Itraconazole (Page 4 of 8)

Hepatotoxicity

Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving itraconazole. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

Neuropathy

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

Cystic Fibrosis

If a cystic fibrosis patient does not respond to Itraconazole Capsules, consideration should be given to switching to alternative therapy. For more information concerning the use of itraconazole in cystic fibrosis patients see the prescribing information for SPORANOX® Oral Solution.

Hearing Loss

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 (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Information for Patients

  • The topical effects of mucosal exposure may be different between Itraconazole Capsules and SPORANOX® (itraconazole) Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Itraconazole Capsules should not be used interchangeably with SPORANOX® Oral Solution.
  • Instruct patients to take Itraconazole Capsules with a full meal. Itraconazole Capsules must be swallowed whole.
  • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole administration, they should discontinue itraconazole and contact their healthcare provider immediately.
  • Instruct patients to stop itraconazole treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.
  • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.
  • Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.
  • Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.

Drug Interactions

Itraconazole is mainly metabolized through CYP3A4. Other drugs that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other drugs that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.

Drugs that may decrease itraconazole plasma concentrations

Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2 -receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from Itraconazole Capsules. It is recommended that these drugs be used with caution when coadministered with Itraconazole Capsules:

  • It is recommended that itraconazole capsules be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.
  • It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of Itraconazole Capsules.
  • Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.

Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include:

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

Drugs that may increase itraconazole plasma concentrations

Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:

It is recommended that these drugs be used with caution when coadministered with Itraconazole Capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary.

Drugs that may have their plasma concentrations increased by itraconazole

Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolized 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. These elevated plasma concentrations may 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. 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.

Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole:

Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class Contraindicated Not Recommended Use with Caution Comments
Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole. It is recommended that the use of the drug 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 coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. Careful monitoring is recommended when the drug is coadministered 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 the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers tamsulosin
Analgesics methadone alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics disopyramide, dofetilide, dronedarone, quinidine digoxin Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials telithromycin, in subjects with severe renal impairment or severe hepatic impairment rifabutin telithromycin Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations‘.
Anticoagulants and Antiplatelet Drugs ticagrelor apixaban, rivaroxaban coumarins, cilostazol, dabigatran Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants carbamazepine Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations‘.
Antidiabetics repaglinide, saxagliptin
Antihelmintics and Antiprotozoals praziquantel
Antimigraine Drugs ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) eletriptan Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics lurasidone, oral midazolam, pimozide, triazolam alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals simeprevir maraviroc, indinavir, ritonavir, saquinavir Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations‘.
Beta Blockers nadolol
Calcium Channel Blockers felodipine, nisoldipine other dihydropyridines, verapamil Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure.
Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous ranolazine aliskiren, sildenafil, for the treatment of pulmonary hypertension bosentan, riociguat Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics eplerenone Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs cisapride aprepitant Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants everolimus, temsirolimus budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs lovastatin, simvastatin atorvastatin The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs salmeterol
Urological Drugs fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment darifenacin, vardenafil fesoterodine, oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QT prolongation.
Other colchicine, in subjects with renal or hepatic impairment colchicine, conivaptan, tolvaptan cinacalcet Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events. Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with Itraconazole Capsules.

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