Itraconazole


Continuing Education Activity

Itraconazole is a medication used in the management and treatment of fungal infections. It is in the antifungal class of medications. This activity reviews the indications, action, and contraindications for itraconazole as a valuable agent in the treatment of systemic fungal infections and other disorders when applicable. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off- label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent for members of the healthcare team in the treatment of patients with systemic fungal infections and related conditions.

Objectives:

  • Identify the mechanism of action and administration of itraconazole.
  • Describe the adverse effects and contraindications of itraconazole.
  • Review the appropriate monitoring and toxicity of itraconazole.
  • Summarize some interprofessional team strategies for improving care coordination and communication to advance itraconazole and improve outcomes.

Indications

Itraconazole can treat many different fungal infections. Many of these fungal infections are rare; however, they can be detrimental to the immunocompromised. Itraconazole treats blastomycosis, histoplasmosis, and aspergillosis and has FDA approval as a treatment for these infections. However, itraconazole has also shown efficacy in treating paracoccidioidomycosis, coccidioidomycosis, and candidiasis, but it does not have approval from the FDA for these conditions.[1][2] In addition to treating infections, itraconazole can be used as prophylaxis in patients at risk of these systemic fungal infections. Some patient populations that frequently use itraconazole prophylaxis are patients with HIV, those receiving chemotherapy, or people who have had an organ transplant. Itraconazole offers excellent prophylaxis for these immunocompromised patients due to its broad-spectrum coverage, safety profile, and minimal fungal resistance.[3]

In addition to treating systemic infections, itraconazole can also treat superficial fungal infections like onychomycosis, which has FDA approval. However, the cure rate of onychomycosis with itraconazole therapy is only 63%.[4] Itraconazole can also be used to treat moderate to severe seborrheic dermatitis and other topical mycoses, although this use does not have FDA approval. Although itraconazole is an effective therapy for seborrheic dermatitis, antifungal shampoos, and topical steroids are first-line therapies. When treating seborrheic dermatitis, itraconazole administration occurs as a pulse therapy, which means large doses of the drug are administered intermittently to avoid side effects but achieve the drug’s therapeutic effects.[5]

Mechanism of Action

Itraconazole is a broad spectrum anti-fungal agent. Itraconazole inhibits ergosterol synthesis, which helps to maintain the cell membrane in fungi. Lanosterol must undergo a 14 alpha-demethylation reaction, which is catalyzed by fungal cytochrome P450 to become ergosterol. Itraconazole blocks this reaction by interacting with the fungal cytochrome P450 substrate-binding site. This impaired ergosterol synthesis leads to fungal membrane abnormalities that increase permeability and changes membrane-bound enzyme activity.[6]

Administration

Itraconazole can be administered intravenously, in a capsule, or as an oral solution that allows administration of the drug in the inpatient or outpatient setting. The absorption of the itraconazole via the capsule is highly variable. This variability results from intestinal epithelial damage and varying gastric acid environments from person to person. However, the newer formulations of the drug, intravenous, and oral solution, which contain hydroxypropyl-beta-cyclodextrin, have shown better absorption and bioavailability.[1][3]

Adverse Effects

While itraconazole is a relatively safe medication, there are some adverse side effects with itraconazole use. Cardiotoxicity is a rare adverse effect. Itraconazole can decrease heart contractility and left ventricular ejection fraction.[7] The risk of cardiotoxicity increases with a dose greater than 400 mg/day. While most patients' heart function improves after discontinuing itraconazole, some patients require a transplant.[8] Another adverse effect is hepatotoxicity, which is often a reversible increase in aminotransferase levels. This side effect is minimizable with intermittent or short-term dosing. In patients already being treated for hypertension, itraconazole can cause resistant hypertension.[9] The most common adverse effects are gastrointestinal disturbances, such as nausea, mild diarrhea, vomiting, and abdominal pain. Researchers noted these side effects in 2 to 39% of patients that have used itraconazole.[2] When itraconazole administration is via the intravenous formulation, there is also a risk of injection site reactions, headache, and rash.

Contraindications

There are some contraindications for itraconazole use. The main one being heart failure or history of heart failure due to itraconazole’s potential cardiotoxic effects. Another contraindication is liver failure or disease because itraconazole can cause hepatotoxicity. Itraconazole is also contraindicated in pregnant patients. It has demonstrated teratogenic and embryotoxic effects in animal studies. In a systematic review, researchers found itraconazole to cause eye defects in babies whose mothers had exposure to the drug during pregnancy.[10]

Itraconazole also has the potential for many drug-drug interactions because it metabolized by cytochrome P450 3A4 in the liver, like many other drugs. For example, patients taking itraconazole and terfenadine, astemizole, or cisapride may have serious cardiac rhythm disturbances. Itraconazole can also prolong the sedative effects of medications such as midazolam and triazolam, which means clinicians should avoid this combination. Itraconazole can also enhance the effects of oral antidiabetic drugs, which can result in severe hypoglycemia. It is essential to consider drug-drug interactions when prescribing itraconazole, especially if the same cytochrome enzyme metabolizes the other drugs in the liver.[2]

Monitoring

Itraconazole should have a trough concentration of 0.5 to 1.0 mg/L for the treatment and prevention of fungal infections. Trough concentration is the drug’s lowest concentration prior to the next dose.[11] Itraconazole typically requires a prolonged period of maintenance treatment, so patients should see their physician regularly to ensure that no adverse effects are developing. The concentration of itraconazole should be checked after a week of use and at regular intervals afterward. The concentration of the drug requires monitoring if the dose of itraconazole changes or if the prescriber adds a medication to a patient’s regimen that is metabolized by the same liver enzyme as itraconazole. Regular monitoring can be useful to exclude issues with unanticipated changes in pharmacokinetics or problems with compliance. In addition to monitoring the drug concentration, patients should also have their liver enzymes checked regularly to ensure there is no hepatotoxicity.[2]

Enhancing Healthcare Team Outcomes

Managing antifungal prophylaxis in immunocompromised patients requires the entire healthcare team, including laboratory technologists, pharmacists, nurses, and physicians. If itraconazole therapy is not adequately managed patients are likely to contract life-threatening fungal infections or experience adverse side effects. Whether these patients are immunocompromised due to HIV, chemotherapy, or organ transplant, drugs like itraconazole can be lifesaving.[1] When an immunocompromised patient presents to the hospital, the physician and assigned nurse are responsible for the coordination of care. This includes:

  • Assessing the patient for any signs of current fungal infections
  • Reviewing the patient’s cardiac history. If the patient has any history of arrhythmias or heart failure, consult cardiology. 
  • Ordering liver enzymes to evaluate the liver’s function.[2]
  • Consult with an infectious disease physician to ensure that itraconazole will provide adequate coverage for the patient.
  • Consult with the pharmacist to ensure that there are no drug-drug interactions between itraconazole and the patient’s current medication.

The management of itraconazole prophylaxis does not stop after the initial visit. Following administration of the drug, itraconazole levels require regular monitoring, and the patients require monitoring for the development of any adverse reactions. These patients may also benefit from a mental health counselor, many of these patients are very sick, and that can take a toll on mental health. Furthermore, social workers should be involved in the care of these patients. Many immunocompromised patients are using many costly medications, which can be a burden. Social workers can help get drugs covered or find other ways to assist these patients financially. Only by working together can an interprofessional team provide safe and effective itraconazole prophylaxis in immunocompromised patients.


Article Details

Article Author

Heidi Kurn

Article Editor:

Roopma Wadhwa

Updated:

11/7/2020 7:51:08 PM

PubMed Link:

Itraconazole

References

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Boogaerts M,Maertens J, Clinical experience with itraconazole in systemic fungal infections. Drugs. 2001;     [PubMed PMID: 11219549]

[2]

Piérard GE,Arrese JE,Piérard-Franchimont C, Itraconazole. Expert opinion on pharmacotherapy. 2000 Jan;     [PubMed PMID: 11249550]

[3]

Willems L,van der Geest R,de Beule K, Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. Journal of clinical pharmacy and therapeutics. 2001 Jun;     [PubMed PMID: 11422598]

[4]

Westerberg DP,Voyack MJ, Onychomycosis: Current trends in diagnosis and treatment. American family physician. 2013 Dec 1;     [PubMed PMID: 24364524]

[5]

Gupta AK,Richardson M,Paquet M, Systematic review of oral treatments for seborrheic dermatitis. Journal of the European Academy of Dermatology and Venereology : JEADV. 2014 Jan;     [PubMed PMID: 23802806]

[6]

De Beule K,Van Gestel J, Pharmacology of itraconazole. Drugs. 2001;     [PubMed PMID: 11219548]

[7]

Abraham AO,Panda PK, Itraconazole Induced Congestive Heart Failure, A Case Study. Current drug safety. 2018;     [PubMed PMID: 28971777]

[8]

Paul V,Rawal H, Cardiotoxicity with Itraconazole. BMJ case reports. 2017 Apr 10;     [PubMed PMID: 28400399]

[9]

Denolle T,Azizi M,Massart C,Zennaro MC, [Itraconazole: a new drug-related cause of hypertension]. Annales de cardiologie et d'angeiologie. 2014 Jun;     [PubMed PMID: 24952675]

[10]

Liu D,Zhang C,Wu L,Zhang L,Zhang L, Fetal outcomes after maternal exposure to oral antifungal agents during pregnancy: A systematic review and meta-analysis. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2020 Jan;     [PubMed PMID: 31691277]

[11]

Ashbee HR,Barnes RA,Johnson EM,Richardson MD,Gorton R,Hope WW, Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. The Journal of antimicrobial chemotherapy. 2014 May;     [PubMed PMID: 24379304]