New drug
Micafungin for invasive candidiasis
- Aust Prescr 2014;37:64-71
- 17 March 2014
- DOI: 10.18773/austprescr.2014.030
ISSUE 2 APRIL
Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Approved indication: invasive candidiasis
Mycamine (Astellas)
vials containing 50 mg or 100 mg powder for reconstitution
Australian Medicines Handbook section 5.2
Like anidulafungin and caspofungin, micafungin is an echinocandin antifungal drug. It selectively inhibits an enzyme, glucan synthase, required for fungal cell wall synthesis. Micafungin has in vitro activity against Candida albicans, C. tropicalis, C. glabrata, C. krusei, C. guilliermondii and C. parapsilosis. It also has activity against Aspergillus species.
Following slow intravenous infusion of micafungin once a day, steady-state concentrations are reached within 4–5 days. Micafungin undergoes minimal hepatic metabolism and has a terminal half-life of around 10–17 hours. It is mainly eliminated in the faeces. The clearance of micafungin in premature infants is 2–6 times faster than in adults.
The efficacy of micafungin has been assessed for the treatment of invasive and oesophageal candidiasis1 (Table). In the trials, C. albicans was the most common species isolated from patients, with C. tropicalis, C. parapsilosis and C. glabrata being less common.
Table 1 Success rates of micafungin in comparative trials1-6
| Indication | Overall treatment success | |
| Invasive candidiasis‡ | micafungin | amphotericin B |
| adults1 | 74.1% (183/247) | 69.6% (172/247) |
| children2 | 72.9% (35/48) | 76% (38/50) |
| micafungin | caspofungin | |
| adults3 | 100 mg: 76.4% (146/191) 150 mg: 71.4% (142/199) |
72.3% (136/188) |
| Oesophageal candidiasisδ | micafungin | fluconazole |
| adults4 | 87.7% (228/260) | 88% (227/258) |
| adults5 | 100 mg: 77.4% (48/62) 150 mg: 89.9% (53/59) |
86.7% (52/60) |
| Prophylaxis in patients undergoing stem cell transplant§ | micafungin | fluconazole |
| adults and children6 | 80% (340/425) | 73.5% (336/457) |
| ‡ eradication of Candida species and clinical improvement for treatment trials δ endoscopic cure rates § absence of proven or probable fungal infection in the prevention trial |
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Micafungin was compared to liposomal amphotericin B for invasive candidiasis in adults1 and children2 (including newborn and premature babies). The median dose of micafungin was 100 mg/day in adults and 2 mg/kg in children, for 15 days. A successful response was defined as mycological eradication and complete or partial clinical improvement. Micafungin was found to be comparable to amphotericin B in both studies.1,2 Similar results were found in another comparison with caspofungin3 (Table).
Micafungin (100–150 mg/day) has also been compared to fluconazole in two trials of adults with oesophageal candidiasis. As this is an opportunistic infection, most of the patients had HIV. In both studies, endoscopic cure rates for micafungin were found to be comparable to fluconazole after two weeks of treatment (see Table).4,5
Micafungin has also been investigated for the prevention of invasive fungal infections in adults and children undergoing stem cell transplant.6 Patients received intravenous micafungin (50 mg/day or 1 mg/kg in patients less than 50 kg) or fluconazole (400 mg/day or 8 mg/kg in patients less than 50 kg) within 48 hours of starting the transplant conditioning regimen. (Most patients were neutropenic at baseline.) Treatment continued until the patient's neutrophil count had recovered or they developed a fungal infection (mean duration of 19 days for adults and 23 days for children). The proportion of patients who remained infection free was higher in the micafungin group than in the fluconazole group (see Table).
Microbial resistance and reduced susceptibility to micafungin has been reported and is thought to be associated with mutations in a gene encoding the major subunit of the glucan synthase. Persistence of Candida species at the end of micafungin treatment occurred in 9% of adults1 and 15.5% of children2 with invasive candidiasis.
In a safety cohort of 3028 patients, adverse reactions possibly caused by micafungin included allergic reactions such as rash (1.9%) and rigors (1.1%), injection-site reactions (2.5%), headache (1.8%), nausea (2.8%), vomiting (2.5%), diarrhoea (2%), fever (2.1%), abdominal pain (0.9%) and pruritus (0.8%). Anaphylactic reactions occurred in two patients. Serious adverse events that led to treatment discontinuation included hepatic, renal and allergic or infusion-related events.
Haematological adverse reactions were observed in up to 10% of patients – leucopenia, neutropenia and anaemia were the most common. Thrombocytopenia was reported less frequently (0.9%). Electrolyte disturbances such as low potassium, magnesium and calcium were also common. Renal effects, including increased serum creatinine and urea, were observed in 1.7% of patients receiving micafungin.
Micafungin was associated with significant liver impairment in healthy volunteers and patients (8.6% in the safety cohort), and hepatic failure has been reported. Monitor liver function and if problems develop, consider stopping treatment. In pre-clinical studies, rats treated with micafungin developed liver tumours after three months. Alternative treatment options may need to be considered for patients with preneoplastic conditions such as liver cirrhosis, viral hepatitis, advanced liver fibrosis and neonatal liver disease, and for those receiving concomitant hepatotoxic or genotoxic drugs.
Some adverse events were more common in children than in adults. Increases in liver enzymes were twice as likely in those under one year. Renal effects were also more common (acute renal failure occurred in 1% of children) as were thrombocytopenia, tachycardia, hypertension and hypotension (1–2% of children).
Micafungin is contraindicated in people who have hypersensitivity to other echinocandin drugs. In animal studies, micafungin was associated with fetal abnormalities and increased abortion rates. It is a category C pregnancy drug and should only be used if the benefit outweighs the risk. Caution is also urged during breastfeeding.
The efficacy of micafungin seems to be comparable to several other antifungal drugs and provides another option for patients with, or at risk of, serious fungal infections. However, allergic and infusion-site reactions are a problem in some patients and hepatic effects may limit treatment.
In clinical practice guidelines, micafungin is one of the options recommended as first-line therapy for candidiasis in adults. However, in neonates the guidelines recommend its use be limited to incidences of fluconazole resistance or toxicity.7
manufacturer provided additional useful information
The Transparency Score () is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
Notes on references
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).
References
- Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candisosis: a phase III randomised double-blind trial. Lancet 2007;369:1519-27.
- Queiroz-Telles F, Berezin E, Leverger G, Freire A, van der Vyver A, Chotpitayasunmondh T, et al. Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial. Pediatr Infect Dis J 2008;27;820-6.
- Pappas PG, Rotstein CMF, Betts RF, Nucci M, Talwar D, De Waele JJ, et al. Micafungin versus caspofungin for treatment of candidaemia and other forms of invasive candidiasis. Clin Infect Dis 2007;45:883-93.
- de Wet NT, Bester AJ, Viljoen JJ, Filho F, Suleiman JM, Ticona E, et al. A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther 2005;21:899-907.
- de Wet NT, Llanos-Cuentas A, Suleiman JM, Baraldi E, Krantz EF, Della Negra M, et al. A randomized, double-blind, parallel-group, dose response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis 2004;39:842-9.
- van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004;39:1407-16.
- Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503-35.
