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| Introduction | Itraconazole 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 walls of fungi. Studies with itraconazole commenced in 1984 and the drug was licensed in 1991. It was discovered and developed by Janssen Pharmaceutica. | |
| 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 and
an IV formulation has recently received FDA
approval.
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. |
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| Fungi - the drug is active against. | Itraconazole is one of the most broad spectrum antifungals available and includes activity in Aspergillus, Blastomyces Candida (all species including many fluconazole resistant isolates) Coccidioides, Cryptoccocus, Histoplasma, Paracoccidioides, Scedosporium apiospermum and Sporothrix schenkii. It is also active against all skin fungi. It is not active against Mucorales or Fusarium and a few other rare fungi. It is the best agent against black moulds, including Bipolaris, Exserohilum etc. Resistance to itraconazole is described in Candida, although less often than with fluconazole and also in Aspergillus. | |
| Typical regimens. |
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.
2 doses of itraconazole (100mg) are sufficient for vaginal thrush. 5-7 days of therapy are sufficient for oral thrush, 7 days of treatment 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 3 weeks are used. 3 months of therapy are used for fingernail disease and 6 months for toenail disease, sometimes in interrupted regimens. 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 course of therapy may be appropriate. For aspergilloma, itraconazole is not very effective, but 400mg per day for many months is partially effective. In histoplasmosis, paraccodioidomycosis, 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 4 infectionstypically 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. |
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| 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 stabilise. If loading doses are used, stabilisation 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 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. | |
| Side effects | Itraconazole is well tolerated, the commonest side effects are nausea and sickness, occasional abdominal discomfort and constipation. 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. | |
| Other information |