Posaconazole: Action as a Triazole Antifungal

Posaconazole (brand name Noxafil) is a triazole antifungal with a very broad spectrum of activity. It has been approved in the USA since 2005 and in Europe since 2006, and is used in hematooncology and in patients with severe immunodeficiencies as a reserve medication. Posaconazole is available as an oral suspension, enteric-coated tablet, and intravenous infusion. The tablet form and intravenous solution have significantly more predictable levels than the older suspension and are now standard.

Compared to itraconazole and voriconazole, posaconazole offers a broader spectrum with activity against Mucorales (moulds such as Mucor and Rhizopus), which are resistant to many other antifungals. In prophylaxis of patients with prolonged neutropenia following chemotherapy or allogeneic hematopoietic stem cell transplantation, posaconazole has a firm place and significantly reduces the incidence of invasive fungal infections.

Mechanism of Action

Posaconazole inhibits the fungal enzyme lanosterol 14 alpha demethylase, a cytochrome P450-dependent enzyme. This blocks the synthesis of ergosterol, the major component of the fungal cell membrane. Toxic sterol precursors accumulate, the membrane becomes permeable, and fungal growth stops. In many pathogens, posaconazole acts fungiostatically, and in Aspergillus also fungicidally.

The spectrum of activity is very broad: Candida species including non-albicans strains, Aspergillus, Mucorales (Mucor, Rhizopus, Lichtheimia), Cryptococcus, Coccidioides, Histoplasma, Fusarium, and several other moulds. Activity against Mucorales distinguishes posaconazole from voriconazole and makes it the first choice for mucormycosis, a severe and rapidly progressive fungal disease in diabetics and immunosuppressed patients.

Pharmacokinetically, the oral tablet shows high bioavailability independent of gastric acid and meals, which is a significant advantage over the older suspension. The half-life is 25 to 35 hours, steady state is reached after 7 to 10 days. Posaconazole is predominantly metabolized hepatically via glucuronidation. Therapeutic drug monitoring is standard because interindividual variability in levels is large.

Applications

• Prophylaxis of invasive fungal infections in patients with prolonged neutropenia after chemotherapy (for example, acute myeloid leukemia) or after allogeneic hematopoietic stem cell transplantation
• Treatment of invasive aspergillosis, especially in case of failure or intolerance of voriconazole
• Treatment of mucormycosis, alone or in combination with amphotericin B
• Fusariosis, coccidioidomycosis, chromoblastomycosis in specialized indications
• Treatment and prophylaxis of oropharyngeal candidiasis in case of failure of fluconazole or itraconazole

Posaconazole is not first-line therapy for simple dermatophyte infections or uncomplicated onychomycosis. Because of drug levels and interaction potential, use is limited to severe and otherwise untreatable indications.

Dosage and Administration

Enteric-coated tablets: Loading dose 300 mg twice daily on day 1, then 300 mg once daily. Steady state after 7 to 10 days.

Intravenous solution: Loading dose 300 mg twice daily on day 1, then 300 mg once daily, via central venous access.

Oral suspension (older, variable levels): 200 mg three times daily or 400 mg twice daily, always with a fatty meal or acidic beverage to enhance absorption.

Therapeutic drug monitoring: Trough level above 0.7 mg per liter for prophylaxis, above 1.0 to 1.25 mg per liter for treatment. Level measurement after 7 days at steady state and in case of clinical deterioration.

Renal insufficiency: no adjustment needed for oral therapy. The intravenous solution with cyclodextrin carrier is contraindicated at eGFR below 50 ml per minute due to accumulation of the carrier material.

Hepatic insufficiency: use caution with moderate to severe impairment, dosage reduction if necessary. Regular liver monitoring.

Duration of therapy: Prophylaxis for as long as the risk persists (often several weeks), treatment individualized according to pathogen, clinical course, and imaging over weeks to months.

Side Effects

Common: nausea, vomiting, diarrhea, abdominal pain, headache, rash, pruritus, elevation of liver transaminases.

Occasional: hypokalemia, hyperkalemia, hypertension, sleep disturbances, dizziness, accommodation disorder, allergic reactions.

Rare but relevant: hepatotoxicity up to acute liver failure, QT prolongation with risk of torsade de pointes, pancreatitis, Stevens-Johnson syndrome, DRESS syndrome.

Endocrine: hyperaldosteronism with hypertension and hypokalemia is a class effect of triazoles, especially with prolonged therapy.

With cyclodextrin-containing intravenous solution: accumulation in renal insufficiency. The newer formulation without cyclodextrin reduces this problem.

QT interval: risk for torsade de pointes especially in hypokalemia, hypomagnesemia, bradycardia, and concomitant medication with other QT-prolonging substances. Consider ECG before and during therapy.

Drug Interactions

• CYP3A4 substrates (statins such as simvastatin or atorvastatin, calcium antagonists, tacrolimus, sirolimus, cyclosporine, vincristine, imatinib): levels increase significantly, risk of toxicity, dosage adjustment or therapy change needed.
• QT-prolonging drugs (quinolones, methadone, citalopram at higher doses, domperidone, erythromycin): cumulative QT prolongation, ECG monitoring.
• Direct oral anticoagulants: level elevation, bleeding risk, observe dosage adjustment.
• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, efavirenz, St. John's wort): lower posaconazole levels, therapy failure threatens, avoid combination if possible.
• Vincristine and other vinca alkaloids: contraindicated due to severe neurotoxic reactions.
• Ergot alkaloids, pimozide, quinidine, cisapride: contraindicated due to risk of severe arrhythmias.
• Glucocorticoids: level elevation possible, additive Cushing risk with prolonged concomitant use.
• Acid suppressors: relevant only for oral suspension because absorption is pH-dependent. No effect on tablets and intravenous solution.

Special Notes

Pregnancy: Posaconazole is teratogenic in animal models. Use in pregnancy is recommended only for life-threatening indications and after individual risk-benefit assessment. Women of childbearing age require reliable contraception during therapy and for approximately one month after. Breastfeeding: Transfer into breast milk, breastfeeding during therapy not recommended.

Children: Use in pediatrics from 2 years of age possible in specialized centers, weight-adjusted dosing.

Before starting therapy: History, ECG, liver and kidney values, electrolytes (potassium, magnesium), check concomitant medication, pregnancy test. Prepare for therapeutic drug monitoring.

Monitoring: Posaconazole trough level at steady state, liver values every two to four weeks, electrolytes regularly, ECG in patients with cardiac risk factors.

Lifestyle: in hematooncology patients, protective measures such as HEPA-filtered rooms, avoidance of potted plants, construction work, and mould-laden environments complement antifungal prophylaxis.

When to see a doctor: for new cardiac symptoms such as syncope or palpitations, signs of hepatotoxicity (nausea, fatigue, jaundice), severe skin reactions, or clinical deterioration despite therapy, immediate medical consultation.

Ability to drive: restricted in case of fatigue or dizziness, individual assessment.

You may also be interested in

• Itraconazole, another triazole antifungal
• Ketoconazole, older imidazole antifungal
• Amphotericin, polyene antifungal as reserve medication
• Clarithromycin, example of CYP3A4 interactions
• Rifampicin, strong CYP3A4 inducer with clinical relevance

Frequently Asked Questions

Sources

• EMA, Noxafil (Posaconazole) EPAR
• Gelbe Liste, Posaconazole active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for invasive fungal infections
• ECIL, European Conference on Infections in Leukemia