Itraconazole

Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolised by CYP3A4 and can inhibit the drug transport by P-glycoprotein which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. The full inhibitory effect of itraconazole is obtained after steady state in plasma is reached. The effects of itraconazole in increasing the AUC of other drugs can be as high as 11-fold, as seen with oral midazolam (a sensitive CYP3A4 substrate) when co-administered with itraconazole 200 mg/d. These elevated plasma concentrations are likely to increase or prolong both therapeutic and adverse effects of these drugs.

CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Full inhibitory effect is not obtained until itraconazole steady state has been reached which takes approximately 2-4 days. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.

Studies have not been conducted with intravenous itraconazole in patients with hepatic impairment. Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered to this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.

In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications.

Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway.

Strong inhibitors of CYP3A4 may increase the exposure of itraconazole. It is recommended that these drugs be used with caution when co-administered with itraconazole. It is recommended that patients who must take itraconazole concomitantly with strong inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and itraconazole dose be decreased as deemed necessary. When appropriate, it is recommended that itraconazole plasma concentrations be measured.

Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Co-administration of itraconazole with strong enzyme inducers of CYP3A4 may decrease the exposure of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced.

Therefore, administration of strong enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs should be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon co-administration, it is recommended that the antifungal activity should be monitored and the itraconazole dose increased as deemed necessary.

Careful monitoring is recommended when coumarins are co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of coumarins, and their dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Caution should be exercised when co-administering itraconazole and calcium channel blockers.

Careful monitoring is recommended when vinca alkaloids are co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of vinca alkaloids, and their dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when alfentanil is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of alfentanil, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when alitretinoin is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of alitretinoin, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when alprazolam is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of alprazolam, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of apixaban be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of apixaban is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when aprepitant is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of aprepitant, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when aripiprazole is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of aripiprazole, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of atorvastatin be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of atorvastatin is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of axitinib be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of axitinib is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when bilastine is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of bilastine, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when bortezomib is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of bortezomib, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when bosentan is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of bosentan, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when brotizolam is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of brotizolam, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when budesonide is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of budesonide, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when buprenorphine is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of buprenorphine, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when buspirone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of buspirone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when busulphan is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of busulphan, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of carbamazepine be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of carbamazepine is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of ciclesonide be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of ciclesonide is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when ciclosporin is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of ciclosporin, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when cilostazol is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of cilostazol, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when bilastine is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of bilastine, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of colchicine be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of colchicine is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of dabrafenib be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of dabrafenib is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of dasatinib be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of dasatinib is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when dexamethasone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of dexamethasone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when digoxin is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of digoxin, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when docetaxel is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of docetaxel, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of ebastine be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of ebastine is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of eletriptan be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of eletriptan is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when erlotinib is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of erlotinib, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of everolimus be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of everolimus is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of felodipine be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of felodipine is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of fentanyl be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of fentanyl is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when fesoterodine is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of fesoterodine, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when fluticasone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of fluticasone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when gefitinib is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of gefitinib, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when haloperidol is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of haloperidol, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of ibrutinib be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of ibrutinib is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when imatinib is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of imatinib, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when indinavir is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of indinavir, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when ixabepilone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of ixabepilone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of lapatinib be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of lapatinib is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when maraviroc is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of maraviroc, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Co-administration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when co-administered with itraconazole, including monitoring for any reduction in efficacy of meloxicam with adjustments to the dose as necessary.

Careful monitoring is recommended when methadone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of methadone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when methylprednisolone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of methylprednisolone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when nadolol is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of nadolol, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of nilotinib be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of nilotinib is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when oxybutynin is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of oxybutynin, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when oxycodone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of oxycodone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when ponatinib is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of ponatinib, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when praziquantel is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of praziquantel, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when reboxetine is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of reboxetine, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when repaglinide is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of repaglinide, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of rifabutin be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of rifabutin is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of riociguat be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of riociguat is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when risperidone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of risperidone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when ritonavir is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of ritonavir, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of rivaroxaban be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of rivaroxaban is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of salmeterol be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of salmeterol is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when saquinavir is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of saquinavir, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when saxagliptin is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of saxagliptin, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when sildenafil (when indicated for erectile dysfunction) is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of sildenafil, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of simeprevir be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of simeprevir is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when sirolimus is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of sirolimus, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when solifenacin is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of solifenacin, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when sufentanil is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of sufentanil, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of sunitinib be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of sunitinib is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when tacrolimus is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of tacrolimus, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when bilastine is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of bilastine, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of tamsulosin be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of tamsulosin is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when telithromycin is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of telithromycin, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of temsirolimus be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of temsirolimus is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of tolterodine be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of tolterodine is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when tolvaptan is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of tolvaptan, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

It is recommended that the use of trabectedin be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of trabectedin is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when trimetrexate is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of trimetrexate, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Careful monitoring is recommended when verapamil is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of verapamil, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

In a healthy volunteer study with itraconazole, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. A similar investigation was not performed in the target patient population.

Itraconazole has been shown to have a negative inotropic effect and itraconazole has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.

Itraconazole should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk.

Physicians should carefully review the risks and benefits of itraconazole therapy for patients with known risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischaemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other oedematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment. If such signs or symptoms do occur during treatment, itraconazole should be discontinued.

If neuropathy occurs that may be attributable to itraconazole, the treatment should be discontinued.

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of itraconazole. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving itraconazole treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs.

Careful monitoring is recommended when perospirone is co-administered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of perospirone, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Itraconazole must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus.

In animal studies itraconazole shows reproduction toxicity.

Epidemiological data on exposure to Sporanox during the first trimester of pregnancy – mostly in patients receiving short-term treatment for vulvovaginal candidosis – did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens. Itraconazole has been shown to cross the placenta in a rat model.

A very small amount of itraconazole is excreted in human milk. Itraconazole must not be used during lactation.

Women of child-bearing potential

Women of childbearing potential taking itraconazole should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of itraconazole therapy.

Fertility

In the rat, itraconazole had no effect on male or female fertility at doses which exhibited signs of general toxicity. The effect in humans is unknown.

No studies on the effects on the ability to drive and use machines have been performed.

When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss, which may occur in some instances, must be taken into account.

Approximately 9% of patients can be expected to experience adverse reactions while taking itraconazole. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological origin.

The list below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:

Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Uncommon: Leucopenia, Neutropenia, Thrombocytopenia

Immune system disorders

Uncommon: Hypersensitivity

Not Known: Serum Sickness, Angioneurotic Oedema, Anaphylactic Reaction, Anaphylactoid Reaction,

Metabolism and nutrition disorders

Uncommon: Hypokalaemia

Not Known: Hypertriglyceridemia

Nervous system disorders

Common: Headache, Dizziness, Dysgeusia

Uncommon: Peripheral Neuropathy, Paraesthesia, Hypoaesthesia

Eye disorders

Uncommon: Visual Disorders, including Vision Blurred and Diplopia

Ear and labyrinth disorder

Uncommon: Tinnitus

Not Known: Transient or permanent hearing loss

Cardiac disorders

Uncommon: Cardiac failure

Not Known: Congestive Heart Failure

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, cough

Not Known: Pulmonary Oedema

Gastrointestinal disorders

Common: Abdominal Pain, Vomiting, Nausea, Diarrhoea, Dyspepsia

Uncommon: Constipation

Not Known: Pancreatitis

Hepato-biliary disorders

Common: Hepatic enzyme increased

Uncommon: Hepatitis, hepatic failure, Hyperbilirubinaemia

Not Known: Hepatotoxicity including some cases of fatal Acute hepatic failure

Skin and subcutaneous tissue disorders

Common: Rash

Uncommon: Urticaria, Pruritus

Not Known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia, arthralgia

Renal and urinary disorders

Not Known: Pollakiuria, urinary incontinence

Reproductive system and breast disorders

Uncommon: Menstrual disorders

Not Known: Erectile dysfunction

General disorders and administration site conditions

Common: Pyrexia

Uncommon: Oedema

Investigations

Not Known: Blood creatine phosphokinase increased

The following is a list of additional ADRs associated with itraconazole that have been reported in clinical trials of itraconazole capsules and itraconazole IV, excluding the ADR term “Injection site inflammation”, which is specific to the injection route of administration.

Infections and infestations: Sinusitis, Upper respiratory tract infection, Rhinitis

Blood and lymphatic system disorders: Granulocytopenia

Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia, Hypomagnesaemia

Psychiatric disorders: Confusional state

Nervous system disorders: Somnolence, Tremor

Cardiac disorders: Left ventricular failure, Tachycardia

Vascular disorders: Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders: Dysphonia

Gastrointestinal disorders: Gastrointestinal disorder, Flatulence

Hepatobiliary disorders: Hepatic function abnormal

Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis

Renal and urinary disorders: Renal impairment

General disorders and administration site conditions: Face oedema, Chest pain, Pain, Fatigue, Chills

Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal

Propylene Glycol: Various adverse events, such as hyperosmolality, lactic acidosis; renal dysfunction (acute tubular necrosis), acute renal failure; cardiotoxicity (arrhythmia, hypotension); central nervous system disorders (depression, coma, seizures); respiratory depression, dyspnoea; liver dysfunction; haemolytic reaction (intravascular haemolysis) and haemoglobinuria; or multisystem organ dysfunction, have been reported with high doses or prolonged use of propylene glycol.

Adverse events usually reverse following weaning off of propylene glycol, and in more severe cases following haemodialysis.

Paediatric Population

The safety of itraconazole oral solution was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of itraconazole for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhoea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.