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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

New headings: Mycamine 50& 100 mg

 4.1     Therapeutic indications

Consideration should be given to official/national guidance on the appropriate use of antifungal agents.

 4.2     Posology and method of administration

Consideration should be given to official/national guidance on the appropriate use of antifungal agents.

Treatment with Mycamine should be initiated by a physician experienced in the management of fungal infections.

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Posology

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Oesophageal candidiasis: For the treatment of oesophageal candidiasis, micafungin Mycamine should be administered for at least one week after resolution of clinical signs and symptoms.

Prophylaxis of Candida infections: For prophylaxis of Candida infection, micafungin Mycamine should be administered for at least one week after neutrophil recovery.

Use in children (including neonates) < 4 months of age

*

Prophylaxis of Candida infections: For prophylaxis of Candida infection, micafungin Mycamine should be administered for at least one week after neutrophil recovery. Experience with Mycamine in patients less than 2 years of age is limited.

Gender/race

No dose adjustment is necessary based on gender or race (see section 5.2).

The safety and efficacy in children (including neonates) less than 4 months of age of doses of 4 and 10 mg/kg for the treatment of invasive candidiasis with CNS involvement has not been adequately established. Currently available data are described in section 4.8, 5.1, 5.2.

 4.6     Fertility, pregnancy and lactation

Inclusion of Fertility in heading

 
4.7     Effects on ability to drive and use machines

Micafungin has no or negligible influence on the ability to drive or use machines. However, patients should be informed that dizziness has been reported during treatment with micafungin (see section 4.8).

No studies on the effects on the ability to drive and use machines have been performed. However, adverse reactions may occur, which may influence the ability to drive and use machines (see section 4.8).

 
4.8     Undesirable effects

Summary of the safety profile

The safety profile of micafungin is based on 3028 patients treated with micafungin in clinical studies: 2.002 patients with Candida infections (including candidaemia, invasive candidiasis and oesophageal candidiasis), 375 with invasive aspergillosis (primarily refractory infections) and 651 for prophylaxis of systemic fungal infections.

The patients treated with micafungin in clinical studies represent a critically ill patient population that requires multiple medicinal products including antineoplastic chemotherapy, potent systemic immunosuppressants and broad spectrum antibiotics. These patients had a wide variety of complex underlying conditions such as haematological malignancies and HIV-infection or were transplant recipients and/or treated in intensive care. Patients treated prophylactically with micafungin were those undergoing haematopoetic stem cell transplantation (HSCT) who were at high risk for fungal infections.

Based on clinical trial experience, overall 32.2% of the patients experienced adverse drug reactions. The most frequently reported adverse reactions were nausea (2.8%), blood alkaline phosphatase increased (2.7%), phlebitis (2.5%, primarily in HIV infected patients with peripheral lines), vomiting (2.5%), and aspartate aminotransferase increased (2.3%). No clinically significant differences were seen when the safety data were analysed by gender or race.

 9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 April 2008

Date of latest renewal: 20 December 2012 19 February 2018

 10.     DATE OF REVISION OF THE TEXT

29 June 2016
19 February 2018

Information on dosing and instructions for use in children (including neonates) < 4 months has been added

Section 4.9:
Reported case of overdose in newborn patient added

Section 5.2:
Information on the pharmacokinetic properties in children less than 4 months has been added

Section 10:
Date of revision updated to 29 June 2016

5.2 Pharmacokinetic properties (text in bold added, strikethrough text deleted)

Special Populations

Paediatric patients: In paediatric patients AUC values were dose proportional over the dose range of 0.5 4 mg/kg. Clearance was influenced by weight, with mean values of weight-adjusted clearance 1.35 times higher in the younger children (4 months to 5 years) and 1.14 times higher in paediatric patients aged 6 to 11 years. Older children (12-16 years) had mean clearance values similar to those determined in adult patients.Clearance was influenced by age, with mean values of clearance in younger children (2 11 years) being approximately 1.3 fold greater than those in older children (12 17 years). Older children had mean clearance values similar to those determined in adult patients. Mean clearance in premature infants (gestational age approximately 26 weeks) is approximately 5 fold greater than in adults.

Date of revision of the text: 17-Dec-2015

4.8     Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the online reporting option (preferable method) accessible from the IMB homepage (www.imb.ie).  A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

PK/PD relationship

An additive or synergistic pharmacodynamic interaction of micafungin and amphotericin B was found in a mouse model of pulmonary aspergillosis (immunosuppression with hydrocortisone, intranasal infection with Aspergillus fumigatus)In animals models of candidiasis, a correlation was observed between exposure of micafungin divided by MIC (AUC/MIC) and efficacy defined as the ratio required to prevent progressive fungal growth. A ratio of ~2400 and ~1300 was required for C. albicans and C. glabrata, respectively, in these models. At the recommended therapeutic dosage of Mycamine, these ratios are achievable for the wild-type distribution of Candida spp.

Mechanism(s) of resistance

As for all antimicrobial agents, cases of reduced susceptibility and resistance have been reported and cross-resistance with other echinocandins cannot be excluded. Reduced susceptibility to echinocandins has been associated with mutations in the Fks1 and Fks2 genes coding for a major subunit of glucan synthase.

Breakpoints

Susceptibility testing was performed with modifications according to the Clinical and Laboratory Standards Institute (CLSI) methods M27‑A2 (Candida species) and M38‑A (Aspergillus species), respectively. To date, standardised techniques for susceptibility testing for 1,3‑b‑D‑glucan synthesis inhibitors have not been established and results of susceptibility testing do not necessarily correlate with clinical outcome.

Although no MIC breakpoints for echinocandins have been established, a MIC of < 2 mg/l encompasses > 99% of all clinical isolates of Candida spp. without bisecting any species group and represents a concentration that is easily maintained throughout the dosing interval. Infections due to Candida spp. in this MIC range are likely to respond to therapy.

Astellas Pharma Europe B.V.

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2333 EB Leiden

Netherlands

4.4     Special warnings and precautions for use

The following text has been deleted:

“This medicinal product for intravenous use contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.”

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal: 20^th December 2012

All other changes made are in line with the QRD template.

4.3     Contraindications

Hypersensitivity to the active substance, to other echinocandins or to any of the excipients.

During administration of micafungin, anaphylactic/anaphylactoid reactions including shock may occur. If these reactions occur, micafungin infusion should be discontinued and appropriate treatment administered.

Exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. If patients develop a rash they should be monitored closely and micafungin discontinued if lesions progress.

4.8     Undesirable effects

4.4     Special warnings and precautions for use

Co-administration of micafungin and amphotericin B desoxycholate should only be used when the benefits clearly outweigh the risks, with close monitoring of amphotericin B desoxycholate toxicities (see section 4.5).

Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or itraconazole dosage should be reduced if necessary (see section 4.5).

The incidence of some adverse reactions was higher in paediatric patients than in adult patients (see section 4.8).

4.5     Interaction with other medicinal products and other forms of interaction

Drug interaction studies in healthy human subjects were conducted to evaluate the potential for interaction between micafungin and mycophenolate mofetil, ciclosporin, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin B. In these studies, no evidence of altered pharmacokinetics of micafungin was observed. No micafungin dose adjustments are necessary when these medicines are administered concomitantly. Exposure (AUC) of itraconazole, sirolimus and nifedipine was slightly increased in the presence of micafungin (22%, 21% and 18% respectively).

Co-administration of micafungin and amphotericin B desoxycholate was associated with a 30% increase in amphotericin B desoxycholate exposure. Since this may be of clinical significance this co-administration should only be used when the benefits clearly outweigh the risks, with close monitoring of amphotericin B desoxycholate toxicities (see section 4.4).

Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or itraconazole dosage should be reduced if necessary (see section 4.4).

10.     DATE OF REVISION OF THE TEXT

December 2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

Changes in Red

4.4     Special warnings and precautions for use

Micafungin may cause kidney problems, renal failure, and abnormal renal function test. Patients should be closely monitored for worsening of renal function.

Co-administration of micafungin and amphotericin B desoxycholate should only be used when the benefits clearly outweigh the risks, with close monitoring of amphotericin B desoxycholate toxicities (see section 4.5).

10.     DATE OF REVISION OF THE TEXT

August  2010

Change detail Mycamine SPC

Version April 2009 versus November 2009

Section 4.2 Posology and method of administration.

Use in patients with hepatic impairment

There are currently no data available for the use of Mycamine in patients with severe hepatic impairment and its use is not recommended in these patients (see section 4.4).

Was updated to read:

There are currently insufficient data available for the use of Mycamine in patients with severe hepatic impairment and its use is not recommended in these patients (see section 4.4 and 5.2).

Section 4.4       Special warnings and precautions for use

Removed the following sentence:

There are insufficient data on the pharmacokinetics of micafungin in patients with severe hepatic impairment (see section 5.2).

Section 5.2       Pharmacokinetic properties

Deleted the following sentence: The pharmacokinetics of micafungin has not been studied in patients with severe hepatic insufficiency.

Inserted the following: In a study performed in patients with severe hepatic impairment (Child-Pugh score 10-12) (n=8), lower plasma concentrations of micafungin and higher plasma concentrations of the hydroxide metabolite (M-5) were seen compared to healthy subjects (n=8). These data are insufficient to support a dosing recommendation in patients with severe hepatic impairment.

Section  9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Removed: Date of first authorisation

Section 10.       DATE OF REVISION OF THE TEXT

Inserted 11/2009.