole: Statins

Tacrolimus

Tacrolimus concentrations and toxicity are affected by itraconazole.

  • In a 17-year-old man with cystic fibrosis who received a hepato-pulmonary transplant, there was an interaction of itraconazole 600 mg bd with tacrolimus. High trough concentrations of tacrolimus were noted, despite the relatively low dosage (0.1-0.3 mg/kg/day).
  • Another patient experienced an interaction of tacrolimus 0.085 mg /kg bd with itraconazole 200-400 mg per day, with resulting ketoacidosis, neutropenia, and thrombocytopenia, requiring the withdrawal of both drugs.
  • A 30-year-old man with a renal transplant had a more than two-fold increase in blood tacrolimus concentrations after starting to take itraconazole 200 mg/day, accompanied by a reduced glomerular filtration rate and biopsy-proven tacrolimus-associated tubulopathy.

Because of the narrow therapeutic index of tacrolimus, blood concentrations should be monitored particularly carefully when itraconazole is co-administered, and the dosage of tacrolimus may have to be altered.

The interaction of itraconazole (100 mg bd) with tacrolimus has been studied in 28 heart or lung transplant recipients. Tacrolimus blood concentrations were monitored on alternate days for up to 21 days after the start of itraconazole therapy or withdrawal. The dose of tacrolimus was adjusted with the aim of keeping the 12-hour trough blood concentration at 7-12 micrograms/ml.

The mean dose of tacrolimus during itraconazole therapy fell significantly from 8.4 to 2.9 mg/ day. There was no significant change in serum creatinine or liver function tests. In patients in whom itraconazole was withdrawn, the mean dose of tacrolimus required increased significantly from 4.7 to 8.8 mg/day. Thus, substantial changes in the dose of tacrolimus were required both when itraconazole was begun and when it was withdrawn, and it was difficult to maintain tacrolimus blood concentrations within the target range during the first 2 weeks. However, major toxicity or rejection did not occur.

Co-administration of itraconazole may reduce the cost of post-transplant immunosuppression. This interaction is probably due to inhibition of CYP3A4 by itraconazole.

Vinca alkaloids

Enhanced and potentially life-threatening neurotoxicity of vinca alkaloids through concomitant therapy with itraconazole has been the subject of several compelling reports. Enhancement of vincristine neurotoxicity results in polyneuropathy and paralytic ileus. The interaction is reversible, and readminis-tration of vinca alkaloids may be safe after a prolonged washout. The mechanism has not been formally elucidated, but may be either competition for oxidative metabolism, leading to increased systemic exposure, or inhibition of the transmembrane P glycoprotein efflux pump, leading to increased intracellular concentrations of vinca alkaloids. The concomitant use of itraconazole and vinca alkaloids is therefore contraindi-cated.

Two adults with acute lymphoblastic leukemia developed unusually severe neurotoxicity caused by vincristine, which was probably the result of an interaction with itraconazole suspension.

Warfarin

Itraconazole can alter warfarin concentrations.

Following the addition of itraconazole to a treatment regimen comprising warfarin, ranitidine, and terfenadine, cardiac dysrhythmias developed in a 62-year-old man. The signs and symptoms included prolongation of the QT interval and ventricular fibrillation.

This particular regimen apparently resulted in a second interaction, since unexpectedly very high concentrations of terfenadine were found. The phenomenon has been described by others, with a marked rise in terfenadine serum concentrations, and increased toxicity of the drug during concurrent ingestion of itraconazole. The mechanism is not known, but it is likely to be related to inhibition of CYP3A4.

Zolpidem

Zolpidem is mainly transformed by CYP3A4. However, itraconazole 200 mg did not alter the pharmacokinetics and pharmacodynamics of zolpidem 10 mg in 10 healthy volunteers. Therefore, zolpidem may be used in normal or nearly normal doses together with itraconazole.

Itraconazole: Drug-Drug Interactions

Amphotericin

The in vitro effects of the combination of amphotericin with itraconazole was tested using six strains of A. fumi-gatus, and an antagonistic effect was found after pretreat-ment for all strains in vitro and for one strain in a mouse model of aspergillosis.

The effect of the combination of itraconazole with amphotericin on liver enzyme activities has been studied retrospectively in 20 patients with hematological malignancies or chronic lung disease complicated by fungal infection or colonization. They took itraconazole 200-600 mg/day for a median of 143 (range 44 days. Nine had no abnormal liver function tests, including periods of high concentrations of itraconazole (over 5000 µg/ml) and its active hydroxylated metabolite; only one had received concomitant amphotericin. All of the 11 patients with liver function abnormalities had received concomitant amphotericin.

For each patient, liver function abnormalities were greatest during the time of concomitant therapy with both antifungal drugs. Although liver enzyme abnormalities are uncommon with amphotericin, and although this retrospective analysis was subject to several flaws and potential biases, it nevertheless suggests that hepatotoxicity should be carefully monitored if itraconazole and amphotericin are co-administered.

Antihistamines

It seems likely that combining itraconazole with astemi-zole and terfenadine will lead to increased effects of these antihistamines.

Barbiturates

Barbiturates lower itraconazole concentrations.

Benzodiazepines

The effect of itraconazole on the single oral dose pharma-cokinetics and pharmacodynamics of estazolam has been studied in a double-blind, randomized, crossover study in 10 healthy male volunteers, who took oral itraconazole 100 mg/day or placebo for 7 days and on day 4 a single oral dose of estazolam 4 mg. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analogue Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam. There was no significant difference between the placebo and itraconazole phases in peak plasma concentration, clearance, and half-life. Similarly, psycho-motor function was unaffected. These findings suggest that CYP3A4 is not involved to a major extent in the metabolism of estazolam.

In a study of the effects of itraconazole 200 mg/day and rifampicin 600 mg/day on the pharmacokinetics and pharmacodynamics of oral midazolam 7.5-15 mg during and 4 days after the end of the treatment, switching from inhibition to induction of metabolism caused an up to 400-fold change in the AUC of oral midazolam.

Bupivacaine

The interaction of itraconazole 200 mg orally od for 4 days with a single intravenous dose of racemic bupivacaine (0.3 mg /kg given over 60 minutes) has been examined in a placebo-controlled crossover study in 10 healthy volunteers. Itraconazole reduced the clearance of .R-bupivacaine by 21% and that of 5-bupivacaine by 25%, but had no other significant effects on the pharmacokinetics of the enantiomers. Reduction of bupivacaine clearance by itraconazole is likely to increase steady-state concentrations of bupivacaine enantiomers by 20-25%, and this should be taken into account in the concomitant use of itraconazole and bupivacaine.

Buspirone

The interaction of itraconazole with the active l-(2-pyrimidinyl)-piperazine metabolite of buspirone has been studied after a single oral dose of buspirone 10 mg. Itraconazole reduced the mean AUC of the metabolite by 50% and the Cmax by 57%, whereas the mean AUC and Cmax of the parent drug were increased 14.5-fold and 10.5-fold respectively. Thus, itraconazole caused relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspirone, although it had major effects on the concentrations of buspirone after a single oral dose.

Busulfan

Reduced elimination and increased toxicity of busulfan co-administered with itraconazole has been postulated.

Carbamazepine

Low and sometimes very low serum concentrations of itraconazole have been seen during concurrent therapy of itraconazole with carbamazepine.

Ciclosporin

The combination of itraconazole with ciclosporin leads to a marked increase in blood ciclosporin concentrations, and this can result in a rise in serum creatinine, clearly pointing to renal damage as a result of the high ciclosporin concentrations. However, an interaction has not been demonstrated in all cases.

Two cases of rhabdomyolysis caused by itraconazole in heart transplant recipients taking long-term ciclosporin and simvastatin have been reported. To avoid severe myopathy, ciclosporin concentrations should be monitored frequently and statins should be withdrawn or the dosage should be reduced, as long as azoles need to be prescribed in transplant recipients. Patients need to be educated about signs and symptoms that require immediate physician intervention.

Citrate-phosphate buffer

The citrate-phosphate buffer used to facilitate the absorption of dideoxyinosine (didanosine), prescribed for the treatment of AIDS, may interfere with the absorption of itraconazole.

Clarithromycin

A report of three HIV-negative patients has suggested that concomitant therapy with itraconazole and clarithromycin can lead to increased clarithromycin exposure, with an increased metabolic ratio, possibly related to itraconazole's effect on CYP3A4. Nevertheless, in none of the three reported individuals were there adverse effects from this presumed interaction.

Clozapine

Itraconazole 200 mg had no significant effect on serum concentrations of clozapine 200-550 mg/day or desmethylclozapine in 7 schizophrenic patients.

Digoxin

Itraconazole inhibits the elimination of digoxin, eventually leading to toxicity.

Itraconazole increases the digoxin AUC0_72 by about 50%, and reduces its renal clearance by about 20%. Apart from inhibition of the renal secretion of digoxin, which is probably mediated by inhibition of P glycoprotein, a study in guinea pigs also showed significantly reduced biliary excretion of digoxin by itraconazole, suggesting that the interaction between itraconazole and digoxin may not only be due to a reduction in renal clearance, but also to a reduction in the metabolic clearance of digoxin by itraconazole.

The importance of this interaction has been emphasized by a report of two renal transplant patients who had digoxin toxicity when they took itraconazole concurrently.

Famotidine

Famotidine 40 mg/kg/day reduced the peak and trough concentrations of itraconazole 200 mg/kg/day by about 35% in 18 patients undergoing chemotherapy for hematological malignancies.

Fentanyl

Fentanyl is a substrate of CYP3A4, CYP2C9, and CYP2C19. However, in one study, the pharmacokinetics and pharmacodynamics of fentanyl 3 micrograms/kg were similar after itraconazole 200 mg and placebo in 10 healthy volunteers.

An interaction of itraconazole with fentanyl has been reported in a 67-year-old man with cancer on a stable dose of transdermal fentanyl 50 micrograms/hour. He took itraconazole 200 mg bd for oropharyngeal candidiasis, and 24 hours later developed signs of opioid toxicity, which was reversed by withdrawal of fentanyl and replacement with short-acting opioids.

This may be an interaction to which only some individuals are susceptible.

Flucytosine

The activity of itraconazole against black fungi can be augmented by combining it with flucytosine; the combination has prevented the development of flucytosine resistance.

Itraconazole: Second-Generation Effects

Teratogenicity

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

Susceptibility Factors

Age

The safety, tolerability, and pharmacokinetics of itraconazole and its active metabolite hydroxyitraconazole after administration of itraconazole solution in hydroxy-propyl-P-cyclodextrin have been investigated in a multi-center 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 hydro-xypropyl-P-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 x 106/1) 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 7.46 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, suspected drug interactions, abdominal pain, and constipation. The most common adverse events considered definitely or possibly related to itraconazole were vomiting, abnormal liver function, and abdominal pain.

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.

Other features of the patient

Adverse effects due to drug-drug interactions are not expected in diabetic patients using insulin and oral hypo-glycemic drugs that are not metabolized by CYP3A4 (for example tolbutamide, gliclazide, glibenclamide, glipizide, and metformin). The pharmacokinetic and safety data from clinical trials and postmarketing surveillance have been reviewed to assess the safety of itraconazole in diabetic patients with onychomycosis or dermatomycosis.

Postmarketing surveillance, including all adverse event reports in patients taking itraconazole concomitantly with insulin or an oral hypoglycemic drug, revealed 15 reports suggestive of hyperglycemia and nine reports suggestive of hypoglycemia. In most patients there was no change in antidiabetic effect. From clinical trials in 189 diabetic patients taking itraconazole for various infections, one itraconazole-related adverse event was recorded; this was a case of aggravated diabetes in a renal transplant patient who was also taking ciclosporin.

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