Ezokamine 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 Ezokamine should take into account a potential risk for the development of liver
tumours (see section 4.4). Ezokamine 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.
 

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

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

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 Ezokamine in patients less than 2 years of age is limited.
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.
 

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

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.
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).
 

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).
 

Pregnancy Category: C
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.
Ezokamine 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 Ezokamine should be made taking into account the benefit of
breast-feeding to the child and the benefit of Ezokamine 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.
 

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).
 

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.

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

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).

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.
 

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-β-D-glucan, an essential component of the
fungal cell wall. 1,3-β-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.

- Please contact the relevant competent authority.

At the recommended therapeutic dosage of Ezokamine, 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
EUCAST breakpoints

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.

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.
 

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.
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 (ChildPugh 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.
 

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.
 

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

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

2 years. Reconstituted solutions in vial Reconstituted solutions is stable for 24 hours if stored at NMT 25°C. Diluted infusion solution All tested concentrations of Micafungin in infusion solutions, including the lowest and the highest concentration, are stable during storage for 24 hours at NMT 25°C. Ezokamine 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, unless the reconstitution and dilution have taken place in controlled and validated aseptic conditions.

Unopened vials
Do not store above 30 °C
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
 

Individually packaged 50 mg single-dose vials, coated with a light protective film,
sealed with aluminium seal with royal blue flip off cap. (NDC 70594-036-01).
Pack size: packs of 1 vial.
 

Any unused product or waste material should be disposed of in accordance with local requirements.
Ezokamine must not be mixed or co-infused with other medicinal products except those mentioned
below. Using aseptic techniques at room temperature, Ezokamine 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 solution will foam, every effort should be made to
minimise the amount of foam generated. A sufficient number of vials of Ezokamine 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
solution should be used immediately. The vial is for single use only. Therefore, unused reconstituted
solution must be discarded immediately.
4. All of the reconstituted solution 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 24 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 protected from light.