Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, Netherlands
Hypersensitivity to the active substance, to other echinocandins or to any of the excipients listed in section 6.1.
The development of foci of altered hepatocytes (FAH) and hepatocellular tumours after a treatment period of 3 months or longer were observed in rats. The assumed threshold for tumour development in rats is approximately in the range of clinical exposure. The clinical relevance of this finding is not known. Liver function should be carefully monitored during micafungin treatment. To minimise the risk of adaptive regeneration and potentially subsequent liver tumour formation, early discontinuation in the presence of significant and persistent elevation of ALT/AST is recommended. Micafungin treatment should be conducted on a careful risk/benefit basis, particularly in patients having severe liver function impairment or chronic liver diseases known to represent preneoplastic conditions, such as advanced liver fibrosis, cirrhosis, viral hepatitis, neonatal liver disease or congenital enzyme defects, or receiving a concomitant therapy including hepatotoxic and/or genotoxic properties.
Micafungin treatment was associated with significant impairment of liver function (increase of ALT, AST or total bilirubin > 3 times ULN) in both healthy volunteers and patients. In some patients more severe hepatic dysfunction, hepatitis, or hepatic failure including fatal cases have been reported. Paediatric patients < 1 year of age might be more prone to liver injury (see section 4.8).
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.
Rare cases of haemolysis, including acute intravascular haemolysis or haemolytic anaemia, have been reported in patients treated with micafungin. Patients who develop clinical or laboratory evidence of haemolysis during micafungin therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin therapy.
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).
Patients receiving sirolimus, nifedipine or itraconazole in combination with micafungin 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).
Micafungin has a low potential for interactions with medicines metabolised via CYP3A mediated pathways.
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 coadministration 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 micafungin 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).
There are no data from the use of micafungin in pregnant women. In animal studies micafungin crossed the placental barrier and reproductive toxicity was seen (see section 5.3). The potential risk for humans is unknown. Mycamine should not be used during pregnancy unless clearly necessary.
It is not known whether micafungin is excreted in human breast milk. Animal studies have shown excretion of micafungin in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Mycamine should be made taking into account the benefit of breast-feeding to the child and the benefit of Mycamine therapy to the mother.
Testicular toxicity was observed in animal studies (see section 5.3). Micafungin may have the potential to affect male fertility in humans.
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).
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%).
In the following table adverse reactions are listed by system organ class and MedDRA preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1,000, Not known (frequency cannot be estimated from available data).
Common: leukopenia, neutropenia, anaemia
Uncommon: pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminaemia
Rare: haemolytic anaemia, haemolytic anaemia, haemolysis (see section 4.4)
Not known: disseminated intravascular coagulation
Uncommon: anaphylactic/anaphylactoid reaction (see section 4.4), hypersensitivity
Not known: anaphylactic and anaphylactoid shock (see section 4.4)
Uncommon: hyperhidrosis
Common: hypokalaemia, hypomagnesaemia, hypocalcaemia
Uncommon: hyponatraemia, hyperkalaemia, hypophosphataemia, anorexia
Uncommon: insomnia, anxiety, confusion
Common: headache
Uncommon: somnolence, tremor, dizziness, dysgeusia
Uncommon: tachycardia, palpitations, bradycardia
Common: phlebitis
Uncommon: hypotension, hypertension, flushing
Not known: shock
Uncommon: dyspnoea
Common: nausea, vomiting, diarrhoea, abdominal pain
Uncommon: dyspepsia, constipation
Common: blood alkaline phosphatase increased, aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased (including hyperbilirubinaemia), liver function test abnormal
Uncommon: hepatic failure (see section 4.4), gammaglutamyltransferase increased, jaundice, cholestasis, hepatomegaly, hepatitis
Not known: hepatocellular damage including fatal cases (see section 4.4)
Common: rash
Uncommon: urticaria, pruritus, erythema
Not known: toxic skin eruption, erythema multiforme, StevensJohnson syndrome, toxic epidermal necrolysis (see section 4.4)
Uncommon: blood creatinine increased, blood urea increased, renal failure aggravated
Not known: renal impairment (see section 4.4), acute renal failure
Common: pyrexia, rigors
Uncommon: injection site thrombosis, infusion site inflammation, injection site pain, peripheral oedema
Uncommon: blood lactate dehydrogenase increased
Symptoms such as rash and rigors have been reported in clinical studies. The majority were of mild to moderate intensity and not treatment limiting. Serious reactions (e.g. anaphylactoid reaction 0.2%, 6/3028) were uncommonly reported during therapy with micafungin and only in patients with serious underlying conditions (e.g. advanced AIDS, malignancies) requiring multiple co-medications.
The overall incidence of hepatic adverse reactions in the patients treated with micafungin in clinical studies was 8.6% (260/3028). The majority of hepatic adverse reactions were mild and moderate. Most frequent reactions were increase in AP (2.7%), AST (2.3%), ALT (2.0%), blood bilirubin (1.6%) and liver function test abnormal (1.5%). Few patients (1.1%; 0.4% serious) discontinued treatment due to a hepatic event. Cases of serious hepatic dysfunction occurred uncommonly (see section 4.4).
None of the injection-site adverse reactions were treatment limiting.
The incidence of some adverse reactions (listed in the table below) was higher in paediatric patients than in adult patients. Additionally, paediatric patients <1 year of age experienced about two times more often an increase in ALT, AST and AP than older paediatric patients (see section 4.4). The most likely reason for these differences were different underlying conditions compared with adults or older paediatric patients observed in clinical studies. At the time of entering the study, the proportion of paediatric patients with neutropenia was several-fold higher than in adult patients (40.2% and 7.3% of children and adults, respectively), as well as allogeneic HSCT (29.4% and 13.4%, respectively) and haematological malignancy (29.1% and 8.7%, respectively).
Common: thrombocytopenia
Common: tachycardia
Common: hypertension, hypotension
Common: hyperbilirubinaemia, hepatomegaly
Common: acute renal failure, blood urea increased
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 national reporting system listed in Appendix V.
This medicinal product must not be mixed or co-infused with other medicinal products except those mentioned in section 6.6.
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