ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

Mycamine 50 mg powder for concentrate for solution for infusion

Mycamine 100 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Mycamine 50 mg

Each vial contains 50 mg micafungin (as sodium).

After reconstitution each ml contains 10 mg micafungin (as sodium).

Mycamine 100 mg

Each vial contains 100 mg micafungin (as sodium).

After reconstitution each ml contains 20 mg micafungin (as sodium).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion

White compact powder

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Mycamine is indicated for:

Adults, adolescents ≥ 16 years of age and elderly:

- Treatment of invasive candidiasis.
- Treatment of oesophageal candidiasis in patients for whom intravenous therapy is appropriate.
- Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell
transplantation or patients who are expected to have neutropenia (absolute neutrophil
count < 500 cells / µl) for 10 or more days.

Children (including neonates) and adolescents < 16 years of age:

- Treatment of invasive candidiasis.
- Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell
transplantation or patients who are expected to have neutropenia (absolute neutrophil
count < 500 cells / µl) for 10 or more days.

The decision to use Mycamine should take into account a potential risk for the development of liver
tumours (see section 4.4). Mycamine should therefore only be used if other antifungals are not
appropriate.

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

4.2 Posology and method of administration

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

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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.

The dose regimen of micafungin depends on the body weight of the patient as given in the following
tables:

Use in adults, adolescents ≥ 16 years of age and elderly

Indication
Body weight > 40 kg Body weight ≤ 40 kg
Treatment of invasive candidiasis 100 mg/day* 2 mg/kg/day*
Treatment of oesophageal candidiasis 150 mg/day 3 mg/kg/day
Prophylaxis of Candida infection 50 mg/day 1 mg/kg/day
*If the patient’s response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, the
dose may be increased to 200 mg/day in patients weighing > 40 kg or 4 mg/kg/day in patients ≤ 40 kg.

Treatment duration
Invasive candidiasis: The treatment duration of Candida infection should be a minimum of 14 days.
The antifungal treatment should continue for at least one week after two sequential negative blood
cultures have been obtained and after resolution of clinical signs and symptoms of infection.

Oesophageal candidiasis: Micafungin should be administered for at least one week after resolution of
clinical signs and symptoms.

Prophylaxis of Candida infections: Micafungin should be administered for at least one week after
neutrophil recovery.

Use in children ≥ 4 months of age up to adolescents < 16 years of age

Indication
Body weight > 40 kg Body weight ≤ 40 kg
Treatment of invasive candidiasis 100 mg/day* 2 mg/kg/day*
Prophylaxis of Candida infection 50 mg/day 1 mg/kg/day
*If the patient’s response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, the
dose may be increased to 200 mg/day in patients weighing > 40 kg or 4 mg/kg/day in patients weighing ≤ 40 kg.

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

Indication
Treatment of invasive candidiasis 4 -10 mg/kg/day*
Prophylaxis of Candida infection 2 mg/kg/day
*Micafungin dosed at 4 mg/kg in children less than 4 months approximates drug exposures achieved in adults
receiving 100 mg/day for the treatment of invasive candidiasis. If central nervous system (CNS) infection is
suspected, a higher dosage (e.g. 10 mg/kg) should be used due to the dose-dependent penetration of micafungin
into the CNS (see section 5.2).

Treatment duration
Invasive candidiasis: The treatment duration of Candida infection should be a minimum of 14 days.
The antifungal treatment should continue for at least one week after two sequential negative blood
cultures have been obtained and after resolution of clinical signs and symptoms of infection.

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

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Hepatic impairment
No dose adjustment is necessary in patients with mild or moderate hepatic impairment (see section
5.2). There are currently insufficient data available for the use of micafungin in patients with severe
hepatic impairment and its use is not recommended in these patients (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is necessary in patients with renal impairment (see section 5.2).

Paediatric population
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.

Method of administration

For intravenous use.

After reconstitution and dilution, the solution should be administered by intravenous infusion over
approximately 1 hour. More rapid infusions may result in more frequent histamine mediated reactions.
For reconstitution instructions see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance, to other echinocandins or to any of the excipients listed in
section 6.1.

4.4 Special warnings and precautions for use

Hepatic effects:
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).

Anaphylactic reactions

During administration of micafungin, anaphylactic/anaphylactoid reactions, including shock, may

occur. If these reactions occur, micafungin infusion should be discontinued and appropriate treatment
administered.

Skin reactions

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.

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Haemolysis

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.

Renal effects

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

Interactions with other medicinal products

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).

Paediatric population

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

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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 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 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).

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4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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.

Fertility

Testicular toxicity was observed in animal studies (see section 5.3). Micafungin may have the potential
to affect male fertility in humans.

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).

4.8 Undesirable effects

Summary of the safety profile

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%).

Tabulated list of adverse reactions

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.

System Organ Common Uncommon Rare Not known

Class ≥ 1/100 to < 1/10 ≥ 1/1,000 to < 1/100 ≥ 1/10,000 to (frequency
< 1/1,000 cannot be
estimated from
available data)
Blood and leukopenia, pancytopenia, haemolytic disseminated
lymphatic system neutropenia, anaemia thrombocytopenia, anaemia, intravascular
disorders eosinophilia, haemolysis coagulation
hypoalbuminaemia (see section
4.4)
Immune system anaphylactic / anaphylactic
disorders anaphylactoid and
reaction (see section anaphylactoid
4.4), hypersensitivity shock (see
section 4.4)

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System Organ Common Uncommon Rare Not known
Class ≥ 1/100 to < 1/10 ≥ 1/1,000 to < 1/100 ≥ 1/10,000 to (frequency
< 1/1,000 cannot be
estimated from
available data)
Endocrine hyperhidrosis
disorders
Metabolism and hypokalaemia, hyponatraemia,
nutritional hypomagnesaemia, hyperkalaemia,
disorders hypocalcaemia hypophosphataemia,
anorexia
Psychiatric insomnia, anxiety,
disorders confusion
Nervous system headache somnolence, tremor,
disorders dizziness, dysgeusia
Cardiac disorders tachycardia,
palpitations,
bradycardia
Vascular phlebitis hypotension, shock
disorders hypertension,
flushing
Respiratory, dyspnoea
thoracic and
mediastinal
disorders
Gastrointestinal nausea, vomiting, dyspepsia,
disorders diarrhoea, abdominal constipation
pain
Hepatobiliary blood alkaline hepatic failure (see hepatocellular
disorders phosphatase increased, section 4.4), gamma- damage
aspartate glutamyltransferase including fatal
aminotransferase increased, jaundice, cases (see
increased, alanine cholestasis, section 4.4)
aminotransferase hepatomegaly,
increased, blood hepatitis
bilirubin increased
(including
hyperbilirubinaemia),
liver function test
abnormal
Skin and rash urticaria, pruritus, toxic skin
subcutaneous erythema eruption,
tissue disorders erythema
multiforme,
Stevens-
Johnson
syndrome,
toxic
epidermal
necrolysis (see
section 4.4)
Renal and urinary blood creatinine renal
disorders increased, blood urea impairment
increased, renal (see section
failure aggravated 4.4), acute
renal failure

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 System Organ Common Uncommon Rare Not known
Class ≥ 1/100 to < 1/10 ≥ 1/1,000 to < 1/100 ≥ 1/10,000 to (frequency
< 1/1,000 cannot be
estimated from
available data)
General disorders pyrexia, rigors injection site
and thrombosis, infusion
administration site inflammation,
site conditions injection site pain,
peripheral oedema
Investigations blood lactate
dehydrogenase
increased

Description of selected adverse reactions

Possible allergic-like symptoms

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.

Hepatic adverse reactions

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).

Injection-site reactions
None of the injection-site adverse reactions were treatment limiting.

Paediatric population

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).

Blood and lymphatic system disorders

common thrombocytopenia

Cardiac disorders
common tachycardia

Vascular disorders
common hypertension, hypotension

Hepatobiliary disorders
common hyperbilirubinaemia, hepatomegaly

Renal and urinary disorders

common acute renal failure, blood urea increased

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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 national reporting system
listed in Appendix V.

4.9 Overdose

Repeated daily doses up to 8 mg/kg (maximum total dose 896 mg) in adult patients have been
administered in clinical trials with no reported dose-limiting toxicity. In one spontaneous case, it was
reported a dosage of 16 mg/kg/day was administered in a newborn patient. No adverse reactions
associated with this high dose were noted.
There is no experience with overdoses of micafungin. In case of overdose, general supportive
measures and symptomatic treatment should be administered. Micafungin is highly protein-bound and
not dialysable.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, other antimycotics for systemic use, ATC
code: J02AX05

Mode of action
Micafungin non-competitively inhibits the synthesis of 1,3--D-glucan, an essential component of the
fungal cell wall. 1,3--D-glucan is not present in mammalian cells.
Micafungin exhibits fungicidal activity against most Candida species and prominently inhibits actively
growing hyphae of Aspergillus species.

PK/PD relationship

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.

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Breakpoints

EUCAST breakpoints (version 10.0, valid from 2020-02-04)

Candida species MIC breakpoint (mg/L)
≤S (Susceptible) >R (Resistant)
Candida albicans 0.016 0.016
Candida glabrata 0.03 0.03
Candida parapsilosis 2 2
1
Candida tropicalis Insufficient evidence
1
Candida krusei Insufficient evidence
1
Candida guilliermondii Insufficient evidence
Other Candida spp. Insufficient evidence
1
MICs for C. tropicalis are 1-2 two-fold dilution steps higher than for C. albicans and C. glabrata.
In the clinical study, successful outcome was numerically slightly lower for C. tropicalis than for C.
albicans at both dosages (100 and 150 mg daily). However, the difference was not significant and
whether it translates into a relevant clinical difference is unknown. MICs for C. krusei are
approximately 3 two-fold dilution steps higher than those for C. albicans and, similarly, those for C.
guilliermondii are approximately 8 two-fold dilutions higher. In addition, only a small number of
cases involved these species in the clinical trials. This means there is insufficient evidence to
indicate whether the wild-type population of these pathogens can be considered susceptible to
micafungin.

Information from clinical studies

Candidaemia and Invasive Candidiasis: Micafungin (100 mg/day or 2 mg/kg/day) was as effective as
and better tolerated than liposomal amphotericin B (3 mg/kg) as first-line treatment of candidaemia
and invasive candidiasis in a randomised, double-blind, multinational non-inferiority study.
Micafungin and liposomal amphotericin B were received for a median duration of 15 days (range, 4 to
42 days in adults; 12 to 42 days in children).
Non-inferiority was proven for adult patients, and similar findings were demonstrated for the
paediatric subpopulations (including neonates and premature infants). Efficacy findings were
consistent, independent of the infective Candida species, primary site of infection and neutropenic
status (see Table). Micafungin demonstrated a smaller mean peak decrease in estimated glomerular
filtration rate during treatment (p<0.001) and a lower incidence of infusion-related reactions (p=0.001)
than liposomal amphotericin B.

Overall Treatment Success in the Per Protocol Set, Invasive Candidiasis Study
Micafungin Liposomal % Difference
Amphotericin B [95% CI]
N n (%) N n (%)
Adult Patients
Overall Treatment Success 202 181 (89.6) 190 170 (89.5) 0.1 [-5.9, 6.1] †
Overall Treatment Success by Neutropenic Status
Neutropenia at baseline 24 18 (75.0) 15 12 (80.0) 0.7 [-5.3, 6.7] ‡
No neutropenia at baseline 178 163 (91.6) 175 158 (90.3)
Paediatric Patients
Overall Treatment Success 48 35 (72.9) 50 38 (76.0) -2.7 [-17.3, 11.9] §
< 2 years old 26 21 (80.8) 31 24 (77.4)
Premature Infants 10 7 (70.0) 9 6 (66.7)
Neonates (0 days to 7 7 (100) 5 4 (80)
< 4 weeks)
2 to 15 years old 22 14 (63.6) 19 14 (73.7)
Adults and Children Combined, Overall Treatment Success by Candida Species
Candida albicans 102 91 (89.2) 98 89 (90.8)

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 Micafungin Liposomal % Difference
Amphotericin B [95% CI]
N n (%) N n (%)
Non-albicans species ¶: all 151 133 (88.1) 140 123 (87.9)
C. tropicalis 59 54 (91.5) 51 49 (96.1)
C. parapsilosis 48 41 (85.4) 44 35 (79.5)
C. glabrata 23 19 (82.6) 17 14 (82.4)
C. krusei 9 8 (88.9) 7 6 (85.7)
† Micafungin rate minus the liposomal amphotericin B rate, and 2-sided 95% confidence interval for
the difference in overall success rate based on large sample normal approximation.
‡ Adjusted for neutropenic status; primary endpoint.
§ The paediatric population was not sized to test for non-inferiority.
¶ Clinical efficacy was also observed (< 5 patients) in the following Candida species: C. guilliermondii, C.
famata, C. lusitaniae, C. utilis, C. inconspicua and C. dubliniensis.

Oesophageal Candidiasis: In a randomised, double-blind study of micafungin versus fluconazole in

the first-line treatment of oesophageal candidiasis, 518 patients received at least a single dose of study
drug. The median treatment duration was 14 days and the median average daily dose was 150 mg for
micafungin (N=260) and 200 mg for fluconazole (N=258). An endoscopic grade of 0 (endoscopic
cure) at the end of treatment was observed for 87.7% (228/260) and 88.0% (227/258) of patients in the
micafungin and fluconazole groups, respectively (95% CI for difference: [-5.9%, 5.3%]). The lower
limit of the 95% CI was above the predefined non-inferiority margin of -10%, proving non-inferiority.
The nature and incidence of adverse events were similar between treatment groups.

Prophylaxis: Micafungin was more effective than fluconazole in preventing invasive fungal infections
in a population of patients at high risk of developing a systemic fungal infection (patients undergoing
haematopoietic stem cell transplantation [HSCT] in a randomised, double-blind, multicentre study).
Treatment success was defined as the absence of a proven, probable, or suspected systemic fungal
infection through the end of therapy and absence of a proven or probable systemic fungal infection
through the end of study. Most patients (97%, N=882) had neutropenia at baseline (< 200
neutrophils/µL). Neutropenia persisted for a median of 13 days. There was a fixed daily dose of 50 mg
(1.0 mg/kg) for micafungin and 400 mg (8 mg/kg) for fluconazole. The mean period of treatment was
19 days for micafungin and 18 days for fluconazole in the adult population (N=798) and 23 days for
both treatment arms in the paediatric population (N=84).
The rate of treatment success was statistically significantly higher for micafungin than fluconazole
(1.6% versus 2.4% breakthrough infections). Breakthrough Aspergillus infections were observed in 1
versus 7 patients, and proven or probable breakthrough Candida infections were observed in 4 versus
2 patients in the micafungin and fluconazole groups, respectively. Other breakthrough infections were
caused by Fusarium (1 and 2 patients, respectively) and Zygomycetes (1 and 0 patients, respectively).
The nature and incidence of adverse reactions were similar between treatment groups.

5.2 Pharmacokinetic properties

Absorption

Pharmacokinetics are linear over the daily dose range of 12.5 mg to 200 mg and 3 mg/kg to 8 mg/kg.
There is no evidence of systemic accumulation with repeated administration and steady-state is
generally reached within 4 to 5 days.

Distribution

Following intravenous administration concentrations of micafungin show a biexponential decline. The

drug is rapidly distributed into tissues.
In systemic circulation, micafungin is highly bound to plasma protein (> 99%), primarily to albumin.
Binding to albumin is independent of micafungin concentration (10-100 µg/ml).
The volume of distribution at steady state (Vss) was approximately 18-19 litres.

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Biotransformation

Unchanged micafungin is the principal circulating compound in systemic circulation. Micafungin has
been shown to be metabolised to several compounds; of these M-1 (catechol form), M-2 (methoxy
form of M-1) and M-5 (hydroxylation at the side chain) of micafungin have been detected in systemic
circulation. Exposure to these metabolites is low and metabolites do not contribute to the overall
efficacy of micafungin.
Even though micafungin is a substrate for CYP3A in vitro, hydroxylation by CYP3A is not a major
pathway for micafungin metabolism in vivo.

Elimination and excretion

The mean terminal half-life is approximately 10-17 hours and stays consistent across doses up to
8 mg/kg and after single and repeated administration. Total clearance was 0.15-0.3 ml/min/kg in
healthy subjects and adult patients and is independent of dose after single and repeated administration.
Following a single intravenous dose of 14C-micafungin (25 mg) to healthy volunteers, 11.6% of the
radioactivity was recovered in the urine and 71.0% in the faeces over 28 days. These data indicate that
elimination of micafungin is primarily non-renal. In plasma, metabolites M-1 and M-2 were detected
only at trace concentrations and metabolite M-5, the more abundant metabolite, accounted for a total
of 6.5% relative to parent compound.

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. Mean weight-adjusted clearance in children less than 4 months of age is
approximately 2.6-fold greater than older children (12-16 years) and 2.3-fold greater than in adults.

PK/PD bridging study demonstrated dose-dependent penetration of micafungin into CNS with the
minimum AUC of 170 µg*hr/L required to achieve maximum eradication of fungal burden in the CNS
tissues. Population PK modeling demonstrated that a dose of 10 mg/kg in children less than 4 month of
age would be sufficient to achieve the target exposure for the treatment of CNS Candida infections.

Elderly: When administered as a single 1-hour infusion of 50 mg the pharmacokinetics of micafungin

in the elderly (aged 66-78 years) were similar to those in young (20-24 years) subjects. No dose
adjustment is necessary for the elderly.

Patients with hepatic impairment: In a study performed in patients with moderate hepatic impairment
(Child-Pugh score 7-9), (n=8), the pharmacokinetics of micafungin did not significantly differ from
those in healthy subjects (n=8). Therefore, no dose adjustment is necessary for patients with mild to
moderate hepatic impairment. 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.

Patients with renal impairment: Severe renal impairment (Glomerular Filtration Rate
[GFR] < 30 ml/min) did not significantly affect the pharmacokinetics of micafungin. No dose
adjustment is necessary for patients with renal impairment.

Gender/Race: Gender and race (Caucasian, Black and Oriental) did not significantly influence the
pharmacokinetic parameters of micafungin. No dose adjustment of micafungin is required based on
gender or race.

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5.3 Preclinical safety data

The development of foci of altered hepatocytes (FAH) and hepatocellular tumours in rats was
dependent on both dose and duration of micafungin treatment. FAH recorded after treatment for 13
weeks or longer persisted after a 13-week withdrawal period and developed into hepatocellular
tumours following a treatment free period which covered the life span of rats. No standard
carcinogenicity studies have been conducted but the development of FAH was assessed in female rats
after up to 20 and 18 months after cessation of a 3 and 6 month treatment, respectively. In both studies
increased incidences/numbers of hepatocellular tumours were observed after the 18 and 20 month
treatment free period in the high dose group of 32 mg/kg/day as well as in a lower dose group
(although not statistically significant). The plasma exposure at the assumed threshold for tumour
development in rats (i.e. the dose where no FAH and liver tumours were detected) was in the same
range as the clinical exposure. The relevance of the hepatocarcinogenic potential of micafungin for the
human therapeutic use is not known.

The toxicology of micafungin following repeated intravenous dosing in rats and/or dogs showed
adverse responses in liver, urinary tract, red blood cells, and male reproductive organs. The exposure
levels at which these effects did not occur (NOAEL) were in the same range as the clinical exposure or
lower. Consequently, the occurrence of these adverse responses may be expected in human clinical use
of micafungin.

In standard safety pharmacology tests, cardiovascular and histamine releasing effects of micafungin
were evident and appeared to be time above threshold dependent. Prolongation of infusion time
reducing the plasma concentration peak appeared to reduce these effects.

In repeated dose toxicity studies in rat signs of hepatotoxicity consisted of increased liver enzymes and
degenerative changes of hepatocytes which were accompanied by signs of compensatory regeneration.
In dog, liver effects consisted of increased weight and centrilobular hypertrophy, no degenerative
changes of hepatocytes were observed.

In rats, vacuolation of the renal pelvic epithelium as well as vacuolation and thickening (hyperplasia)
of the bladder epithelium were observed in 26-week repeat dose studies. In a second 26-week study
hyperplasia of transitional cells in the urinary bladder occurred with a much lower incidence. These
findings showed reversibility over a follow-up period of 18 months. The duration of micafungin
dosing in these rat studies (6 months) exceeds the usual duration of micafungin dosing in patients (see
section 5.1).

Micafungin haemolysed rabbit blood in vitro. In rats, signs of haemolytic anaemia were observed after
repeated bolus injection of micafungin. In repeat dose studies in dogs, haemolytic anaemia was not
observed.

In reproductive and developmental toxicity studies, reduced birth weight of the pups was noted. One
abortion occurred in rabbits at 32 mg/kg/day. Male rats treated intravenously for 9 weeks showed
vacuolation of the epididymal ductal epithelial cells, increased epididymis weights and reduced
number of sperm cells (by 15%), however, in studies of 13 and 26 weeks duration these changes did
not occur. In adult dogs, atrophy of seminiferous tubules with vacuolation of the seminiferous
epithelium and decreased sperm in the epididymides were noted after prolonged treatment (39 weeks)
but not after 13 weeks of treatment. In juvenile dogs, 39 weeks treatment did not induce lesions in the
testis and epididymides in a dose dependent manner at the end of treatment but after a treatment free
period of 13 weeks a dose dependent increase in these lesions were noted in the treated recovery
groups. No impairment of male or female fertility was observed in the fertility and early embryonic
development study in rats.

Micafungin was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and in
vivo tests, including an in vitro study on unscheduled DNA synthesis using rat hepatocytes.

13
6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate
Citric acid anhydrous (to adjust the pH)
Sodium hydroxide (to adjust the pH)

6.2 Incompatibilities

This medicinal product must not be mixed or co-infused with other medicinal products except those
mentioned in section 6.6.

6.3 Shelf life

Unopened vial: 3 years.

Reconstituted concentrate in vial

Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25°C when
reconstituted with sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%)
solution for infusion.

Diluted infusion solution

Chemical and physical in-use stability has been demonstrated for 96 hours at 25°C when protected
from light when diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose
50 mg/ml (5%) solution for infusion.

Mycamine contains no preservatives. From a microbiological point of view, the reconstituted and
diluted solutions should be used immediately. If not used immediately, in-use storage times and
conditions prior to use are the responsibility of the user and would normally not be longer than 24
hours at 2 to 8°C, unless the reconstitution and dilution have taken place in controlled and validated
aseptic conditions.

6.4 Special precautions for storage

Unopened vials

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

10 ml Type I glass vial with an isobutylene-isoprene (Fluoro resin film laminated) rubber stopper and
a flip-off cap. The vial is wrapped with an UV-protective film.

Pack size: packs of 1 vial.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Mycamine must not be mixed or co-infused with other medicinal products except those mentioned
below. Using aseptic techniques at room temperature, Mycamine is reconstituted and diluted as
follows:

1. The plastic cap must be removed from the vial and the stopper disinfected with alcohol.

14
2. Five ml of sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%)
solution for infusion (taken from a 100 ml bottle/bag) should be aseptically and slowly injected
into each vial along the side of the inner wall. Although the concentrate will foam, every effort
should be made to minimise the amount of foam generated. A sufficient number of vials of
Mycamine must be reconstituted to obtain the required dose in mg (see table below).
3. The vial should be rotated gently. DO NOT SHAKE. The powder will dissolve completely. The
concentrate should be used immediately. The vial is for single use only. Therefore, unused
reconstituted concentrate must be discarded immediately.
4. All of the reconstituted concentrate should be withdrawn from each vial and returned into the
infusion bottle/bag from which it was originally taken. The diluted infusion solution should be
used immediately. Chemical and physical in-use stability has been demonstrated for 96 hours at
25°C when protected from light and diluted as described above.
5. The infusion bottle/bag should be gently inverted to disperse the diluted solution but NOT
agitated in order to avoid foaming. The solution must not be used if it is cloudy or has
precipitated.
6. The infusion bottle/bag containing the diluted infusion solution should be inserted into a
closable opaque bag for protection from light.

Preparation of the solution for infusion

Dose Mycamine Volume of sodium Volume Standard infusion

(mg) vial chloride (0.9%) or (concentration) (added up to
to be used glucose (5%) to be of reconstituted 100 ml)
(mg/vial) added per vial powder Final
concentration
50 1 x 50 5 ml approx. 5 ml 0.5 mg/ml
(10 mg/ml)
100 1 x 100 5 ml approx. 5 ml 1.0 mg/ml
(20 mg/ml)
150 1 x 100 + 1 x 5 ml approx. 10 ml 1.5 mg/ml
50
200 2 x 100 5 ml approx. 10 ml 2.0 mg/ml

After reconstitution and dilution, the solution should be administered by intravenous infusion over
approximately 1 hour.

7. MARKETING AUTHORISATION HOLDER

Astellas Pharma Europe B.V.

Sylviusweg 62
2333 BE Leiden
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/448/001
EU/1/08/448/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 April 2008

Date of latest renewal: 19 February 2018

15
10. DATE OF REVISION OF THE TEXT

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

16
 ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH

RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT

17
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Astellas Ireland Co. Ltd

Killorglin
Co. Kerry
Ireland

Haupt Pharma Wolfratshausen GmbH

Pfaffenrieder Straβe 5
82515 Wolfratshausen
Germany

The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

• Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed
subsequent updates of the RMP.

An updated RMP should be submitted

• At the request of the European Medicines Agency.
• Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.

18
 ANNEX III

LABELLING AND PACKAGE LEAFLET

19
A. LABELLING

20
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Mycamine 50 mg powder for concentrate for solution for infusion

micafungin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains: 50 mg micafungin (as sodium).

After reconstitution each ml contains 10 mg of micafungin (as sodium).

3. LIST OF EXCIPIENTS

Lactose monohydrate, citric acid anhydrous and sodium hydroxide.

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for concentrate for solution for infusion

1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Intravenous use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

21
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Astellas Pharma Europe B.V.

Sylviusweg 62
2333 BE Leiden
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/448/001

13. BATCH NUMBER

Lot:

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER - 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:

22
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Mycamine 50 mg powder for concentrate for solution for infusion

micafungin
Intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

50 mg

6. OTHER

23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Mycamine 100 mg powder for concentrate for solution for infusion

micafungin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains: 100 mg micafungin (as sodium).

After reconstitution each ml contains 20 mg of micafungin (as sodium).

3. LIST OF EXCIPIENTS

Lactose monohydrate, citric acid anhydrous and sodium hydroxide.

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for concentrate for solution for infusion

1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Intravenous use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP:

9. SPECIAL STORAGE CONDITIONS

24
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Astellas Pharma Europe B.V.

Sylviusweg 62
2333 BE Leiden
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/448/002

13. BATCH NUMBER

Lot:

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER - 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:

25
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Mycamine 100 mg powder for concentrate for solution for infusion

micafungin
Intravenous use.

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

100 mg

6. OTHER

26
B. PACKAGE LEAFLET

27
 Package leaflet: Information for the user

Mycamine 50 mg powder for concentrate for solution for infusion

Mycamine 100 mg powder for concentrate for solution for infusion

micafungin

Read all of this leaflet carefully before you start using this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Mycamine is and what it is used for
2. What you need to know before you use Mycamine
3. How to use Mycamine
4. Possible side effects
5. How to store Mycamine
6. Contents of the pack and other information

1. What Mycamine is and what it is used for

Mycamine contains the active substance micafungin. Mycamine is called an antifungal medicine
because it is used to treat infections caused by fungal cells.
Mycamine is used to treat fungal infections caused by fungal or yeast cells called Candida. Mycamine
is effective in treating systemic infections (those that have penetrated within the body). It interferes
with the production of a part of the fungal cell wall. An intact cell wall is necessary for the fungus to
continue living and growing. Mycamine causes defects in the fungal cell wall, making the fungus
unable to live and grow.

Your doctor has prescribed Mycamine for you in the following circumstances when there are no other
suitable antifungal treatments available (see section 2):

• To treat adults, adolescents and children including neonates who have a serious fungal infection
called invasive candidiasis (infection that has penetrated the body).
• To treat adults and adolescents ≥ 16 years of age who have a fungal infection in the gullet
(oesophagus) where treatment into a vein (intravenous) is appropriate.
• To prevent infection with Candida in patients who are having a bone-marrow transplant or who
are expected to have a neutropenia (low levels of neutrophils, a type of white blood cell) for 10
days or more.

2. What you need to know before you use Mycamine

Do not use Mycamine

- if you are allergic to micafungin, other echinocandins (Ecalta or Cancidas) or any of the other
ingredients of this medicine (listed in section 6).

Warnings and precautions

In rats, long-term treatment with micafungin led to liver damage and subsequent liver tumours. The
potential risk of developing liver tumours in humans is not known, and your doctor will assess the
benefits and risks of Mycamine treatment before starting your medicine. Please tell your doctor if you
have severe liver problems (e.g. liver failure or hepatitis) or have had abnormal liver function tests.
During treatment your liver functions will be monitored more closely.

28
Talk to your doctor or pharmacist before using Mycamine
- if you are allergic to any medicine.
- if you have haemolytic anaemia (anaemia due to breakdown of red blood cells) or haemolysis
(breakdown of red blood cells).
- if you have kidney problems (e.g. kidney failure and abnormal kidney function test). If this
happens, your doctor may decide to monitor your kidney function more closely.

Micafungin may also cause severe inflammation/eruption of the skin and mucous membranes
(Stevens-Johnson syndrome, toxic epidermal necrolysis).

Other medicines and Mycamine

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.

It is especially important to inform your doctor if you are using amphotericin B desoxycholate or
itraconazole (antifungal antibiotics), sirolimus (an immunosuppressant) or nifedipine (calcium channel
blocker used to treat high blood pressure). Your doctor may decide to adjust the dose of these
medicines.

Mycamine with food and drink

As Mycamine is given intravenously (into a vein), no restrictions on food or drink are required.

Pregnancy and breast-feeding

If you are pregnant of breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking this medicine.
Mycamine should not be used during pregnancy unless clearly necessary. If you use Mycamine you
should not breast-feed.

Driving and using machines

Micafungin is unlikely to have an effect on driving or using machines. However some people may feel
dizzy when taking this medicine and if this happens to you, do not drive or use any tools or machines.
Please inform your doctor if you experience any effects that may cause you to have problems with
driving or using other machinery.

Mycamine contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’.

3. How to use Mycamine

Mycamine must be prepared and given to you by a doctor or another healthcare professional.
Mycamine should be administered once daily by slow intravenous (into a vein) infusion. Your doctor
will determine how much Mycamine you will receive each day.

Use in adults, adolescents ≥ 16 years of age and elderly

- The usual dose to treat an invasive Candida infection is 100 mg per day for patients weighing
40 kg or more and 2 mg/kg per day for patients weighing 40 kg or less.
- The dose to treat a Candida infection of the oesophagus is 150 mg for patients weighing more
than 40 kg and 3 mg/kg per day for patients weighing 40 kg or less.
- The usual dose to prevent invasive Candida infections is 50 mg per day for patients weighing
more than 40 kg and 1 mg/kg per day for patients weighing 40 kg or less.

Use in children > 4 months of age and adolescents < 16 years of age
- The usual dose to treat an invasive Candida infection is 100 mg per day for patients weighing
40 kg or more and 2 mg/kg per day for patients weighing 40 kg or less.
- The usual dose to prevent invasive Candida infections is 50 mg per day for patients weighing
more than 40 kg and 1 mg/kg per day for patients weighing 40 kg or less.

29
Use in children and newborns < 4 months of age
- The usual dose to treat an invasive Candida infection is 4-10 mg/kg per day.
- The usual dose to prevent invasive Candida infections is 2 mg/kg per day.

If you receive more Mycamine than you should

Your doctor monitors your response and condition to determine what dose of Mycamine is needed.
However, if you are concerned that you may have been given too much Mycamine, speak to your
doctor or another healthcare professional immediately.

If you miss a dose of Mycamine

Your doctor monitors your response and condition to determine what Mycamine treatment is needed.
However, if you are concerned that you may have missed a dose, speak to your doctor or another
healthcare professional immediately.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience an allergic attack, or a severe skin reaction (e.g. blistering and peeling of the skin),
you must inform your doctor or nurse immediately.

Mycamine may cause the following other side effects:

Common (may affect up to 1 in 10 people)

- abnormal blood tests (decreased white blood cells [leucopenia; neutropenia]); decreased red
blood cells (anaemia)
- decreased potassium in the blood (hypokalaemia); decreased magnesium in the blood
(hypomagnesaemia); decreased calcium in the blood (hypocalcaemia)
- headache
- inflammation of the vein wall (at injection-site)
- nausea (feeling sick); vomiting (being sick); diarrhoea; abdominal pain
- abnormal liver function tests (increased alkaline phosphatase; increased aspartate
aminotransferase, increased alanine aminotransferase)
- increased bile pigment in the blood (hyperbilirubinaemia)
- rash
- fever
- rigors (shivering)

Uncommon (may affect up to 1 in 100 people)

- abnormal blood tests (decreased blood cells [pancytopenia]); decreased blood platelets
(thrombocytopenia); increases in a certain type of white blood cells called eosinophils;
decreased albumin in the blood (hypoalbuminaemia)
- hypersensitivity
- increased sweating
- decreased sodium in the blood (hyponatraemia); increased potassium in the blood
(hyperkalaemia); decreased phosphates in the blood (hypophosphataemia); anorexia (eating
disorder)
- insomnia (difficulty in sleeping); anxiety; confusion
- feeling lethargic (somnolence); trembling; dizziness; disturbed taste
- increased heart rate; stronger heartbeat; irregular heartbeat
- high or low blood pressure; skin flushing
- shortness of breath
- indigestion; constipation

30
- liver failure; increased liver enzymes (gamma-glutamyltransferase); jaundice (yellowing of the
skin or whites of the eyes caused by liver or blood problems); reduced bile reaching the intestine
(cholestasis); enlarged liver; liver inflammation
- itchy rash (urticaria); itching; skin flushing (erythema)
- abnormal kidney function tests (increased blood creatinine; increased urea in the blood);
aggravated kidney failure
- increase in an enzyme called lactate dehydrogenase
- clotting in vein at injection-site; inflammation at injection-site; pain at injection-site; collection
of fluid in your body

Rare (may affect up to 1 in 1,000 people)

- anaemia due to breakdown of red blood cells (haemolytic anaemia), breakdown of red blood
cells (haemolysis)

Not known (frequency cannot be estimated from the available data)

- disorder of blood clotting system
- (allergic) shock
- damage to liver cells including death
- kidney problems; acute kidney failure

Additional side effects in children and adolescents

The following reactions have been reported more often in paediatric patients than in adult patients:

Common (may affect up to 1 in 10 people)

- decreased blood platelets (thrombocytopenia)
- increased heart rate (tachycardia)
- high or low blood pressure
- increased bile pigment in the blood (hyperbilirubinaemia); enlarged liver
- acute kidney failure; increased urea in the blood

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Mycamine

Keep this medicine out of the sight and reach of children.

Do not use Mycamine after the expiry date which is stated on the vial and on the carton. The expiry
date refers to the last day of that month.

The unopened vial does not require any special storage conditions.
The reconstituted concentrate and the diluted infusion solution should be used immediately, because it
does not contain any preservatives to prevent bacterial contamination. Only a trained healthcare
professional who has read the complete directions properly can prepare this medicine for use.

Do not use the diluted infusion solution if it is cloudy or precipitated.

In order to protect the infusion bottle / bag containing the diluted infusion solution from light it should
be inserted into a closable opaque bag.

The vial is for single use only. Therefore, please discard unused reconstituted concentrate
immediately.

31
6. Contents of the pack and other information

What Mycamine contains

- The active substance is micafungin (as sodium).

1 vial contains 50 mg or 100 mg micafungin (as sodium).
- The other ingredients are lactose monohydrate, citric acid anhydrous and sodium hydroxide.

What Mycamine looks like and contents of the pack

Mycamine 50 mg or 100 mg powder for concentrate for solution for infusion is a white compact
freeze-dried powder. Mycamine is supplied in a box containing 1 vial.

Marketing Authorisation Holder

Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
Netherlands

Manufacturer
Astellas Ireland Co., Ltd.
Killorglin, County Kerry
Ireland

Haupt Pharma Wolfratshausen GmbH

Pfaffenrieder Straβe 5
82515 Wolfratshausen
Germany

For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Astellas Pharma B.V. Branch Biocodex UAB
Tél/Tel: +32 (0)2 5580710 Tel: +370 37 408 681

България Luxembourg/Luxemburg
Астелас Фарма ЕООД Astellas Pharma B.V. Branch
Teл: +359 2 862 53 72 Belgique/Belgien
Tél/Tel: +32 (0)2 5580710
Česká republika Magyarország
Astellas Pharma s.r.o. Astellas Pharma Kft.
Tel: +420 221 401 500 Tel: +36 1577 8200

Danmark Malta
Astellas Pharma a/s Astellas Pharmaceuticals AEBE
Tlf: +45 43430355 Greece
Τel: +30 210 8189900
Deutschland Nederland
Astellas Pharma GmbH Astellas Pharma B.V.
Tel: +49 (0)89 454401 Tel: +31 (0)71 5455745

Eesti Norge
Biocodex OÜ Astellas Pharma
Tel: +372 6 056 014 Tlf: +47 6676 4600

Ελλάδα Österreich

32
 Astellas Pharmaceuticals AEBE Astellas Pharma Ges.m.b.H.
Tηλ: +30 210 8189900 Tel: +43 (0)1 8772668
España Polska
Astellas Pharma S.A. Astellas Pharma Sp.z o.o.
Tel: +34 91 4952700 Tel: +48 225451 111

France Portugal
Astellas Pharma S.A.S. Astellas Farma, Lda.
Tél: +33 (0)1 55917500 Tel: +351 21 4401320

Hrvatska România
Astellas d.o.o. S.C.Astellas Pharma SRL
Tel: + 385 1 670 01 02 Tel: +40 (0)21 361 04 95/96/92

Ireland Slovenija
Astellas Pharma Co. Ltd. Astellas Pharma d.o.o.
Tel: +353 (0)1 4671555 Tel: +386 (0) 14011 400

Ísland Slovenská republika

Vistor hf. Astellas Pharma s.r.o., organizačná zložka
Tel: +354 535 7000 Tel: +421 2 4444 2157

Italia Suomi/Finland
Astellas Pharma S.p.A. Astellas Pharma
Tel: +39 02 921381 Puh/Tel: +358 (0)9 85606000

Κύπρος Sverige
Astellas Pharmaceuticals AEBE Astellas Pharma AB
Ελλάδα Tel: +46 (0)40-650 15 00
Tηλ: +30 210 8189900

Latvija United Kingdom (Northern Ireland)

Biocodex SIA Astellas Pharma Co., Limited
Tel: +371 67 619365 Free call from Northern Ireland: 0800 783 5018
International number: +353 (0)1 4671555

This leaflet was last approved in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.

---------------------------------------------------------------------------------------------------------------------------

33
The following information is intended for medical or healthcare professionals only:

Mycamine must not be mixed or co-infused with other medicinal products except those mentioned
below. Using aseptic techniques at room temperature, Mycamine is reconstituted and diluted as
follows:

1. The plastic cap must be removed from the vial and the stopper disinfected with alcohol.
2. Five ml of sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%)
solution for infusion (taken from a 100 ml bottle/bag) should be aseptically and slowly injected
into each vial along the side of the inner wall. Although the concentrate will foam, every effort
should be made to minimise the amount of foam generated. A sufficient number of vials of
Mycamine must be reconstituted to obtain the required dose in mg (see table below).
3. The vial should be rotated gently. DO NOT SHAKE. The powder will dissolve completely. The
concentrate should be used immediately. The vial is for single use only. Therefore, unused
reconstituted concentrate must be discarded immediately.
4. All of the reconstituted concentrate should be withdrawn from each vial and returned into the
infusion bottle/bag from which it was originally taken. The diluted infusion solution should be
used immediately. Chemical and physical in-use stability have been demonstrated for 96 hours
at 25°C when protected from light and diluted as described above.
5. The infusion bottle/bag should be gently inverted to disperse the diluted solution but NOT
agitated in order to avoid foaming. The solution must not be used if it is cloudy or has
precipitated.
6. The infusion bottle/bag containing the diluted infusion solution should be inserted into a
closable opaque bag for protection from light.

Preparation of the solution for infusion

Dose Mycamine Volume of sodium Volume Standard infusion

(mg) vial chloride (0.9%) or (concentration) (added up to
to be used glucose (5%) to be of reconstituted 100 ml)
(mg/vial) added per vial powder Final
concentration
50 1 x 50 5 ml approx. 5 ml 0.5 mg/ml
(10 mg/ml)
100 1 x 100 5 ml approx. 5 ml 1.0 mg/ml
(20 mg/ml)
150 1 x 100 + 1 x 5 ml approx. 10 ml 1.5 mg/ml
50
200 2 x 100 5 ml approx. 10 ml 2.0 mg/ml

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