Posaconazole

Posaconazole (Noxafil®; Merck and Co. New Jersey, USA) is an azole antifungal medication indicated for:

• prevention of invasive aspergillus and candida infections in high risk severely immunocompromised patients (such as haematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with haematologic malignancies with prolonged neutropaenia from chemotherapy.
• treatment of oropharyngeal candidiasis (OPC) including OPC refractory to itraconazole and/or fluconazole.

How does posaconazole work?

• Posaconazole is a triazole antifungal agent.
• It works by preventing fungi from producing a substance called ergosterol, which is a component of fungal cell membranes.
• Posaconazole is a potent inhibitor of the enzyme lanosterol 14α-demethylase, which catalyses an essential step in ergosterol biosynthesis in the fungal cell membrane.
• The cell membranes of fungi are vital for their survival.
• They keep unwanted substances from entering the cells and stop the contents of the cells from leaking out.
• Without ergosterol as part of the cell membrane, the membrane is weakened and damaged and essential constituents of the fungal cells can leak out.
• This kills the fungi and hence clears up the infection.

Dosage and administration of posaconazole

Posaconazole is available as:

• an injection (18 mg/ml for patients 18 years and older; US FDA approved in 2014)
• delayed-release tablets (100 mg for patients 13 years and older; US FDA-approved in 2013)
• oral suspension (40 mg/ml for patients 13 years and older; US FDA-approved in 2006).

Prophylaxis of invasive aspergillus and candida infections

• The recommended dose is 300 mg IV posaconazole twice a day on the first day, then once a day thereafter until recovery from neutropaenia or immunosuppression.
• With delayed-release tablets, the loading dose is 300 mg twice a day on day 1, then 300 mg once daily commencing on day 2.
• Dosage with oral suspension is 200 mg three times a day until recovery from neutropaenia or immunosupression.

Oropharyngeal candidiasis

• Treatment is with an oral suspension.
• The loading dose is 100 mg twice a day on day 1 then 100 mg daily for 13 days.

Azole-resistant oropharyngeal candidiasis

• Oropharyngeal candidiasis refractory to itraconazole and/or fluconazole can be treated with an oral suspension of posaconazole.
• Posaconazole 400 mg is administered twice daily.
• Duration of therapy is based on severity of the patient's underlying disease and clinical response.

Dosage modifications

• The pharmacokinetics of posaconazole oral suspension are not significantly affected by renal impairment.
• Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.
• Posaconazole injection should be avoided in patients with moderate or severe renal impairment unless an assessment of the benefit/risk to the patient justifies its use.
• Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to posaconazole oral therapy.
• It is recommended that no dose adjustment of posaconazole oral or injectable preparation is needed in patients with mild to severe hepatic impairment.

Contraindications to treatment with posaconazole

• Hypersensitivity: posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.
• Posaconazole is also a strong inhibitor of hepatic CYP3A4 enzymes and its use is contraindicated with CYP3A4 substrates, such as pimozide and quinidine, which result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes.
• Posaconazole is contraindicated with ergot alkaloids. Most of the ergot alkaloids are substrates of CYP3A4 and posaconazole may increase the plasma concentrations of ergot alkaloids (such as ergotamine and dihydroergotamine) leading to ergotism.
• Co-administration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 enzymes (eg atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis.

Link to key clinical-trial evidence about posaconazole

Potential drug interactions with posaconazole

• Posaconazole is not metabolized to a clinically significant extent through the hepatic cytochrome P450 enzyme system. However, posaconazole is an inhibitor of CYP3A4 and thus the plasma levels of drugs that are metabolized through this enzyme pathway may increase when administered with posaconazole.
• Sirolimus: concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus.
• Tacrolimus: posaconazole has been shown to significantly increase the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of tacrolimus. At initiation of posaconazole treatment, the dose of tacrolimus should be reduced to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly.
• Ciclosporin: posaconazole has been shown to increase ciclosporin whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce ciclosporin dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of ciclosporin whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the ciclosporin dose adjusted accordingly.
• Benzodiazepines: concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (eg midazolam, alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects.
• Calcium channel blockers: posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (eg verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during co-administration. Dose reduction of calcium channel blockers may be needed.
• Posaconazole is metabolised via UDP glucuronidation and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations.
• Phenytoin: is metabolized by CYP3A4 enzymes and induces UDP glucronidase. Therefore, co-administration of phenytoin with posaconazole increases phenytoin but decreases posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed and dose reduction of phenytoin should be considered.
• Rifabutin: (300 mg once a day) decreased the Cmax and AUC of posaconazole by 43 % and 49 %, respectively. Posaconazole increased the Cmax and AUC of rifabutin by 31 % and 72% respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk.
• No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.
• Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with posaconazole oral suspension results in decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.

What are the adverse effects of posaconazole?

• The most frequently reported adverse reactions in clinical trials with IV posaconazole 300 mg once daily were diarrhoea (32%), hypokalaemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with posaconazole oral suspension.
• The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhoea, pyrexia, and nausea.upper respiratory tract infection (2.5%).
• The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%).

Use of posaconazole in pregnancy

• There are no adequate and well controlled trials of posaconazole in pregnant women.
• Posaconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use of posaconazole in nursing mothers

• It is not known whether posaconazole or its metabolites are present in human milk.
• Women should be advised to discontinue breastfeeding during treatment.

Use of posaconazole in children

• The safety and effectiveness of posaconazole injection in paediatric patients below the age of 18 years of age has not been established.
• In the 13–17 year age groups, the safety profile of posaconazole 600 mg/day oral suspension for the treatment of invasive fungal infection was similar to that observed in adult patients.

Use of posaconazole in the elderly

• In clinical trials, there were no differences in safety or efficacy of posaconazole injectable, delayed-release or oral suspension, between older (> 65 years) and younger subjects.

Antifungal drug resistance

In recent years, both topical and oral allylamine and triazole antifungal drug resistance has become a problem, particularly in the Indian subcontinent.

Extensive therapy-resistant dermatophyte infection should prompt this as a possible problem. Where available, fungal culture and estimation of drug minimum inhibitory concentration determined to guide appropriate medication

For more information, see antifungal drug resistance.