Itraconazole - Antimicrobial Prescribing Guidelines for Adults

• Introduction
• Antimicrobial activity
• Contraindications (patient conditions and concomitant medicines) and allergies
• Prophylaxis-indications
• Treatment - indications
• Routes of Administration/Dose
• Pharmacokinetics
• Side effects
• Therapeutic drug monitoring (TDM)
• Prescribing restriction

This document provides guidelines for clinicians prescribing Itraconazole . It is relevant for all patients who receive Itraconazole for the treatment of systemic fungal disease or prophylaxis, but the section on therapeutic drug monitoring is not relevant to patients who receive itraconazole for superficial infections (onychomycosis; tinea corporis, tinea manuum or tinea pedis).

The use of Itraconazole can be considered within its currently approved LTHT Drugs and Therapeutics Committee [DTC] application; other indications will require chairman’s action.

This prescribing guideline is for ADULTS only.

Introduction

Itraconazole is a triazole antifungal licensed for the treatment of oral and oesophageal candidosis, prophylaxis against fungal infections in neutropenic patients and treatment of aspergillosis or cryptococcosis in patients who are refractory or intolerant to first line agents. Different formulations have different bioavailabilities which vary with food intake and gastric pH. Additionally, drug interactions mediated via the cytochrome P450 system are numerous.

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Antimicrobial activity

• Yeasts, including most species of Candida and Cryptococcus
• Moulds, including most clinically relevant species of Aspergillus and some activity against moulds of other genera
• A range of other fungi which may cause infections, including Scedosporium apiospermum, Trichosporon, Histoplasma and Coccidioides.

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Contraindications (patient conditions and concomitant medicines) and allergies

• Acute porphyria.
• Pregnancy, except in life-threatening infections, where the potential benefit outweighs the potential risk.
• Ventricular dysfunction such as congestive heart failure except in life-threatening infections.
• Co-administration with:
  • CYP3A4 metabolised HMG-CoA reductase inhibitors (statins) or ticagrelor.
  • CYP3A4 metabolised drugs that can prolong the QT interval, e.g. cisapride, mizolastine, pimozide.
  • Oral midazolam
  • Ergot alkaloids e.g. ergometrine, ergotamine.
  • Eletriptan
  • Certain cytotoxics such as cyclophosphamide, busulphan, gemtuzumab, vincristine, vinblastine and vinorelbine
• Indigestion remedies (i.e. drugs that reduce gastric acidity) must not be taken 2 hours before or 2 hours after taking Itraconazole capsules (e.g. H2 -antagonists, proton-pump inhibitors).
• For intravenous Itraconazole , the excipient hydroxypropyl-β-cyclodextrin is eliminated through glomerular filtration, so this preparation is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 ml/min).

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Prophylaxis-indications

Prophylaxis of deep fungal infections in adult patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to have prolonged neutropenia (including all ALL, AML and relapsed lymphoma patients receiving inpatient chemotherapy, post-autograft for 3 months and post-allograft whilst on immunosuppression, or other conditions at discretion of haematology consultant)

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Treatment - indications

The following guidelines indicate Itraconazole for treatment and will require monitoring of levels:
Diagnosis and Treatment of Pulmonary fungal disease (including aspergillosis) in the Immunocompetent adult; Guideline 3097

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Routes of Administration/Dose

Route of administration

Itraconazole is available in various formulations, including capsules, an oral solution and a concentrate for intravenous infusion. The bioavailability of the capsules and oral solution varies significantly with dietary intake. Itraconazole capsules are maximally absorbed in the presence of food¹ and their absorption is further improved in the presence of an acidic drink (e.g. a cola drink² or vitamin C drink³). Gastric acidity is important for absorption, which is decreased during fasting⁴, in certain disease states such as AIDS⁵ and during the use of H2-receptor agonists or omeprazole6, all of which result in reduced Itraconazole absorption. The oral Itraconazole solution, containing cyclodextrin has enhanced bioavailability compared to the capsules (~30-35%), but in contrast to the capsules, is maximally absorbed in the fasted state⁷.

Doses in haematology patients (Applies to adult patients only)

Prophylaxis in haematology patients:
ORAL: Itraconazole 10mg/ml LIQUID 2.5 mg/kg twice daily

It should be taken at least 60 minutes before food, or two hours after food for maximal absorption.

If patient is already neutropenic or at high risk of fungal infections, consider IV loading prior to oral prophylaxis

IV Loading: Itraconazole IV 200mg 12 hourly for two days (4 doses)

In haematology patients where oral therapy is not tolerated (e.g.mucositis), continuous intravenous prophylaxis may be used at 200 mg once daily (after the initial loading doses).

Treatment in haematology patients:
Itraconazole is not generally used for treatment in haematology patients.

Refer to “ Guidelines for the use of Antifungal Treatments in Adult Haematology Patients”

Doses in immunocompetent patients (Applies to adults and paediatric patients)

Also refer to “Diagnosis and Treatment of Pulmonary fungal disease (including aspergillosis) in the Immunocompetent adult” guidelines

In immunocompetent patients, capsules are used first and if required, liquid can be used second line for example if low levels are obtained with capsules.

• First line: Itraconazole CAPSULES should be taken immediately after a meal for maximum absorption.
• Second line: Itraconazole LIQUID should be taken at least 60 minutes before food, or two hours after food for maximum absorption

Dose in Allergic Bronchopulmonary Aspergillosis (ABPA) and Severe Asthma with Fungal Sensitisation (SAFS)
ORAL: Itraconazole 200mg TWICE a day.

For the treatment of ABPA and SAFS, Itraconazole capsules are preferred to Itraconazole liquid as the capsule formulation is better tolerated, and is more cost effective However the liquid has a higher bioavailability and fewer food interactions, and so maybe beneficial if therapeutic serum concentrations cannot be achieved using Itraconazole capsules.

For those patients with ABPA who are corticosteroid-dependent, a trial of Itraconazole 200mg twice a day is warranted as a steroid sparing agent. Due to problems with bioavailability, pre-dose levels should be checked within 5 to 7 days to ensure adequate absorption (See Therapeutic Drug Monitoring section below). Response to treatment should be assessed over 16-32 weeks. If there is no improvement, repeat measurement of serum concentrations may be useful as a guide to appropriate dosing, or susceptibility testing of the infecting isolate of Aspergillus may be advisable. If a therapeutic serum concentration is not achieved, then Itraconazole liquid should be used as this may provide better serum concentrations.

For those patients who respond within 16 to 32 weeks, a dose of at least 200mg daily should be continued until no further improvement is seen (usually 6-9 months).

Itraconazole interacts with several inhaled corticosteroids, including budesonide, fluticasone and ciclesonide. Patients using these inhaled steroids may need to have their dose of steroids reduced and should be observed for any adverse steroid-related effects.

Dose in Chronic Pulmonary Aspergillosis (CPA)
ORAL: Itraconazole 200mg TWICE a day.

The duration of treatment for treatment of chronic cavitary aspergillosis is long term and probably life-long.

Itraconazole interacts with several inhaled corticosteroids, including budesonide, fluticasone and ciclesonide. Patients using these inhaled steroids may need to have their dose of steroids reduced and should be observed for any adverse steroid-related effects.

Dose in renal impairment: Oral preparations are dosed as in normal renal function. Itraconazole is extensively metabolised in the liver, and pharmacokinetics are unchanged in patients with renal impairment.

Hydroxypropyl-β-cyclodextrin, a component of the IV formulation, is eliminated through glomerular filtration. Therefore in patients with a creatinine clearance below 30 ml/min, the use of IV Itraconazole is contraindicated. In patients with mild and moderate renal impairment, IV Itraconazole should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to a suitable alternative.

Dose in haemodialysis: Itraconazole is not dialysed. The oral dose in patients with renal impairment is the same as in normal renal function.

For intravenous Itraconazole , the excipient hydroxypropyl-β-cyclodextrin is removed by haemodialysis, and so this preparation is can be used at the same dose as in patients with normal renal function.

Dose in liver disease: Itraconazole is predominately metabolised by the liver. A dose reduction may be necessary and patients should be monitored closely. Itraconazole should only be used if the potential benefit outweighs the risk of hepatotoxicity.

The intravenous infusion is available for loading haematology patients at high risk of fungal infections to help achieve therapeutic levels or in patients who are temporarily unable to take an oral formulation e.g. due to mucositis. Due to the presence of hydroxypropyl-β-cyclodextrin in the IV formulation, its use is contraindicated in patients with a creatinine clearance below 30 ml/min. IV Itraconazole should be used with caution in patients with mild and moderate renal impairment.

IV Itraconazole has the potential to precipitate when diluted in solutions other than the 50ml 0.9% sodium chloride injection supplied by the manufacturers. Follow the directions for administration supplied with the drug.

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Pharmacokinetics

The pharmacokinetics of Itraconazole are complicated by not only variable absorption, but also its drug interactions, which are mainly mediated through the cytochrome P450 system. It is metabolised by CYP3A4, being both a substrate and inhibitor of the enzyme⁸. Itraconazole metabolism results in more than 30 metabolites^9,10, several of which are also inhibitors of CYP3A4^11,12. The interaction of Itraconazole metabolites with CYP3A4 in addition to the parent drug may explain why Itraconazole is such a potent inhibitor of this cytochrome. Drug interactions mediated via CYP3A include those between Itraconazole and midazolam¹³, cyclosporin¹⁴, rifampicin¹⁵, phenobarbital¹⁶, tacrolimus¹⁷ and methylprednisolone¹⁸. Itraconazole is an inhibitor of P-glycoprotein¹⁹ and some drug interactions may be mediated via this pathway²⁰.
[Link to BNF for interactions]

Drug Interactions

(This list is not exhaustive, consult your ward pharmacist or contact medicines information (ext 65377) for further advice on interactions.)

1. Drugs affecting the absorption of Itraconazole :
   • Indigestion remedies (i.e. drugs that reduce gastric acidity) must not be taken 2 hours before or 2 hours after taking Itraconazole capsules (e.g. H2 -antagonists, proton-pump inhibitors). If these medicines need to be taken within 2 hours of Itraconazole , the itraconzole capsules should be taken with a drink of cola.
   • Absorption of Itraconazole CAPSULES is improved if taken after food.
   • Absorption of Itraconazole LIQUID is improved if taken at least 60 minutes before food, or two hours after food.
2. Drugs affecting the metabolism of Itraconazole :
   • Enzyme inducers (e.g. rifampicin, rifabutin, phenytoin, carbamazepine, Phenobarbital and St. John’s Wort) may reduce the serum concentration of Itraconazole (avoid use)
   • Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents, due to the risks of treatment failure.
   • Enzyme inhibitors (e.g. ritonavir, indinavir, clarithromycin and erythromycin) may increase the serum concentration of Itraconazole .
3. Effect of Itraconazole on the metabolism of other drugs:
   Itraconzole can inhibit the metabolism of certain drugs that are metabolised by the cytochrome CYP3A family.
   • Co-administration with the following drugs is contra-indicated:
     • CYP3A4 metabolised HMG-CoA reductase inhibitors (statins) or ticagrelor.
     • CYP3A4 metabolised drugs that can prolong the QT interval, e.g. cisapride, mizolastine, pimozide. Co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.
     • Oral midazolam.
     • Ergot alkaloids e.g. ergometrine, ergotamine.
     • Eletriptan
     • Certain cytotoxics such as cyclophosphamide, busulphan, vincristine, vinblastine and vinorelbine
   • The following drugs should be used with caution, and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with Itraconazole , should be reduced if necessary:
     • Oral anticoagulants;
     • HIV protease inhibitors such as ritonavir, indinavir, saquinavir;
     • Certain antineoplastic agents such as busulfan, docetaxel, trimetrexate and vinca alkaloids;
     • CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;
     • Certain immunosuppressive agents: cyclosporine, tacrolimus, sirolimus;
     • Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone;
     • Digoxin (via inhibiton of P-glycoprotein)
     • Others: cilostazol, disopyramide, carbamazepine, buspirone, alfentanil, alprazolam, intravenous midazolam, rifabutin, repaglinide, fentanyl, reboxetine and loperamide. The importance of the concentration increase and the clinical relevance of these changes during the co-administration with Itraconazole remain to be established.

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Side effects

Side effects are more commonly experienced with the Itraconazole solution than the capsules and include headache; nausea, vomiting and diarrhoea; skin rashes; and deranged liver function. One study demonstrated that the probability of toxicity increased with increasing concentrations of Itraconazole ²¹.

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 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.

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Therapeutic drug monitoring (TDM)

Evidence for the utility of therapeutic drug monitoring
The outcome of Itraconazole therapy has been shown to relate to the levels which are achieved in serum during treatment. In patients with cryptococcosis²², aspergillosis²³ and oral candidosis²⁴ outcome was better when higher serum Itraconazole levels were achieved. In neutropenic patients receiving Itraconazole for prophylaxis, patients with Itraconazole trough concentrations < 0.5mg/L were significantly more likely to develop breakthrough infections. In patients who develop breakthrough infections, the last trough concentration was significantly lower in those who died of their infection than those who survived²⁵. There has been some debate about what is the target trough concentration and whether it should be the same for prophylaxis and treatment, but a level of 0.5mg/L has been suggested and is widely used^26,27.

When to monitor Itraconazole levels:

1. 5-7 days after the start of therapy
2. after a dose has been adjusted as a result of a previous sample outside the target level
   
3. if another drug is started or stopped which is known to affect the levels of Itraconazole
4. if a patient receiving Itraconazole for prophylaxis deteriorates clinically and shows signs of infection (e.g. fever, characteristic changes on chest X-ray or HRCT, rising CRP)
5. where drug compliance is uncertain
6. where the nutritional status of the patients taking capsules deteriorates
7. in patients who have diarrhoea, especially for prolonged periods

Once good therapeutic levels have been achieved, there is no need to monitor levels again unless any of conditions (iii) - (vii) apply.

Sample and assay details:

• Levels are assayed using liquid chromatography - tandem mass spectrometry, which allows levels of Itraconazole to be measured even if the patient is receiving more than one antifungal.
• Serum should taken into a plain serum tube immediately prior to a dose (trough level)
• Assays are carried out twice weekly on Monday and Thursday.
• Repeat samples from the same patient taken less than 7 days after the last sample will not be assayed, unless there is a clear indication to do so which must be stated on the request form (see (iii) – (vii) above)

Target levels

• Trough levels should be maintained above 0.5 mg/L.
• Toxicity may be associated with levels above 4 mg/L

Action if trough levels are within target range (>0.5 - 4 mg/L)

• If trough levels are within the target range, ensure the patient is responding clinically and continue with the present dose.

Action if trough levels are low (<0.5 mg/L)

• Discuss compliance with the patient. Ensure that the Itraconazole is taken regularly.
• If the patient is taking capsules, ensure they are taken with food and preferably with a cola drink.
• If the patient is taking liquid, ensure it is taken without food and that no food is consumed for 2 hours after dosing.
• Many drugs interact with Itraconazole and may lower the levels. Discuss with a pharmacist if the patient is on multiple drugs to determine whether interactions may be reducing the level of Itraconazole .
• Increase dose, if appropriate and repeat monitoring 5-7 days later. Consult with a clinician or pharmacist for further advice if necessary.
• In patients taking capsules, if therapeutic levels cannot be achieved, consider switching to Itraconazole liquid at the same dose, and rechecking trough levels 5-7 days later.
• If the patient is unable to tolerate Itraconazole consider changing to a suitable alternative as per guidelines or microbiology advice.

Action if trough levels are high (> 4.0 mg/L)

• Ensure the sample is a pre-dose, trough level
• If levels are above 4 mg/L, toxicity may result, although the data are limited. Observe for any signs of toxicity (e.g. deranged LFTs, peripheral neuropathy)
• Check the dose has been prescribed correctly and whether any drugs may interact with Itraconazole to increase levels. Discuss with a pharmacist as appropriate.
• Consider reducing the dose by 50%. Consult with a clinician or pharmacist as to whether dose adjustment is appropriate.

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Prescribing restriction

As per guidelines