Continuing Education Activity

Itraconazole is a medication used in the management and treatment of fungal infections. It is in the antifungal class of drugs. Many of these fungal infections are rare; however, they can be detrimental to the immunocompromised. Some patient populations that frequently use itraconazole prophylaxis are patients with HIV, those receiving chemotherapy, or people who have had an organ transplant. This activity reviews the indications, mechanism of action, adverse event profile, and contraindications for itraconazole as a valuable agent in treating systemic fungal infections and other disorders, including off-label indications pertinent for healthcare team members in the treatment of patients with systemic fungal infections and related conditions.

Objectives:

• Identify the mechanism of action of itraconazole.
• Describe the potential adverse effects of itraconazole.
• Review the appropriate monitoring of patients using 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 (sometimes abbreviated ITZ) 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 FDA approval 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 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 antifungal agent; it has an active metabolite; hydroxyitraconazole. Itraconazole inhibits ergosterol synthesis, which helps maintain the cell membrane in fungi. Lanosterol must undergo a 14 alpha-demethylation reaction to become ergosterol, which is catalyzed by fungal 14 alpha-demethylase. Itraconazole blocks this reaction by interacting with the fungal 14 alpha-demethylase substrate-binding site. This impaired ergosterol synthesis leads to fungal membrane abnormalities that increase permeability and disrupt fungal cell membrane integrity, changing membrane-bound enzyme activity.[6]

The drug is metabolized extensively via the CYP450 system; specifically, itraconazole is a CYP3A4 substrate. It has a half-life of 34 to 42 hours. The drug is excreted in the urine (35%) feces (between 3 and 18%).

Administration

Itraconazole can be administered intravenously (10 mg/mL), in a capsule (100 mg), or as an oral solution (10 mg/mL) that allows administering 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 solutions, which contain hydroxypropyl-beta-cyclodextrin, have shown better absorption and bioavailability.[1][3]

Dosing by indication (FDA-approved) is as follows:

• Onychomycosis of the Fingernails
  • 200 mg orally twice daily (capsules) for seven days, followed by 21 days off. Give two courses for immunocompromised patients.

• Fungal Infections 
  • 200 mg by mouth daily or twice daily (capsules); start 200 mg twice daily for three days in life-threatening infections. The maximum dose is 600 mg daily. Divide doses over 200 mg daily; give with food.

• Onychomycosis of the Toenails
  • 200 mg orally (capsules) each day for 12 weeks

• Candidiasis
  • Oropharyngeal: 20 mL orally for one to two weeks; swish and swallow. Alternately, dose 10 mL orally twice daily for 2 to 4 weeks.
  • Esophageal: 20 mL orally twice daily for 14 to 21 days. 

• Blastomycosis
  • 200 mg orally daily (capsules); maximum dose 400 mg per day. Pulmonary and extrapulmonary disease can increase dosing by 100 mg increments if there is no therapeutic response; divide doses above 200 mg daily. The maximum dose is 600 mg daily.

• Histoplasmosis
  • 200 mg orally daily (capsules), maximum dosage of 400 mg per day. Can increase dosing by 100 mg increments if there is no therapeutic response; divide doses above 200 mg daily.

• Invasive Aspergillosis
  • 20 mL orally every 12 hours; alternatively, 200 to 400 mg daily (capsules) - give the patient the oral solution without food and the capsules with food; divide doses above 200 mg daily.

Off-label indications and dosing:

• Mycoses, superficial: 100 mg orally daily or twice daily Maximum dose 600 mg per day; divide doses above 200 mg.
• Coccidioidomycosis: 200 mg every 12 hours.
• Cutaneous or lymphocutaneous sporotrichosis: 200 mg daily by mouth; can be increased to 200 mg twice daily - continue therapy until two to four weeks after the resolution of lesions. The oral solution preparation is preferable.

The capsules and the oral solution are not bioequivalent; the oral solution has higher bioavailability, so caution is advised when switching between formulations.

Renal dosing: CrCl under 10; reduce dose by 50%. In peritoneal and hemodialysis patients, dosing is 100 mg every 12 to 24 hours, with no supplement.

Hepatic dosing is undefined, but clinicians should exercise caution.

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 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 is heart failure or a 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. Researchers found itraconazole to cause eye defects in babies whose mothers had exposure to the drug during pregnancy in a systematic review.[10]

Itraconazole also has the potential for many drug-drug interactions because it is metabolized by cytochrome P450 (specifically CYP3A4) 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 to treat and prevent fungal infections. Trough concentration is the drug’s lowest concentration immediately prior to the next dose.[11] Itraconazole typically requires a prolonged maintenance treatment period, 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 drug concentration requires monitoring if the dose of itraconazole changes or if the prescriber adds a medication to a patient’s regimen 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 no hepatotoxicity.[2] LFTs should be taken at baseline and checked periodically in patients with hepatic impairment or if treatment extends past one month.

Toxicity

Toxic trough levels for itraconazole are over 3 mcg/mL.[12] There is no specific antidote available.

Enhancing Healthcare Team Outcomes

Managing antifungal prophylaxis in immunocompromised patients requires the entire interprofessional healthcare team, including clinicians (MDs, DOs, PAs, NPs), infectious disease specialists in severe cases, nursing staff, pharmacists, and laboratory technologists. 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 coordinating 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 no drug-drug interactions exist between itraconazole and the patient’s current medication; in severe cases, an infectious disease specialty pharmacist can be a valuable addition to the interprofessional team.

The management of itraconazole prophylaxis does not stop after the initial visit and therefore requires the efforts of an interprofessional healthcare team, including clinicians, infectious disease specialists, nursing staff, pharmacists, and other healthcare personnel. Following ordering/prescribing and 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, which can take a toll on their mental health. Furthermore, social workers should be involved in the care of these patients. Many immunocompromised patients use 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. [Level 5]