Itraconazole (Sporanox, Janssen) is a fat soluble synthetic triazole antifungal drug. It has the same mechanism of action as all azoles and prevents the formation of ergosterol necessary for the cell membranes of fungi. Studies with itraconazole commenced in 1984 and the drug was licensed in 1991. It is now off patent, although the IV and oral solution formulations are still patent protected. It interferes with fungal biosynthesis of ergosterol like all azoles, by interfering with the activity of 14alpha demethylase.
Dose & Delivery
Until 1997 capsules only were available. Capsules are better absorbed taken with food. A liquid form was then introduced, particularly for the management of fluconazole resistant oral thrush in patients with AIDS. An IV formulation in cyclodextrin is also licensed. There is some variation in bioavailability between different capsule formulations and switching between them has lead to clinical failure.
The oral liquid is typically used in patients with oral thrush, especially AIDS, and in the prophylaxis of fungal infections in leukaemia or after bone marrow transplantation. It is also used in patients who are on acid reducing drugs. Suspension is better absorbed taken on an empty stomach.
Intravenous itraconazole is usually given a dose of 5mg per kg twice a day and is used when patients are unable to take oral medication or are very ill.
Fungi - the drug is active against
Itraconazole is one of the most broad spectrum antifungals available and includes activity in Aspergillus spp, Blastomyces dermatitidis, Candida (all species and most isolates including some fluconazole resistant isolates), Coccidioides spp., Cryptococcus spp., Histoplasma spp, Paracoccidioides brasiliensis, Scedosporium apiospermum and Sporothrix schenckii. It is also active against all skin fungi. It is not active against Mucorales or Fusarium spp. and a few other rare fungi. Until the development of posaconazole, it was the most active against black moulds, including Bipolaris, Exserohilum etc. Resistance to itraconazole is described in Candida spp. and in Aspergillus fumigatus and A. niger.
Two doses of itraconazole (200mg) are sufficient for most cases of vaginal thrush. Five to seven days of therapy are sufficient for oral thrush. Occasionally in AIDS continuous therapy is required for fluconazole resistant disease.
Seven days of 200 mg itraconazole daily is usually used for most skin infections, except for extensive tinea pedis (fungal infection of the feet and between the toes) and some scalp infections in which case 100 mg daily for 3-4 weeks therapy is used. Three months of therapy (200mg daily) are used for fingernail disease and 6 months for toenail disease, sometimes in interrupted regimens (so called pulse therapy ( 200mg twice daily for 7 days, repeated 3 weeks later).
Loading doses of 200mg 3 or 4 times a day for 3 to 4 days are appropriate for serious or life-threatening disease, especially invasive aspergillosis. In invasive aspergillosis, typically 400mg per day or more are used for periods of at least 3 months and often as long as a year or more. In allergic bronchopulmonary aspergillosis 400mg appears to be slightly superior to 200mg, although there is activity at 200mg per day. A minimum of 3 months therapy is required and relapse is common after discontinuation - therefore a longer, even continuous, course of therapy may be appropriate. For chronic pulmonary aspergillosis, itraconazole is not very effective, but 400mg per day for many months is partially effective. Therapeutic monitoring of blood levels is appropriate to ensure adequate levels and compliance, and minimize toxicity.
In histoplasmosis, paraccoidioidomycosis, blastomycosis and sporotrichosis 200mg per day given for 3-6 months is effective in the vast majority of cases. In AIDS larger doses are used for these infections, typically 400mg per day and treatment may be lifelong, although a dose reduction to 200mg per day after control of disease is appropriate. In coccidioidomycosis 400mg per day appears to be the best dose. For black mould infections affecting the sinuses, substantially larger doses of 400-1200mg per day have been used, but specialist advice is necessary.
Metabolism and excretion
The absorption of itraconazole from the gut is incomplete. The drug is extensively metabolised and one metabolite (hydroxyitraconazole) has antifungal activity. The drug is extensively protein bound and therefore does not get into urine or cerebrospinal fluid. However, it does bind avidly to keratin and so high concentrations are found in the skin and nails. The half life itraconazole in the blood varies with a dose, but is typically 48 to 60 hours and it takes 2 weeks for blood levels to stabilize (steady state). If loading doses are used, steady state can be achieved in a week.
Drug/ Drug interactions
There are numerous drug/drug interactions with itraconazole which is one of its limitations. The absorption of capsules is reduced if given with antacid drugs but increased if the solution formulation is used. If enzyme inducing drugs such as rifampicin (rifampin), phenytoin or carbamazepine are used, there is a marked reduction in the blood levels of itraconazole and treatment may fail. Itraconazole also prevents some drugs being metabolised, in particular terfenadine, astemizole and cisapride, which can lead to serious heart arrhythmias. These drugs should not be given with itraconazole. Certain sedatives will have prolonged action if given with itraconazole, in particular midazolam and triazolam. Itraconazole may also increase the blood levels of digoxin, cyclosporin and warfarin and these drugs and their effects should be carefully monitored. Anticancer therapy with the drug vincristine given together with itraconazole, may have prolonged action and cause neurological damage, which is usually temporary but can be very problematic. Interactions with inhaled steroids can be profound, leading to permanent adrenal failure. View drug interactions database.
Itraconazole is usually tolerated adequately. The commonest side effects are nausea and sickness, occasional abdominal discomfort and constipation. These side effects, and diarrhoea, are more common with itraconazole solution. In older people fluid retention can be a problem. Rashes occur in approximately 1 in 20 patients and occasionally are severe. Abnormal liver function tests occasionally occur and in rare cases severe liver disease or jaundice. Occasionally adrenal gland suppression, low blood potassium and raised blood pressure can occur. Peripheral neuropathy and tremor are also problematic in some patients. View video "skin reactions to antifungal agents" and video "Neurological toxicity"
Structure of Itraconazole