Itraconazole [Sporanox 100mg Capsules]
Drug Nomenclature
Pharmacopoeias in Europe
European Pharmacopoeia, 6th ed. (Itraconazole)
A white or almost white powder. Practically insoluble in water very slightly soluble in alcohol freely soluble in dichloromethane sparingly soluble in tetrahy-drofuran. Protect from light.
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Itraconazole: Organs and Systems
Cardiovascular
Ventricular fibrillation has been attributed to itracona-zole-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 Itraconazole was withdrawn.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 ketocona-zole, 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.
Psychological, 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, occurring either in isolation or with hypertension, has been reported regularly in a small fraction of patients. 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. 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.
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 effects 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.
In 50 women with acute vaginal candidiasis, adverse effects were reported in 17 (35%), nausea in seven, headache in six, dizziness in three, and bloating in three, while aspartate transaminase activity was raised in one.
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 perphena-zine, 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.
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 maculo-papular 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 reduced minimal erythema dose for both UVB (0.12 J/cm and UVA (20.1 J/cm, negative photopatch testing, and a positive photochal-lenge. 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 steroids, 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). Incidence rates for current use were 15 per 10 000 person-years (1 for itraconazole, 11.1 (3 for terbinafine, 10 (1 for fluconazole, and 4.6 (0 for griseofulvin. Cutaneous disorders associated with the use of oral antifungal drugs in this study were all mild.
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 whom 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 Meniere’s disease.
Itraconazole: Dosage and Administration
Reconstitution and Administration
Itraconazole is administered orally or by IV infusion.
Oral Administration
Bioavailability of oral itraconazole varies depending on whether the drug is administered as capsules or as an oral solution, and the manufacturer states that these preparations should not be used interchangeably. Itraconazole oral solution (not itraconazole capsules) is indicated for the treatment of oropharyngeal or esophageal candidiasis. While itraconazole oral solution should be administered without food if possible, itraconazole capsules should be administered with a full meal to ensure maximal absorption of the drug. The possibility that GI absorption of the drug may be decreased in patients with hypochlorhydria, which has been reported in HIV-infected individuals, should be considered.
IV Infusion
Commercially available itraconazole injection must be diluted prior to IV infusion. The entire contents of an ampul containing itraconazole injection (250 mg) should be added to the 0.9% sodium chloride injection diluent (50 mL) provided by the manufacturer to provide a solution containing 3.33 mg/mL in a resultant volume of 75 mL.
Correct preparation and administration of the itraconazole solution are necessary to ensure maximum safety and efficacy. It is critical that the appropriate ratio of itraconazole to diluent be used and that a final concentration of 3.33 mg/mL be maintained to provide a stable admixture and avoid formation of a precipitate.
Itraconazole injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. To provide a 200-mg dose of itraconazole, the diluted solution should be mixed gently and then 15 mL of the solution should be withdrawn and discarded. The remaining 60 mL of diluted solution containing 3.33 mg/mL should be given by IV infusion over 60 minutes.
The infusion should be given using a controlled-infusion device, the infusion set provided by the manufacturer, and a dedicated IV line. Itraconazole should not be admixed with other drugs and should not be administered through the same IV line as other drugs. Following completion of the infusion, the manufacturer recommends that the infusion set be flushed via the 2-way stopcock using 15-20 mL of 0.9% sodium chloride injection over 30 seconds to 15 minutes; the entire IV line should then be discarded. Bacteriostatic sodium chloride solution should not be used for the flush solution since the compatibility of itraconazole solution with flush solutions other than 0.9% sodium chloride is not known.
Dosage
Because of differences in oral bioavailability, itraconazole capsules and oral solution should not be used interchangeably on a mg-for-mg basis.
Dosage of itraconazole capsules should be based on the type and severity of infection, identity of the causative organism, and patient’s response to therapy. The drug appears to undergo saturable metabolism in the liver; therefore, increases in dosage can result in more than proportional increases in plasma concentrations.
For the treatment of life-threatening systemic fungal infections, IV itraconazole or oral itraconazole capsules should be initiated using a loading dosage. If IV itraconazole is used initially, the recommended loading dosage in adults is 200 mg IV twice daily for 4 consecutive doses followed by 200 mg once daily thereafter.
Although clinical studies evaluating the safety and efficacy of oral itraconazole capsules did not include a loading dosage, based on pharmacokinetic considerations, the manufacturer and some clinicians state that oral itraconazole capsules should be initiated in life-threatening infections in adults using an initial loading dose of 200 mg 3 times daily (600 mg daily) for the first 3-4 days of therapy. Subsequent therapy then can be continued at the usual oral dosage of 200-400 mg daily.
The manufacturer states that itraconazole therapy should be continued for at least 3 months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. Some clinicians state that while the optimal duration of therapy for serious fungal infections has not been established, itraconazole therapy probably should be continued for at least 12 months for disseminated or chronic pulmonary histoplasmosis and for 6-12 months for blastomycosis. An inadequate period of treatment can result in recurrence of active infection.
Aspergillosis
For the treatment of pulmonary or extrapulmonary aspergillosis in patients who do not respond to or cannot tolerate amphotericin B, the recommended adult dosage of itraconazole capsules is 200-400 mg daily. Higher oral dosages (i.e., 600 mg daily) also have been used for such infections, and some clinicians recommend that itraconazole dosages of at least 400 mg daily be used for the treatment of invasive aspergillosis. When IV itraconazole is used for the treatment of aspergillosis in adults, the manufacturer recommends that therapy be initiated with a dosage of 200 mg IV twice daily for 4 doses, then dosage decreased to 200 mg IV once daily. Safety and efficacy of IV itraconazole administered for longer than 14 days has not been established, and itraconazole therapy should be completed using oral itraconazole capsules.
Blastomycosis or Histoplasmosis
For the treatment of pulmonary or extrapulmonary blastomycosis or for nonmeningeal histoplasmosis, the manufacturer recommends that itraconazole capsules be administered to adults in an initial dosage of 200 mg once daily. If there is no apparent improvement or there is evidence of progression of the fungal infection at this dosage, the manufacturer recommends increasing oral itraconazole dosage in 100-mg increments daily up to a maximum dosage of 400 mg daily. Oral dosages exceeding 200 mg daily should be divided into 2 doses daily.
For the treatment of mild to moderate pulmonary blastomycosis or nonmeningeal, disseminated blastomycosis, some clinicians suggest that oral itraconazole be given in a dosage of 200-400 mg daily for at least 6 months (12 months in those with bone disease).
For the treatment of histoplasmosis, some clinicians recommend that oral itraconazole be given in a dosage of 200 mg once or twice daily for 12-24 months for the treatment of chronic pulmonary infections or for 6-18 months for the treatment of mild to moderate, nonmeningeal, disseminated infections. When IV itraconazole is used for the treatment of blastomycosis or histoplasmosis in adults, the manufacturer recommends that therapy be initiated with a dosage of 200 mg IV twice daily for 4 doses, then dosage decreased to 200 mg IV once daily. Safety and efficacy of IV itraconazole administered for longer than 14 days have not been established, and more prolonged itraconazole therapy should be completed using oral itraconazole capsules.
Oropharyngeal and Esophageal
Candidiasis For the treatment of oropharyngeal or esophageal candidiasis, the recommended dosage of itraconazole oral solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and then swallowed. The recommended dosage of itraconazole oral solution for the treatment of oropharyngeal candidiasis is 200 mg (20 mL) daily for 1-2 weeks. Clinical signs and symptoms generally resolve within several days.
When itraconazole oral solution is used for the treatment of oropharyngeal candidiasis in patients who have not responded to or are refractory to oral fluconazole therapy, the recommended itraconazole dosage is 100 mg (10 mL) twice daily. A response to itraconazole in these patients generally is evident within 2-4 weeks; however, relapse may be expected shortly after the drug is discontinued.
Data are limited to date regarding the safety of long-term use of itraconazole oral solution (i.e., longer than 6 months). The recommended dosage of itraconazole oral solution for the treatment of esophageal candidiasis is 100 mg (10 mL) daily; however, depending on the patient’s response to the drug, a dosage up to 200 mg (20 mL) daily may be given. Oral itraconazole therapy should be administered for a minimum of 3 weeks in patients with esophageal candidiasis, and should be continued for 2 weeks after symptoms resolve.
Sporotrichosis
If itraconazole is used for the treatment of sporotrichosis, some clinicians recommend that adults receive an oral dosage of 100-200 mg once daily for 3-6 months for cutaneous or lymphocutaneous infections or an oral dosage of 200 mg twice daily for 12 months for osteoarticular infections.
Onychomycosis
For the treatment of onychomycosis (tinea unguium) of the toenails (with or without fingernail involvement), the recommended oral dosage of itraconazole capsules is 200 mg once daily for 12 consecutive weeks. A pulse-dosing regimen that involves administering itraconazole capsules in a dosage of 400 mg once daily for one week each month for 3 months also has been effective for the treatment of tinea unguium of the toenails.
For the treatment of onychomycosis involving only the fingernails, itraconazole capsules are given in a pulse-dosing regimen that involves administering 200 mg of the drug twice daily during the first week, no itraconazole during weeks 2-4, and 200 mg of itraconazole twice daily during the fifth week.
Empiric Therapy in Febrile Neutropenic Patients
For empiric therapy of presumed fungal infections in febrile neutropenic patients, itraconazole therapy is initiated with a dosage of 200 mg IV twice daily for 4 doses, then dosage is decreased to 200 mg IV once daily for up to 14 days; therapy should then be continued with itraconazole oral solution given in a dosage of 200 mg (20 mL) twice daily until clinically important neutropenia has resolved. Safety and efficacy of itraconazole administered for longer than 28 days for this indication are not known.
Prevention of Fungal Infections in HIV-infected Individuals
Primary Prophylaxis
If itraconazole is used for primary prophylaxis against cryptococcosis in HIV-infected adults and adolescents with CD+ T-cell counts less than 50/mm3, the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) recommends that oral itraconazole capsules be given in a dosage of 200 mg once daily. If itraconazole is used for primary prophylaxis against cryptococcosis in HIV-infected infants and children with severe immunosuppression, a dosage of 2-5 mg/kg orally every 12-24 hours is recommended by the USPHS/IDSA.
For primary prophylaxis against histoplasmosis in adults and adolescents with human immunodeficiency virus (HIV) infection and CD4+ T-cell counts less than 100/mm3, the USPHS/IDSA recommends that itraconazole capsules be given in a dosage of 200 mg once daily.
For primary prophylaxis against histoplasmosis in HIV-infected infants and children with severe immunosuppression, a dosage of 2-5 mg/kg orally every 12-24 hours is recommended by the USPHS/IDSA.
Prevention of Recurrence
When itraconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of coccidioidomycosis or histoplasmosis in HIV-infected individuals whose fungal infection has been adequately treated, the USPHS/IDSA recommends that adults and adolescents receive oral itraconazole capsules in a dosage of 200 mg twice daily and that infants and children receive an oral dosage of dosage of 2-5 mg/kg every 12-48 hours.
When itraconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of cryptococcosis in HIV-infected individuals whose fungal infection has been adequately treated, the USPHS/IDSA recommends that adults and adolescents receive oral itraconazole capsules in a dosage of 200 mg once daily and that infants and children receive an oral dosage of 2-5 mg/kg every 12-24 hours.
When oral itraconazole is used for long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse of mucocutaneous candidiasis, the USPHS/IDSA recommends that HIV-infected adults or adolescents with frequent or severe recurrences of oropharyngeal, esophageal, or vaginal candidiasis receive itraconazole oral solution in a dosage of 200 mg once daily and that HIV-infected infants and children with frequent or severe recurrences of esophageal candidiasis receive the oral solution in a dosage of 5 mg/kg once daily.
Suppressive or maintenance therapy to prevent recurrence or relapse of candidiasis, coccidioidomycosis, cryptococcosis, or histoplasmosis in HIV-infected individuals generally is continued for life. However, the USPHS/IDSA states that consideration can be given to discontinuing such therapy for prophylaxis against recurrence or relapse of cryptococcosis in certain individuals if immune recovery has occurred as a result of potent antiretroviral therapy.
Dosage in Renal and Hepatic Impairment
Adjustment of oral itraconazole dosage in patients with renal impairment does not appear to be necessary. Itraconazole injection should not be administered to patients with renal impairment (i.e., creatinine clearance less than 30 mL/minute) since severe renal impairment reduces clearance of hydroxypropyl-b-cyclodextrin (an excipient contained in itraconazole injection).
While the effect of hepatic impairment on itraconazole pharmacokinetics currently remains to be elucidated, the manufacturer states that plasma concentrations of the drug should be monitored carefully in patients with such impairment.
Adverse Effects
The most common adverse effects associated with itraconazole include dyspepsia, abdominal pain, nausea, vomiting, constipation, diarrhoea, headache, and dizziness. Others include allergic reactions such as pruritus, rash, urticaria, and angioedema. Isolated cases ofthe Stevens-Johnson syndrome have been associated with itraconazole. An increase in liver enzyme values has occurred in some patients and cases of hepatitis and cholestatic jaundice have been observed, especially in those treated for more than one month.
There have been rare cases of liver failure and death. Heart failure and pulmonary oedema have been reported rarely and serious cardiovascular events including arrhythmias and sudden death have been attributed to drug interactions in patients receiving itraconazole (see Interactions, below). Alopecia, oedema, and hypokalaemia have also been associated with prolonged use.
Menstrual disorders and peripheral neuropathy have been reported in a few patients.
Incidence of adverse effects
Itraconazole 50 to 400 mg daily for a median of 5 months was considered to be well tolerated in 189 patients with systemic fungal infections. of 86 patients with underlying disease, including 49 with AIDS, 16 with diabetes, and 23 with malignancy, nausea and vomiting occurred in 19 patients, hypertriglyceridaemia in 16, hypokalaemia in 11, and elevated liver enzyme values in 13. The role of itraconazole in hypertriglyceridaemia could not be assessed because all the samples were not drawn in the fasting state and hypertriglyceridaemia is a complication of HIV infection.
Gynaecomastia occurred in 2 patients, 1 of whom also took spironolactone.
Rash occurred in 4 patients. Of 49 patients taking itraconazole 100 to 400 mg daily for up to 39 months, 23 did not experience adverse effects during treatment, while 6 had nausea and vomiting, 5 developed oedema, and 2 developed hypertension 3 of the patients who developed oedema and 1 who became hypertensive were diabetic. Three patients stopped itraconazole, 1 due to vomiting, 1 to leucopenia, and 1 to nephrotic syndrome. The patient with nephrotic syndrome had pre-existing oedema and hypertension the syndrome cleared when itraconazole was stopped.
Effects on the heart
Between September 1992, when itraconazole was approved in the USA, and April 2001, the FDA had received 58 reports of potential cases of heart failure associated with itraconazole. There had been 28 patients admitted to hospital, and 13 had died. However, a causal relationship was difficult to prove. Overall, 43 patients had risk factors or diseases which might confound an association between the use of itraconazole and development of heart failure.
Unpublished studies in dogs and humans had suggested a negative inotropic effect with intravenous itraconazole. In August 2001, the UK CSM published a similar alert. By this time, about 67 million patients worldwide had received itraconazole and there had been 75 spontaneously reported cases of suspected heart failure and an additional 63 reports of oedema suggestive of heart failure associated with oral formulations there had been only 1 report of suspected heart failure in the UK. The CSM considered that the risk of heart failure with itraconazole was low, especially in young healthy patients receiving short courses of treatment (e.g. for vulvovaginal candidiasis).
However, the risks appeared to be higher for older patients, patients with pre-existing heart disease or risk factors for heart failure, and for those receiving high doses and longer treatment courses (e.g. for onychomycosis). The CSM therefore advised caution when prescribing itraconazole to patients at risk of heart failure, whereas the FDA contra-indicated it for the treatment of onychomycosis in patients with evidence of ventricular dysfunction.
Precautions
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Itraconazole has caused abnormalities in fetal development in rodents and is therefore contra-indicated in pregnancy.
For further information, see Pregnancy, under Precautions of Fluconazole.
Itraconazole should be avoided in patients with hepatic impairment. Liver function should be monitored if treatment lasts more than one month or if there are symptoms suggestive of hepatitis. Treatment should be stopped if abnormal liver function is detected.
Plasma-itraconazole concentrations should be monitored in patients with active liver disease and the dosage adjusted if necessary. Dose adjustments may also be required in some patients with renal impairment. Licensed product information warns that the use of intravenous preparations of itraconazole formulated with hydroxypropylbetadex is contra-indicated in patients with a creatinine clearance of less than 30 mL/minute.
Itraconazole should be stopped if neuropathy develops. Itraconazole should not be used for the treatment of less severe fungal infections such as onychomycosis in patients with evidence of, or a history of, ventricular dysfunction such as heart failure. Hypochlorhydria, which may be present in patients with AIDS, can reduce absorption of itraconazole. In this case absorption may be improved by giving itraconazole with an acidic drink, such as a cola beverage.
Breast feeding
Breast feeding while receiving itraconazole is not recommended by the manufacturer although only small amounts of itraconazole are distributed into breast milk.
Interactions
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Enzyme-inducing drugs such as carbamazepine, isoniazid, nevirapine, phenobarbital, phenytoin, rifabutin, or rifampicin may decrease plasma concentrations of itraconazole sufficiently to reduce its effectiveness. Conversely, enzyme inhibitors such as clarithromycin, erythromycin, HIV-protease inhibitors, including ritonavir-boosted HIV-protease inhibitors, may increase plasma concentrations of itraconazole. Use of drugs that reduce stomach acidity, such as antimuscarinics, antacids, proton pump inhibitors, and histamine H2-receptor antagonists, may reduce the absorption of itraconazole. Like other triazole antifungals, itraconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP3A4, and may increase plasma concentrations of other drugs reliant upon it for their metabolism.
This increases the risk of adverse effects and such combinations should be given with caution and careful monitoring, if at all.
Drugs so affected may include:
- antiarrhythmics such as dofetilide and quinidine
- antiepileptics such as carbamazepine (which in turn decreases the concentration of the antifungal, see above)
- antihistamines such as astemizole and terfenadine
- the antimycobacterial rifabutin (which again also decreases antifungal concentrations)
- antineoplastics such as busulfan, docetaxel, and the vinca alkaloids
- antipsychotics such as pimozide and sertindole
- anxiolytics and sedatives such as buspirone
- benzodiazepines such as alprazolam, diazepam, midazolam, and triazolam
- calcium channel Mockers such as verapamil, and the dihydropyridines felodipine, nifedipine, and nisol-dipine (see also below)
- cardiac glycosides such as digoxin
- some corticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone
- the coumarin anticoagulant warfarin
- ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, and methylergometrine
- the gastrointestinalprokinetic cisapride
- HIV-protease inhibitors such as indinavir, ritonavir, and saquinavir (concentrations of the antifungal may be increased in turn by indinavir, ritonavir, or co-formulated lopinavir-ritonavir, but not by saquinavir)
- immunosuppressants such as ciclosporin, sirolimus, and tacrolimus
- opioids such as alfentanil and levacetylmethadol
- some oral hypoglycaemics
- the phosphodiesterase inhibitors sildenafil and var-denafil
- statins (HMG Co-A reductase inhibitors) such as atorvastatin, lovastatin, and simvastatin
Where drugs metabolised via CYP3A4 also prolong the QT interval, the risk of serious cardiovascular effects such as torsade de pointes means that the combination should be avoided this includes astemizole, cisapride, dofetilide, levacetylmethadol, pimozide, quinidine, sertindole, and terfenadine. Care is also required with calcium channel Mockers, which may increase the risk of congestive heart failure if given together, and nisoldipine in particular is considered contra-indicated. Use with the statins is also best avoided because of the risk of muscle damage.
Immunosuppressants
Fatal hepatitis occurred in a 68-year-old woman after 2 months of use of itraconazole and leflunomide. The authors suggested that the combined hepatotoxicity of both drugs might have accounted for this.
Metal ions
Didanosine in a formulation containing aluminium and magnesium ion buffering agents could reduce the absorption of itraconazole due to the resultant increase in gastric pH.
Antimicrobial Action
Itraconazole is a triazole antifungal drug that in sensitive fungi inhibits cytochrome P450-dependent enzymes resulting in impairment of ergosterol synthesis in fungal cell membranes. It has a slightly wider spectrum of activity than ketoconazole. It is active against Aspergillus spp., Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Epidermophyton spp., Histoplasma capsulatum, Malassezia furfur, Microsporum spp., Paracoccidioides brasiliensis, Sporothrix schenckii, and Trichophyton spp. Itraconazole also has some antiprotozoal activity againstLeishmania spp. Acquired resistance to itraconazole is rare but ketoco-nazole-resistant strains of Candida albicans have been found to be cross resistant to itraconazole.
Microbiological interactions
Synergistic antifungal effects were seen in vitro with terbinafine and itraconazole against strains of Candida albicans and Scedosporium prolificans. For effects on the antifungal activity of azoles when given with amphotericin B.
Resistance
For a discussion of increasing resistance of Candida spp. to azoles, see under Antimicrobial Action of Fluconazole. Decreased susceptibility to itraconazole and cross-resistance to fluconazole has been reported in C albicans isolated from patients with AIDS given long-term prophylaxis with itraconazole.l Aspergillus fumigatus resistant to itraconazole has also been seen.
Pharmacokinetics
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Itraconazole is absorbed from the gastrointestinal tract when given orally either as capsules containing itraconazole coated onto sugar spheres or as an oral liquid formulated with hydroxypropylbetadex. Absorption from the capsule formulation is enhanced by an acidic gastric environment and is greatest when doses are taken with food absorption from the oral liquid is not dependent on an acid environment, and absorption is greatest in the fasting state.
Peak plasma concentrations are achieved between 1.5 and 5 hours after a dose of either formulation, and steady state is reached within 15 days during daily dosing. Peak plasma concentrations at steady state of about 2 micrograms/mL have been reported after daily doses of 200 mg. Bioavailability increases with doses of 100 to 400 mg in such a manner as to suggest that itraconazole undergoes saturable metabolism. Itraconazole is highly protein bound only 0.2% circulates as free drug. Itraconazole is widely distributed but only small amounts diffuse into the CSF.
Concentrations attained in the skin, sebum, pus, and many organs and tissues are several times higher than simultaneous plasma concentrations. Therapeutic concentrations of itraconazole remain in the skin and mucous membranes for 1 to 4 weeks after the drug is stopped. Small amounts are distributed into breast milk. Itraconazole is metabolised in the liver mainly by cytochrome P450 isoenzyme CYP3A4.
The major metabolite, hydroxyitraconazole, has antifungal activity comparable with that of itraconazole. Itraconazole is also excreted as inactive metabolites in the bile or urine 3 to 18% is excreted in the faeces as unchanged drug. Small amounts are eliminated in the stratum cor-neum and hair. Itraconazole is not removed by dialysis. The elimination half-life following a single 100-mg dose has been reported as 20 hours, increasing to 30 to 40 hours with continued use.
Uses and Administration
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Itraconazole is a triazole antifungal given orally for the treatment of oropharyngeal and vulvovaginal candidiasis, for pityriasis versicolor, for dermatophytoses unresponsive to topical treatment, for onychomycosis, and for systemic infections including aspergillosis, blastomycosis, candidiasis, chromoblastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioidomycosis, and sporotrichosis. It is also given for the prophylaxis of fungal infections in immunocompromised patients. The place of itraconazole in the treatment of fungal infections is discussed in the various sections under Choice of Antifungal.
Doses of itraconazole oral liquid and capsules are not equivalent and may not be used interchangeably.
In the UK, itraconazole oral liquid is licensed for use in oral and oesophageal candidiasis in a dose of 200 mg daily for 1 week it may be taken as a single daily dose, or, preferably, in 2 divided doses, the liquid being retained in the mouth for 20 seconds before swallowing. if there is no response after a week, treatment may be continued for a further week.
In the USA, a similar regimen is licensed for oropharyngeal candidiasis, but in oesophageal candidiasis an alternative regimen of 100 mg daily for at least 3 weeks is preferred, although the dose may be increased to 200 mg daily if necessary.
For patients with fluconazole-resistant infections the dose in the UK is 100 to 200 mg twice daily for 2 weeks if there is no response, 100 mg twice daily may be given for a further 2 weeks. In the USA the recommended dose is 100 mg twice daily. Itraconazole oral liquid is also licensed in the UK for prophylaxis of susceptible fungal infections in immunocompromised patients, in doses of 5 mg/kg daily, in 2 divided doses. The following oral doses all apply to itraconazole capsules. The dose in oropharyngeal candidiasis is 100 mg (or 200 mg in patients with AIDS or neutropenia) daily for 15 days. Vulvovaginal candidiasis may be treated with itraconazole 200 mg twice daily for 1 day.
Pityriasis versicolor may be treated with itraconazole 200 mg daily for 7 days.
For dermatophytoses the dose is 100 mg daily for 15 days or 200 mg daily for 7 days in tinea corporis or tinea cruris doses are 100 mg daily for 30 days or 200 mg twice daily for 7 days in tinea pedis or tinea manuum.
For nail infections the dose is 200 mg daily for 3 months or pulse therapy with 200 mg twice daily for 7 days repeated once (for fingernails) or twice (for toenails) after drug-free intervals of 21 days.
For systemic infections, itraconazole capsules are given in usual doses of 100 to 200 mg once daily, increased to 200 mg twice daily for invasive or disseminated infections, including cryptococcal meningitis. In life-threatening infections a loading dose of 200 mg three times daily for 3 days has been given. A dose of 200 mg daily is used for primary or secondary prophylaxis in neutropenic patients or those with AIDS. Absorption may be impaired in these patients and monitoring of plasma concentrations is advised with an increase in dose to 200 mg twice daily if necessary.
This higher dose is recommended routinely by some authorities in the USA such as the Centers for Disease Control and Prevention. Itraconazole may also be given by intravenous infusion in a dose of 200 mg given twice daily over 1 hour for two days, then 200 mg daily thereafter.
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Administration
HIGH DOSES
Doses of itraconazole 600 mg daily in two divided doses for 3 to 16 months were used in 8 patients with systemic mycoses resistant to conventional therapy. Two patients with AIDS and cryptococcal meningitis failed to respond and 2 who responded initially later relapsed or developed progressive disease when the dose was reduced. The main adverse effects were hypokalaemia, hypertension, and oedema possibly associated with adrenal suppression. In a patient with cerebral aspergillosis, itraconazole 800 mg daily for 5 months then 400 mg daily for a further 4 / months produced complete resolution of cerebral lesions.
Administration in children and neonates
Itraconazole has been used in children in the treatment of tinea capitis. Doses were 50 mg daily by mouth for those below 20 kg and 100 mg daily for those weighing 20 kg or more. A review of the use of itraconazole in children considered oral itraconazole to be safe and effective against most fungal organisms causing superficial infections. Itraconazole was given to 2 premature infants with disseminated candidiasis in a dose of 10 mg/kg daily in two divided doses for 3 or 4 weeks without adverse effects.
Treatment was successful in both infants. Although itraconazole oral liquid is not licensed for use in children in the UK, and the capsules are only licensed from 12 years of age, the BNFC suggests the following daily oral doses, given as a single dose (unless otherwise specified):
for oropharyngeal candidiasis:
- 1 month to 12 years of age, 3 to 5 mg/kg (to a maximum of 100 mg) daily for 15 days up to 200 mg daily may be given to patients with neutropenia or AIDS
- 12 to 18 years of age, 100 mg (200 mg in those with neutropenia or AIDS) daily for 15 days
for dermatophyte infections:
- 1 month to 12 years of age, 3 to 5 mg/kg daily this is given to a maximum of 200 mg daily for 7 days (pityriasis versicolor), to a maximum of 100 mg daily for 15 days (tinea corporis and tinea cruris), or to a maximum of 100 mg daily for 30 days (tinea pedis and tinea manuum)
- 12 to 18 years of age, 200 mg daily for 7 days (pityriasis versicolor) 100 mg daily for 15 days or as in pityriasis (tinea corporis and tinea cruris) or 100 mg daily for 30 days or 200 mg twice daily for 7 days (tinea pedis and tinea manuum)
for onychomycosis, from 1 year of age:
- 1 to 12 years, courses of 5 mg/kg daily for 7 days, repeated after intervals of 21 days to a total of 2 courses for infections of the fingernails and 3 courses for toenail infections
- 12 to 18 years, either 200 mg daily for 3 months, or courses of 200 mg twice daily for 7 days, repeated after intervals of 21 days to a total of 2 courses for infections of the fingernails and 3 courses for toenail infections
for histoplasmosis or for systemic fungal infections such as aspergillosis, candidiasis, and cryptococcosis (including cryptococcal meningitis) where other antifungal drugs are inappropriate or ineffective:
- from 1 month of age to 18 years, 5 mg/kg (to a maximum of 200 mg) once or twice daily the twice daily dose should be used in invasive or disseminated disease or cryptococcal meningitis.
For intravenous doses see below for maintenance in AIDS patients to prevent relapse of underlying fungal infection, or for prophylaxis in neutropenia when standard therapy is inappropriate:
- from 1 month of age to 18 years, 5 mg/kg (to a maximum of 200 mg) daily, increased to twice daily if plasma-itraconazole concentrations are low
for prophylaxis in haematological malignancy or bone-marrow transplantation (in patients expected to become neutropenic), where standard therapy is inappropriate the oral liquid may be given as follows:
- from 1 month of age to 18 years, 2.5 mg/kg twice daily, starting before transplantation or chemotherapy and continued until the neutrophil count recovers
Like the oral liquid the intravenous product is not licensed in children in the UK: the BNFC suggests the following intravenous doses by infusion in children with systemic fungal infections:
- from 1 month of age to 18 years, 2.5 mg/kg (to a maximum of 200 mg) every 12 hours for 2 days, then the same dose once daily for a maximum of 12 days.
Doses should be given by diluting 250 mg as the intravenous concentrate in 50 mL of sodium chloride 0.9% and infusing over 60 minutes
Amoebic infections
Itraconazole has been suggested for Acanthamoeba keratitis, when it is given orally with topical miconazole.
Leishmaniasis
When systemic therapy is required for the treatment of leishmaniasis, pentavalent antimonials are most commonly used. The successful use of itraconazole has been reported in a few patients with cutaneous disease but infections with Leishmania aethiopica may not respond. Although a pilot study in patients with mucocutaneous leishmaniasis reported benefit with itraconazole this was not confirmed in another study where the response was only transient in the majority of patients. Similarly, itraconazole with terbinafine has been found to be ineffective in post kalaazar dermal leishmaniasis.
Trypanosomiasis
Itraconazole, alone or with allopurinol, may produce beneficial responses in American trypanosomiasis.
Preparations
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Synonyms of Itraconazole:
ITC, ITCZ, ITR, Itraconazol [Spanish], Itraconazole, Itraconazolum [Latin], ITZ
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Therapeutic classes of Itraconazole:
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