Fungal Infections

Posaconazole

Posaconazole (Noxafil, Merckis) fat soluble, synthetic triazole antifungal drug with a chemical structure similar to that of itraconazole.  It was initially studied in patients in 1998 and approved in 2006 for the prophylaxis of fungal infections in acute leukaemia and after allogeneic stem cell transplantation and for the second-line therapy of invasive aspergillosis and mucormycosis. It has the same mechanism of action as all azoles and prevents the formation of ergosterol necessary for the cell membranes of fungi.

Dose & Delivery

Posaconazole is formulated as an oral solution containing numerous ingredients including polysorbate 80 and cherry flavoured, also as tablets and as an intravenous product.   The oral solution  is better absorbed if it is taken with food because this increases the absorption through the gut wall, but the tablet can be taken at any time.

The standard dose of oral solution of  posaconazole dose is 300mg twice daily; 300 mg  1 x day thereafter.  In patients taking posaconazole prophylaxis oral tablets -  the normal dose is 300mg twice  a day for first day thereafter 300mg 1x day.  The concentration of the oral suspension is 40mg /ml so 5ml spoon delivers 200mg.  For posaconazole tablets and intravenous formulation the standard daily dose is 300mg once daily (after the initial day at 300 mg 2x  day).

Fungi the drug is active against

Posaconazole has an extremely wide spectrum of action.  The fungi whose growth are inhibited by posaconazole and include Aspergillus spp., Candida spp., Coccidioides spp., Histoplasma, Paracoccidioides brasiliensis, Blastomyces dermatitidis, Cryptococcus spp., Sporothrix schenckii, various species of Mucorales and Fusarium spp. and numerous other black moulds such as Bipolaris spp. and Exserohilum spp.  The majority of Aspergillus isolates are killed in test tube tests by posaconazole at clinically relevant concentrations; a higher proportion than any other antifungal agent. Acquired resistance to posaconazole does occur in Aspergillus fumigatus and Candida albicans but is otherwise rare.

Typical regimens

Treatment of refractory fungal infections; aspergillosis or zygomycosis, or other rare infection – 300mg twice daily, then 300mg 1x a day thereafter. Monitoring of blood levels of posaconazole shows ~10-fold variation in levels, and low levels are associated with failure. (Dose escalation to 400mg three times daily might be helpful, if the reason for low levels is not a drug interaction).

For prophylaxis of fungal infection, 300mg IV, 2x a day for first day, followed by 300mg IV, 1x day thereafter. Oral tablets 300mg  2x day for first day and thereafter 300mg 1x per day. For oral suspension 200mg 3x day.

For oropharyngeal candidiasis, 100mg  oral suspension twice a day, followed by 100mg daily. For treatment when refractory to itraconazole or fluconazole 400 mg 2x day oral suspension. (see emc recommendation or medscape)

Metabolism and excretion

Posaconazole is absorbed over three to five hours. Increasing doses from 200-800mg daily yield proportional increases in exposure.  It takes 7-10 days to reach steady state levels in blood but most people have sufficient concentrations for activity within two days.  Posaconazole has a very large apparent volume of distribution suggesting extensive tissue uptake.  It is also very highly protein bound (>98%).  Posaconazole is metabolised primarily by the liver into glucuronide conjugates.  The elimination half life is typically 35 hours with most of the drug being excreted in the faeces as unchanged drug.

There is considerable patient to patient variation in drug absorption and exposure, and some transplant patients have consistently low plasma levels.

Drug/Drug interactions

Posaconazole has fewer drug interactions than itraconazole or voriconazole.  Plasma levels fall when posaconazole is co-administered with enzyme reducers such as rifampicin, rifabutin, efavirenz, phenytoin, phenobarbitone, carbomazepine and others.  Posaconacole is less well absorbed when it is given in association with proton pump inhibitors (omeprazole, lansoprazole) or H2 receptor antagonists (cimetidine, ranitidine etc). View drug interaction database.

Posaconazole is a potent inhibitor of CYP3A4. This means that the blood levels of compounds that are metabolised through this system are likely to rise.  Important examples include cyclosporine, tacrolimus and sirolimus, terfenadine, astemizole, and cisapride, ergotamine for migraine, certain statins including simvastatin, lovastatin and atorvastatin, vincristine or vinblastine chemotherapy, midazolam, diazepam and other benzodiazapines and some HIV protease inhibitors.  Other drugs with minor interaction with posaconazole include digoxin and glipizide for diabetes and certain calcium channel blockers such as nifedipine and diltiazem.

Side effects

Common side effects include nausea, mild diarrhoea and abdominal discomfort, indigestion and dry mouth.  Liver function tests may also become elevated with the same frequency as with fluconazole.  Skin rashes due to posaconazole are relatively common.  Fever, fatigue and lacking in energy and loss of appetite is also moderately common. 

Numerous other side effects such as low white blood cells or platelets were apparently associated with posaconazole because the drugs were studied in neutropenia and leukaemia therapy.  The frequency of such events in patients only treated with posaconazole without underlying leukaemia is low.  As with all drugs other less common minor or significant side effects may also occur.  View video "Antifungal skin reactions" .


Structure of posaconazole

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