Noxafil: a new antifungal agent from Schering-Plough

Noxafil (posaconazole) is a new antifungal providing an alternative treatment for patients with invasive fungal infections resistant to or intolerant of amphotericin B or itraconazole.

Brand Name: Noxafil.

Legal category: POM.

Active ingredient: Posaconazole 40 mg per ml.

Description: White oral suspension.

Presentation: 105 ml, £500.69.

Indications: Treatment of invasive fungal infections including:
  • Invasive aspergillosis in patients with disease that is refractory to or who are intolerant of amphotericin B or itraconazole
  • Fusariosis in patients with disease that is refractory to or who are intolerant of amphotericin B.
  • Chromoblastomycosis and mycetoma in patients with disease that is refractory to or who are intolerant of itraconazole.
  • Coccidioidomycosis in patients with disease that is refractory to or who are intolerant of amphotericin B, itraconazole or fluconazole.
Pharmacology: Opportunistic fungal infections often prove to be life-threatening in patients with severely weakened immunity such as those with advanced HIV disease, patients who have undergone organ transplants and those receiving chemotherapy. Posaconazole, a broad spectrum antifungal agent, has been developed for use against invasive opportunistic fungal infections that are resistant to currently available antifungal treatments or where conventional therapies cannot be tolerated.

Posaconazole acts as an inhibitor of the enzyme lanosterol 14α-demethylase (CYP51) which catalyses an essential step in fungal cell wall biosynthesis. In vitro, it is effective against Aspergillus sp. Coccidioides immitis, Fonsecaea pedrosoi and species of Fusarium.

Following oral administration posaconazole is absorbed from the GI tract and peak plasma concentrations are reached within approximately 5 hours of dosing. It is slowly absorbed and slowly eliminated and is highly protein bound. Posaconazole does not have any major circulating metabolites and is excreted in the faeces and urine.

In salvage therapy trials of patients with invasive aspergillosis, refractory to amphotericin B or itraconazole, posaconazole was found to produce an overall successful response in 42% of those treated, compared with 26% of those in the comparator group (derived from retrospective medical records). Moreover, in two large open-label phase III clinical studies, posaconazole treatment resulted in successful clinical outcomes in 71% of patients with zygomycosis, a frequently fatal fungal infection. Likewise posaconazole therapy achieved successful clinical outcomes in 55% of patients (27 of 49) with fungal infections involving the central nervous system.

Investigations involving patients with chronic skin and soft tissue fungal infections such as mycetoma and chromoblastomycosis have demonstrated successful outcomes in 9 of 11 patients treated with posaconazole for up to 377 days, and in patients with coccidioidomycosis 11 of 16 were successfully treated after a period of up to 460 days.

In all clinical studies, posaconazole was generally well tolerated with most reported side effects being characteristic of the underlying disease.

Adult dose: 400 mg (10 ml) twice daily with meal or with 240 ml of nutritional supplement. Alternatively 200 mg (5ml) four times daily without food.

Child dose: Under 18 years, not recommended.

Contraindications: Pregnancy, lactation.

Special precautions: Severe hepatic impairment, monitor liver function. Pro-arrhythmic conditions including QTc prolongation, cardiomyopathy, sinus bradycardia, pre-existing arrhythmia. Monitor electrolyte levels. Diabetes.

Interactions: Ergot alkaloids, CYP3A4 substrates, HMG-CoA reductase inhibitors; contraindicated. Rifabutin, rifamycin, phenytion, carbamazepine, phenobarbital, primidone. Verapamil, ciclosporin, quinidine, clarithromycin, erythromycin. H2 receptor antagonists, proton pump inhibitors. Vinca alkaloids, tacrolimus, sirolimus, antiretroviral agents, digoxin.

Adverse reactions: Neutropenia, anorexia, insomnia, dizziness, headache, paraesthesia, somnolence, hot flushes, GI disturbance, dry skin, pruritus, rash, back pain, asthenia, fatigue, fever, increased hepatic enzymes.
? Report any adverse reaction to CSM.

Further information: Schering-Plough Ltd, Schering-Plough House, Shire Park, Welwyn Garden City, Herts AL7 1TW. Tel: (01707) 363636.
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