ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Mycamine 50 mg powder for solution for infusion
2.
Each vial contains 50 mg micafungin (as sodium).
After reconstitution each ml contains 10 mg micafungin (as sodium).
Excipients:
Each 50 mg vial contains 200 mg lactose.
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion.
White compact powder.
4.
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.
Treatment with Mycamine should be initiated by a physician experienced in the management of fungal
infections.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should
be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted
before the results of the cultures and other laboratory studies are known. However, once these results
become available, antifungal therapy should be adjusted accordingly.
2
The dose regimen of Mycamine 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:
For the treatment of oesophageal candidiasis, Mycamine should be
administered for at least one week after resolution of clinical signs and symptoms.
Prophylaxis of
Candida
infections: For prophylaxis of
Candida
infection, Mycamine should be
administered for at least one week after neutrophil recovery.
Use in children (including neonates) and 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.
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: For prophylaxis of
Candida
infection, Mycamine should be
administered for at least one week after neutrophil recovery. Experience with Mycamine in patients
less than 2 years of age is limited.
Gender/Race
No dose adjustment is necessary based on gender or race (see section 5.2).
Use in patients with 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 Mycamine in patients with severe
hepatic impairment and its use is not recommended in these patients (see section 4.4 and 5.2).
Use in patients with renal impairment
No dose adjustment is necessary in patients with renal impairment (see section 5.2).
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.
3
Hypersensitivity to the active substance or to any of the excipients.
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 relevance
of this finding for the therapeutic use in patients can not be excluded. 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.
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 Mycamine should be
monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or
itraconazole dosage should be reduced if necessary (see section 4.5).
The incidence of some adverse reactions was higher in paediatric patients than in adult patients (see
section 4.8).
This medicinal product for intravenous use contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
Micafungin has a low potential for interactions with medicines metabolised via CYP3A mediated
pathways.
4
Drug interaction studies in healthy human subjects were conducted to evaluate the potential for
interaction between micafungin and mycophenolate mofetil, ciclosporin, tacrolimus, prednisolone,
sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin
B. In these studies, no evidence of altered pharmacokinetics of micafungin was observed. No
micafungin dose adjustments are necessary when these medicines are administered concomitantly.
Exposure (AUC) of itraconazole, sirolimus and nifedipine was slightly increased in the presence of
micafungin (22%, 21% and 18% respectively).
Co-administration of micafungin and amphotericin B desoxycholate was associated with a 30%
increase in amphotericin B desoxycholate exposure. Since this may be of clinical significance this co-
administration should only be used when the benefits clearly outweigh the risks, with close monitoring
of amphotericin B desoxycholate toxicities (see section 4.4).
Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should be
monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or
itraconazole dosage should be reduced if necessary (see section 4.4).
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.
No studies on the effects on the ability to drive and use machines have been performed. However,
adverse reactions may occur, which may influence the ability to drive and use machines (see section
4.8).
The safety profile of micafungin is based on 3028 patients treated with micafungin in clinical studies:
2.002 patients with
Candida
infections (including candidaemia, invasive candidiasis and oesophageal
candidiasis), 375 with invasive aspergillosis (primarily refractory infections) and 651 for prophylaxis
of systemic fungal infections.
The patients treated with micafungin in clinical studies represent a critically ill patient population that
requires multiple medicinal products including antineoplastic chemotherapy, potent systemic
immunosuppressants and broad spectrum antibiotics. These patients had a wide variety of complex
underlying conditions such as haematological malignancies and HIV-infection or were transplant
recipients and/or treated in intensive care. Patients treated prophylactically with micafungin were
those undergoing haematopoetic stem cell transplantation (HSCT) who were at high risk for fungal
infections.
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
5
aminotransferase increased (2.3%). No clinically significant differences were seen when the safety
data were analysed by gender or race.
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
Class
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)
Blood and
lymphatic
system disorders
leukopenia,
neutropenia, anaemia
pancytopenia,
thrombocytopenia,
eosinophilia,
hypoalbuminaemia
haemolytic
anaemia,
haemolysis
(see section
4.4)
Immune system
disorders
anaphylactic /
anaphylactoid
reaction (see section
4.4), hypersensitivity
Endocrine
disorders
hyperhidrosis
Metabolism and
nutritional
disorders
hypokalaemia,
hypomagnesaemia,
hypocalcaemia
hyponatraemia,
hyperkalaemia,
hypophosphataemia,
anorexia
Psychiatric
disorders
insomnia, anxiety,
confusion
Nervous system
disorders
headache
somnolence, tremor,
dizziness, dysgeusia
Cardiac
disorders
tachycardia,
palpitations,
bradycardia
Vascular
disorders
phlebitis
hypotension,
hypertension,
flushing
shock
Respiratory,
thoracic and
mediastinal
disorders
dyspnoea
Gastrointestinal
disorders
nausea, vomiting,
diarrhoea, abdominal
pain
dyspepsia,
constipation
Hepatobiliary
disorders
blood alkaline
phosphatase increased,
aspartate
aminotransferase
increased, alanine
aminotransferase
increased, blood
bilirubin increased
(including
hyperbilirubinaemia),
liver function test
abnormal
hepatic failure (see
section 4.4), gamma-
glutamyltransferase
increased, jaundice,
cholestasis,
hepatomegaly,
hepatitis
hepatocellular
damage
including fatal
cases (see
section 4.4)
6
System Organ
Class
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)
Skin and
subcutaneous
tissue disorders
rash
urticaria, pruritus,
erythema
toxic skin
eruption
Renal and
urinary
disorders
blood creatinine
increased, blood urea
increased, renal
failure aggravated
renal
impairment
(see section
4.4), acute
renal failure
General
disorders and
administration
site conditions
pyrexia, rigors
injection site
thrombosis, infusion
site inflammation,
injection site pain,
peripheral oedema
Investigations
blood lactate
dehydrogenase
increased
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 patients
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
7
Hepatobiliary disorders
common
hyperbilirubinaemia, hepatomegaly
Renal and urinary
disorders
common
acute renal failure, blood urea increased
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. One case of mis-dosage of
7.8 mg/kg/day for 7 days was reported 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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
An additive or synergistic pharmacodynamic interaction of micafungin and amphotericin B was found
in a mouse model of pulmonary aspergillosis (immunosuppression with hydrocortisone, intranasal
infection with
Aspergillus fumigatus
).
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 gene coding for a major subunit of glucan synthase.
Breakpoints
Susceptibility testing was performed with modifications according to the Clinical and Laboratory
Standards Institute (CLSI) methods M27-A2 (
Candida
species) and M38-A (
Aspergillus
species),
respectively. To date, standardised techniques for susceptibility testing for 1,3-β-D-glucan synthesis
inhibitors have not been established and results of susceptibility testing do not necessarily correlate
with clinical outcome.
Although no MIC breakpoints for echinocandins have been established, a MIC of
<
2 mg/l
encompasses > 99% of all clinical isolates of
Candida
spp. without bisecting any species group and
represents a concentration that is easily maintained throughout the dosing interval. Infections due to
Candid
a spp. in this MIC range are likely to respond to therapy.
The prevalence of resistance may vary geographically and with time for selected species and local
information on resistance is desirable, particularly when treating severe infections. This information is
only a guide to the probabilities of whether micro-organisms will be susceptible to micafungin or not.
8
Where applicable the information on the European range of acquired resistance for the individual
micro-organisms is indicated in brackets.
Commonly susceptible species [MIC ranges in Europe, mg/l]
Candida albicans
[0.007 - 0.25]
Candida glabrata
[0.007 - 0.12]
Candida tropicalis
[0.007 - 0.12]
Candida krusei
[0.015 - 0.12]
Candida kefyr
[0.03 - 0.06]
Candida parapsilosis
[0.12 - 2]
Candida guilliermondii
[0.5]
Candida lusitaniae
[0.12 - 0.25]
Candida
spp. [0.015 - 0.5]
(incl.
C. famata, C. dubliniensis, C. lipolytica, C. pelliculosa, C. rugosa, C. stellatoidea
and
C.
zeylanoides)
Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Aspergillus nidulans
Aspergillus versicolor
The mycelial form of dimorphic fungi (e.g.
Histoplasma capsulatum
,
Blastomyces dermatitidis
,
Coccidioides immitis
)
Species for which acquired resistance may be a problem
None
Inherently resistant organisms
Cryptococcus
spp.
Pseudallescheria
spp.
Scedosporium
spp
.
Fusarium
spp
.
Trichosporon
spp
.
Zygomycetes
spp.
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
Amphotericin B
% Difference
[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]
†
9
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
< 4 weeks)
7
7 (100)
5
4 (80)
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)
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
Micafungin is an intravenously administered medication.
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.
10
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.
Metabolism
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
14
C-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 age, with mean values of clearance in younger children
(2-11 years) being approximately 1.3 -fold greater than those in older children (12-17 years). Older
children had mean clearance values similar to those determined in adult patients. Mean clearance in
premature infants (gestational age approximately 26 weeks) is approximately 5-fold greater than in
adults.
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.
5.3 Preclinical safety data
11
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.
6.
12
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 of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
10 ml Type I glass vial with an isobutylene-isoprene (Teflon-laminated) rubber stopper and a flip-off
cap. The vial is wrapped with an UV-protective film.
Supplied in 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.
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
13
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, please
discard unused reconstituted concentrate 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. Do not use if the solution 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
(mg)
Mycamine vial
to be used
(mg/vial)
Volume of sodium
chloride (0.9%) or
glucose (5%) to be
added per vial
Volume
(concentration)
of reconstituted
powder
Standard infusion
(added up to
100 ml)
Final
concentration
50
1 x 50
5 ml
approx. 5 ml
(10 mg/ml)
0.5 mg/ml
100
1 x 100
5 ml
approx. 5 ml
(20 mg/ml)
1.0 mg/ml
150
1 x 100 + 1 x
50
5 ml
approx. 10 ml
1.5 mg/ml
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.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
8.
EU/1/08/448/001
9.
25/04/2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/.
14
1.
Mycamine 100 mg powder for solution for infusion
2.
Each vial contains 100 mg micafungin (as sodium).
After reconstitution each ml contains 20 mg micafungin (as sodium).
Excipients:
Each 100 mg vial contains 200 mg lactose.
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion.
White compact powder.
4.
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.
Treatment with Mycamine should be initiated by a physician experienced in the management of fungal
infections.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should
be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted
before the results of the cultures and other laboratory studies are known. However, once these results
become available, antifungal therapy should be adjusted accordingly.
15
The dose regimen of Mycamine 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:
For the treatment of oesophageal candidiasis, Mycamine should be
administered for at least one week after resolution of clinical signs and symptoms.
Prophylaxis of
Candida
infections: For prophylaxis of
Candida
infection, Mycamine should be
administered for at least one week after neutrophil recovery.
Use in children (including neonates) and 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.
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: For prophylaxis of
Candida
infection, Mycamine should be
administered for at least one week after neutrophil recovery. Experience with Mycamine in patients
less than 2 years of age is limited.
Gender/Race
No dose adjustment is necessary based on gender or race (see section 5.2).
Use in patients with 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 Mycamine in patients with severe
hepatic impairment and its use is not recommended in these patients (see section 4.4 and 5.2).
Use in patients with renal impairment
No dose adjustment is necessary in patients with renal impairment (see section 5.2).
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.
16
Hypersensitivity to the active substance or to any of the excipients.
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 relevance
of this finding for the therapeutic use in patients can not be excluded. 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.
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 Mycamine should be
monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or
itraconazole dosage should be reduced if necessary (see section 4.5).
The incidence of some adverse reactions was higher in paediatric patients than in adult patients (see
section 4.8).
This medicinal product for intravenous use contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
Micafungin has a low potential for interactions with medicines metabolised via CYP3A mediated
pathways.
17
Drug interaction studies in healthy human subjects were conducted to evaluate the potential for
interaction between micafungin and mycophenolate mofetil, ciclosporin, tacrolimus, prednisolone,
sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin
B. In these studies, no evidence of altered pharmacokinetics of micafungin was observed. No
micafungin dose adjustments are necessary when these medicines are administered concomitantly.
Exposure (AUC) of itraconazole, sirolimus and nifedipine was slightly increased in the presence of
micafungin (22%, 21% and 18% respectively).
Co-administration of micafungin and amphotericin B desoxycholate was associated with a 30%
increase in amphotericin B desoxycholate exposure. Since this may be of clinical significance this co-
administration should only be used when the benefits clearly outweigh the risks, with close monitoring
of amphotericin B desoxycholate toxicities (see section 4.4).
Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should be
monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or
itraconazole dosage should be reduced if necessary (see section 4.4).
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.
No studies on the effects on the ability to drive and use machines have been performed. However,
adverse reactions may occur, which may influence the ability to drive and use machines (see section
4.8).
The safety profile of micafungin is based on 3028 patients treated with micafungin in clinical studies:
2.002 patients with
Candida
infections (including candidaemia, invasive candidiasis and oesophageal
candidiasis), 375 with invasive aspergillosis (primarily refractory infections) and 651 for prophylaxis
of systemic fungal infections.
The patients treated with micafungin in clinical studies represent a critically ill patient population that
requires multiple medicinal products including antineoplastic chemotherapy, potent systemic
immunosuppressants and broad spectrum antibiotics. These patients had a wide variety of complex
underlying conditions such as haematological malignancies and HIV-infection or were transplant
recipients and/or treated in intensive care. Patients treated prophylactically with micafungin were
those undergoing haematopoetic stem cell transplantation (HSCT) who were at high risk for fungal
infections.
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
18
aminotransferase increased (2.3%). No clinically significant differences were seen when the safety
data were analysed by gender or race.
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
Class
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)
Blood and
lymphatic
system disorders
leukopenia,
neutropenia, anaemia
pancytopenia,
thrombocytopenia,
eosinophilia,
hypoalbuminaemia
haemolytic
anaemia,
haemolysis
(see section
4.4)
Immune system
disorders
anaphylactic /
anaphylactoid
reaction (see section
4.4), hypersensitivity
Endocrine
disorders
hyperhidrosis
Metabolism and
nutritional
disorders
hypokalaemia,
hypomagnesaemia,
hypocalcaemia
hyponatraemia,
hyperkalaemia,
hypophosphataemia,
anorexia
Psychiatric
disorders
insomnia, anxiety,
confusion
Nervous system
disorders
headache
somnolence, tremor,
dizziness, dysgeusia
Cardiac
disorders
tachycardia,
palpitations,
bradycardia
Vascular
disorders
phlebitis
hypotension,
hypertension,
flushing
shock
Respiratory,
thoracic and
mediastinal
disorders
dyspnoea
Gastrointestinal
disorders
nausea, vomiting,
diarrhoea, abdominal
pain
dyspepsia,
constipation
Hepatobiliary
disorders
blood alkaline
phosphatase increased,
aspartate
aminotransferase
increased, alanine
aminotransferase
increased, blood
bilirubin increased
(including
hyperbilirubinaemia),
liver function test
abnormal
hepatic failure (see
section 4.4), gamma-
glutamyltransferase
increased, jaundice,
cholestasis,
hepatomegaly,
hepatitis
hepatocellular
damage
including fatal
cases (see
section 4.4)
19
System Organ
Class
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)
Skin and
subcutaneous
tissue disorders
rash
urticaria, pruritus,
erythema
toxic skin
eruption
Renal and
urinary
disorders
blood creatinine
increased, blood urea
increased, renal
failure aggravated
renal
impairment
(see section
4.4), acute
renal failure
General
disorders and
administration
site conditions
pyrexia, rigors
injection site
thrombosis, infusion
site inflammation,
injection site pain,
peripheral oedema
Investigations
blood lactate
dehydrogenase
increased
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 patients
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
20
Hepatobiliary disorders
common
hyperbilirubinaemia, hepatomegaly
Renal and urinary
disorders
common
acute renal failure, blood urea increased
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. One case of mis-dosage of
7.8 mg/kg/day for 7 days was reported 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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
An additive or synergistic pharmacodynamic interaction of micafungin and amphotericin B was found
in a mouse model of pulmonary aspergillosis (immunosuppression with hydrocortisone, intranasal
infection with
Aspergillus fumigatus
).
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 gene coding for a major subunit of glucan synthase.
Breakpoints
Susceptibility testing was performed with modifications according to the Clinical and Laboratory
Standards Institute (CLSI) methods M27-A2 (
Candida
species) and M38-A (
Aspergillus
species),
respectively. To date, standardised techniques for susceptibility testing for 1,3-β-D-glucan synthesis
inhibitors have not been established and results of susceptibility testing do not necessarily correlate
with clinical outcome.
Although no MIC breakpoints for echinocandins have been established, a MIC of
<
2 mg/l
encompasses > 99% of all clinical isolates of
Candida
spp. without bisecting any species group and
represents a concentration that is easily maintained throughout the dosing interval. Infections due to
Candid
a spp. in this MIC range are likely to respond to therapy.
The prevalence of resistance may vary geographically and with time for selected species and local
information on resistance is desirable, particularly when treating severe infections. This information is
only a guide to the probabilities of whether micro-organisms will be susceptible to micafungin or not.
Where applicable the information on the European range of acquired resistance for the individual
micro-organisms is indicated in brackets.
21
Commonly susceptible species [MIC ranges in Europe, mg/l]
Candida albicans
[0.007 - 0.25]
Candida glabrata
[0.007 - 0.12]
Candida tropicalis
[0.007 - 0.12]
Candida krusei
[0.015 - 0.12]
Candida kefyr
[0.03 - 0.06]
Candida parapsilosis
[0.12 - 2]
Candida guilliermondii
[0.5]
Candida lusitaniae
[0.12 - 0.25]
Candida
spp. [0.015 - 0.5]
(incl.
C. famata, C. dubliniensis, C. lipolytica, C. pelliculosa, C. rugosa, C. stellatoidea
and
C.
zeylanoides)
Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Aspergillus nidulans
Aspergillus versicolor
The mycelial form of dimorphic fungi (e.g.
Histoplasma capsulatum
,
Blastomyces dermatitidis
,
Coccidioides immitis
)
Species for which acquired resistance may be a problem
None
Inherently resistant organisms
Cryptococcus
spp.
Pseudallescheria
spp.
Scedosporium
spp
.
Fusarium
spp
.
Trichosporon
spp
.
Zygomycetes
spp.
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
Amphotericin B
% Difference
[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] ‡
22
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
< 4 weeks)
7
7 (100)
5
4 (80)
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)
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
Micafungin is an intravenously administered medication.
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
23
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.
Metabolism
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
14
C-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 age, with mean values of clearance in younger children
(2-11 years) being approximately 1.3 -fold greater than those in older children (12-17 years). Older
children had mean clearance values similar to those determined in adult patients. Mean clearance in
premature infants (gestational age approximately 26 weeks) is approximately 5-fold greater than in
adults.
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.
5.3 Preclinical safety data
24
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.
6.
25
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 of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
10 ml Type I glass vial with an isobutylene-isoprene (Teflon-laminated) rubber stopper and a flip-off
cap. The vial is wrapped with an UV-protective film.
Supplied in 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.
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
26
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, please
discard unused reconstituted concentrate 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. Do not use if the solution 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
(mg)
Mycamine vial
to be used
(mg/vial)
Volume of sodium
chloride (0.9%) or
glucose (5%) to be
added per vial
Volume
(concentration)
of reconstituted
powder
Standard infusion
(added up to
100 ml)
Final
concentration
50
1 x 50
5 ml
approx. 5 ml
(10 mg/ml)
0.5 mg/ml
100
1 x 100
5 ml
approx. 5 ml
(20 mg/ml)
1.0 mg/ml
150
1 x 100 + 1 x
50
5 ml
approx. 10 ml
1.5 mg/ml
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.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
8.
EU/1/08/448/002
9.
25/04/2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/.
27
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Astellas Ireland Co. Ltd
Killorglin
Co. Kerry
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH shall ensure that prior to launch of the product prescribers will receive the prescriber
checklist in order to ensure that:
•
Mycamine is contra-indicated if the patient has a history of hypersensitivity to micafungin or
excipients.
•
Mycamine should not be used during pregnancy unless clearly necessary.
•
Caution must be demonstrated if the patient:
-
has severe liver function impairment
-
has chronic liver diseases known to represent preneoplastic conditions (e.g. advanced liver
fibrosis, cirrhosis, viral hepatitis, neonatal liver disease or congenital enzyme defects)
-
is receiving a concomitant therapy including hepatotoxic and/or genotoxic properties
-
has history of haemolysis, haemolytic anaemia or renal impairment.
•
Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should
be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or
itraconazole dosage should be reduced if necessary.
•
Patients should be carefully monitored for liver damage and for worsening of renal function.
•
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.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 4 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 5.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
29
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMA
30
ANNEX III
LABELLING AND PACKAGE LEAFLET
31
A. LABELLING
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Mycamine 50 mg powder 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.
See the package leaflet for further information.
4.
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous infusion after reconstitution and dilution.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
33
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/08/448/001
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
34
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Mycamine 50 mg powder 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
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Mycamine 100 mg powder 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.
See the package leaflet for further information.
4.
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous infusion after reconstitution and dilution.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
36
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/08/448/002
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
37
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Mycamine 100 mg powder 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
38
B. PACKAGE LEAFLET
39
PACKAGE LEAFLET: INFORMATION FOR THE USER
Mycamine 50 mg powder for solution for infusion
Mycamine 100 mg powder for solution for infusion
Micafungin
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Mycamine is and what it is used for
2. Before you use Mycamine
3. How to use Mycamine
4. Possible side effects
5.
How to store Mycamine
6.
Further information
1.
WHAT MYCAMINE IS AND WHAT IT IS USED FOR
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 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 treat adults, adolescents and children who are at risk of developing a Candida
fungal infection
that may penetrate the body.
2.
BEFORE YOU USE MYCAMINE
Do not use Mycamine
-
if you are allergic (hypersensitive) to micafungin or any of the other ingredients of Mycamine.
Take special care with Mycamine
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.
40
-
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.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
It is especially important to inform your doctor if you are using amphotericin B desoxycholate or
itraconazole (antifungal antibiotics), sirolimus (an immunosuppressant) or nifedipine (a calcium
antagonist). Your doctor may decide to adjust the dose of these medicines.
Using 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
Ask your doctor or pharmacist for advice before taking any medicine.
Mycamine should not be used during pregnancy unless clearly necessary. If you use Mycamine you
should not breast-feed.
Driving and using machines
There is no information on the effect of Mycamine on the ability to drive or use machines. Please
inform your doctor if you experience any effects that may cause you to have problems with driving or
using other machinery.
Important information about some of the ingredients of Mycamine
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicinal product.
3.
HOW TO USE MYCAMINE
Mycamine must be prepared and given to you by a doctor or another health care 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 (including newborns) 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.
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 health care professional immediately.
If you miss a dose of Mycamine
41
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
health care professional immediately.
Effects when treatment with Mycamine is stopped
There are no known withdrawal symptoms.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Mycamine can cause side effects, although not everybody gets them.
The safety of Mycamine has been assessed in clinical trials. Patients in these trials were critically ill,
had a wide variety of other medical conditions, and required many other medicines.
Mycamine may cause the following side effects:
Common (affects 1 to 10 users in 100)
-
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 (affects 1 to 10 users in 1,000)
-
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)
-
allergic attack (anaphylactic reaction / anaphylactoid shock); 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
-
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
42
-
clotting in vein at injection-site; inflammation at injection-site; pain at injection-site; collection of
fluid in your body
Rare (affects 1 to 10 users in 10,000)
-
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)
-
shock
-
damage to liver cells including death
- severe skin reaction
-
kidney problems; acute kidney failure
The following reactions have been reported more often in paediatric patients than in adult patients:
Common (affects 1 to 10 users in 100)
-
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
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE MYCAMINE
Keep out of the reach and sight 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.
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.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
Reconstituted Mycamine should be used immediately because it does not contain any preservatives to
prevent bacterial contamination. Only a trained health care professional who has read the complete
directions properly can prepare this medicine for use.
6.
FURTHER INFORMATION
What Mycamine contains
-
The active substance is micafungin sodium.
1 vial contains 50 mg or 100 mg micafungin (as sodium).
43
-
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 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.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
Manufacturer
Astellas Ireland Co., Ltd.
Killorglin, County Kerry
Ireland
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Astellas Pharma B.V. Branch
Erasmus Park/Parc Erasme
Square Marie Curie 50
B-1070 Brüssel/Bruxelles
Tél/Tel: +32 (0)2 5580710
Luxembourg/Luxemburg
Astellas Pharma B.V. Branch
Erasmus Park/Parc Erasme
Square Marie Curie 50
B-1070 Brüssel/Bruxelles
Belgique/Belgien
Tél/Tel: +32 (0)2 5580710
България
Астелас Фарма ЕООД
ул. ”Бигла” 6
София 1407
Teл.: +359 2 862 53 72
Magyarország
Astellas Pharma Kft.
Kelenhegyi út 43
H-1118 Budapest/B.III
Tel.: +36 (06)1 3614673
Česká republika
Astellas Pharma s.r.o.
Sokolovskà 100/94
CZ-18600 Praha 8
Tel: +420 236 080300
Malta
E.J. Busuttil Ltd.
Niche
Triq ix-Xorrox
MT-B'kara BKP 12
Tel: +356 21 447184
Danmark
Astellas Pharma a/s
Naverland 4
DK-2600 Glostrup
Tlf: +45 43430355
Nederland
Astellas Pharma B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Tel: +31 (0)71 5455745
Deutschland
Astellas Pharma GmbH
Georg-Brauchle-Ring 64 – 66
D-80992 München
Tel: +49 (0)89 454401
Norge
Astellas Pharma
Solbråveien 47
N-1383 Asker
Tlf: +47 6676 4600
Eesti
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Österreich
Astellas Pharma Ges.m.b.H.
Linzer Straße 221/E02
A-1140 Wien
44
Holland
Tel: +31 (0)71 5455745
Tel: +43 (0)1 8772668
Ελλάδα
Astellas Pharmaceuticals AEBE
Θουκυδίδου 1
GR-14565, Άγιος Στέφανος Αττικής
Tηλ: +30 210 8189900
Polska
Astellas Pharma Sp.z o.o.
ul. Poleczki 21
PL-02-822 Warszawa
Tel.: +48 (0) 225451 111
España
Astellas Pharma S.A.
Paseo del Club Deportivo n° 1
Bloque 14-2
a
Planta
E-28223 Pozuelo de Alarcón, Madrid
Tel: +34 91 4952700
Portugal
Astellas Farma, Lda.
Edifício Cinema
Rua José Fontana, n.°1, 1°Andar
P-2770-101 Paço de Arcos
Tel: +351 21 4401320
France
Astellas Pharma S.A.S.
114 rue Victor Hugo
F-92300 Levallois Perret
Tél: +33 (0)1 55917500
România
S.C.Astellas Pharma SRL
Detalii de contact pentru România
Şoseaua Bucureşti-Ploieşti 42-44
Clădire 1, Parter
013696-Bucureşti - RO
Tel: +40 (0)21 361 04 95
Ireland
Astellas Pharma Co. Ltd.
25, The Courtyard
Kilcarbery Business Park
Nangor Road
Clondalkin
IRL-Dublin 22
Tel: +353 (0)1 4671555
Slovenija
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Nizozemska
Tel: +31 (0)71 5455745
Ísland
Vistor hf.
Hörgatúni 2
IS-210 Garðabær
Tel: +354 535 7000
Slovenská republika
Astellas Pharma s.r.o., organizačná zložka
Galvániho 15/C
SK-821 04 Bratislava
Tel: +421 2 4444 2157
Italia
Astellas Pharma S.p.A.
Via delle Industrie 1
I-20061 Carugate (Milano)
Tel: +39 02 921381
Suomi/Finland
Algol Pharma Oy
PL 13
FIN-02611 Espoo/Esbo
Puh/Tel: +358 9 50991
Κύπρος
Astellas Pharmaceuticals AEBE
Θουκυδίδου 1
GR-14565, Άγιος Στέφανος Αττικής
Tηλ: +30 210 8189900
Ελλάδα
Sverige
Astellas Pharma AB
Per Albin Hanssons väg 41
S-205 12 Malmö
Tel: +46 (0)40-650 15 00
Latvija
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Nīderlande
Tel: +31 (0)71 5455745
United Kingdom
Astellas Pharma Ltd.
Lovett House
Lovett Road, Staines
Middlesex, TW18 3AZ
Tel: +44 (0) 1784 419615
45
Lietuva
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Nyderlandai
Tel: +31 (0)71 5455745
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site:
http://www.ema.europa.eu/
.
---------------------------------------------------------------------------------------------------------------------------
46
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, please
discard unused reconstituted concentrate 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. Do not use if the solution 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
(mg)
Mycamine vial
to be used
(mg/vial)
Volume of sodium
chloride (0.9%) or
glucose (5%) to be
added per vial
Volume
(concentration)
of reconstituted
powder
Standard infusion
(added up to
100 ml)
Final
concentration
50 1 x 50
5 ml
approx. 5 ml
(10 mg/ml)
0.5 mg/ml
100 1 x 100
5 ml
approx. 5 ml
(20 mg/ml)
1.0 mg/ml
150 1 x 100 + 1 x
50
5 ml
approx. 10 ml
1.5 mg/ml
200 2 x 100
5 ml
approx. 10 ml
2.0 mg/ml
47
ANNEX IV
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE
OF THE MEDICINAL PRODUCT TO BE IMPLEMENTED BY THE MEMBER STATES
48
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE
OF MEDICINAL PRODUCT TO BE IMPLEMENTED BY THE MEMBER STATES
The Member States should ensure that all conditions or restrictions with regard to the safe and
effective use of the medicinal product described below i.e. the details of a prescription checklist are
implemented:
•
Mycamine is contra-indicated if the patient has a history of hypersensitivity to micafungin or
excipients.
•
Mycamine should not be used during pregnancy unless clearly necessary.
•
Caution must be demonstrated if the patient:
-
has severe liver function impairment
-
has chronic liver diseases known to represent preneoplastic conditions (e.g. advanced liver
fibrosis, cirrhosis, viral hepatitis, neonatal liver disease or congenital enzyme defects)
-
is receiving a concomitant therapy including hepatotoxic and/or genotoxic properties
-
has history of haemolysis, haemolytic anaemia or renal impairment.
•
Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should
be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or
itraconazole dosage should be reduced if necessary.
•
Patients should be carefully monitored for liver damage and for worsening of renal function.
•
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.
49
Source: European Medicines Agency
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