ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ECALTA 100 mg powder and solvent for concentrate for solution for infusion.
2.
Each vial contains 100 mg anidulafungin.
The reconstituted solution contains 3.33 mg/ml anidulafungin and the diluted solution contains 0.36
mg/ml anidulafungin.
Excipients: Fructose 102.5 mg per vial
Ethanol 6 g per vial
For a full list of excipients, see section 6.1.
3.
Powder and solvent for concentrate for solution for infusion.
Powder: White to off-white lyophilised solid.
Solvent: Clear colourless solution.
The reconstituted solution has a pH of 4.0 to 6.0.
4.
Treatment of invasive candidiasis in adult non-neutropenic patients.
ECALTA has been studied primarily in patients with candidaemia and only in a limited number of
patients with deep tissue
Candida
infections or with abscess-forming disease
(see section 4.4 and
section 5.1).
4.2
Treatment with ECALTA should be initiated by a physician experienced in the management of
invasive fungal infections.
Specimens for fungal culture should be obtained prior to therapy. Therapy
may be initiated before culture results are known and can be adjusted accordingly once they are
available.
A single 200 mg loading dose should be administered on Day 1, followed by 100 mg daily thereafter.
Duration of treatment should be based on the patient’s clinical response. In general, antifungal
therapy should continue for at least 14 days after the last positive culture.
ECALTA should be reconstituted with the solvent to a concentration of 3.33 mg/ml and subsequently
diluted to a concentration of 0.36 mg/ml before use according to the instructions given in section 6.6.
It is recommended that ECALTA be administered at a rate of infusion that does not exceed
1.1 mg/minute (equivalent to 3.0 ml/minute). Infusion associated reactions are infrequent when the
rate of anidulafungin infusion does not exceed 1.1 mg/minute.
ECALTA should not be administered as a bolus injection.
2
Renal and hepatic impairment
No dosing adjustments are required for patients with mild, moderate, or severe hepatic impairment.
No dosing adjustments are required for patients with any degree of renal insufficiency, including those
on dialysis. ECALTA can be given without regard to the timing of haemodialysis (see section 5.2).
Duration of treatment
There are insufficient data to support the 100 mg dose for longer than 35 days of treatment.
Other special populations
No dosing adjustments are required for adult patients based on gender, weight, ethnicity, HIV
positivity, or geriatric status (see section 5.2).
Children and adolescents
ECALTA is not recommended for use in children below 18 due to insufficient data on safety and
efficacy (see section 5.2).
4.3
Hypersensitivity to the active substance, or to any of the excipients.
Hypersensitivity to other medicinal products of the echinocandin class.
4.4
The efficacy of ECALTA in neutropenic patients with candidaemia and in patients with deep tissue
Candida
infections or intra-abdominal abscess and peritonitis has not been established.
Clinical efficacy has been evaluated primarily in non-neutropenic patients with
C. albicans
infections
and in a smaller number of patients infected with non-albicans, mainly
C. glabrata
,
C. parapsilosis
and
C. tropicalis.
Patients with candida endocarditis, osteomyelitis or meningitis and known
C.krusei
infection have not been studied.
Hepatic effects
Increased levels of hepatic enzymes have been seen in healthy subjects and patients treated with
anidulafungin. In some patients with serious underlying medical conditions who were receiving
multiple concomitant medicines along with anidulafungin, clinically significant hepatic abnormalities
have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or hepatic failure have been
reported. Patients with increased hepatic enzymes during anidulafungin therapy should be monitored
for evidence of worsening hepatic function and evaluated for risk/benefit of continuing anidulafungin
therapy.
Infusion-related reactions
Exacerbation of infusion-related reactions by coadministration of anaesthetics has been seen in a non-
clinical (rat) study (see section 5.3). The clinical relevance of this is unknown. Nevertheless, care
should be taken when co-administering anidulafungin and anaesthetic agents.
Alcohol content
This medicinal product contains 24 vol% ethanol (alcohol); this is equivalent to 6 g ethanol in the
100 mg maintenance dose (administered over a 1.5-hour period), and 12 g ethanol in the 200 mg
loading dose (administered over a 3-hour period). Ethanol could be harmful for those suffering from
alcoholism. This should be taken into account in pregnant or breast-feeding women, children, and in
high-risk groups such as those with liver disease or epilepsy.
The amount of alcohol in this medicinal product may alter the effects of other medicines.
The amount of alcohol in this medicinal product may impair the ability to drive or use machines.
3
Fructose content
Patients with rare hereditary problems of fructose intolerance should not take this medicine
.
4.5
Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450
isoenzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A). Of note,
in vitro
studies do not fully exclude
possible
in vivo
interactions.
Drug interaction studies were performed with anidulafungin and other medicinal products likely to be
co-administered. No dosage adjustment of either medicinal product is recommended when
anidulafungin is co-administered with ciclosporin, voriconazole or tacrolimus, and no dosage
adjustment for anidulafungin is recommended when co-administered with amphotericin B or
rifampicin.
4.6
There are no data regarding the use of anidulafungin in pregnant women. Slight developmental effects
have been observed in rabbits administered anidulafungin during pregnancy, in the presence of
maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore anidulafungin
is not recommended in pregnancy.
Animal studies have shown excretion of anidulafungin in breast milk. It is not known whether
anidulafungin is excreted in human breast milk. A decision on whether to continue/discontinue breast-
feeding or therapy with anidulafungin should be made taking into account the benefit of breast-feeding
to the child and the benefit of anidulafungin to the mother.
4.7
No studies on the effects on the ability to drive and use machines have been performed.
The amount of alcohol in this medicinal product may impair the ability to drive or use machines.
4.8
Nine hundred and twenty-nine (929) subjects received single or multiple doses of intravenous
anidulafungin in clinical trials: 672 in Phase 2/3 trials (287 patients with candidaemia/invasive
candidiasis, 355 patients with oral/oesophageal candidiasis, 30 patients with invasive aspergillosis),
and 257 in Phase I studies.
Three studies (one comparative vs fluconazole, two non-comparative) assessed the efficacy of
anidulafungin in patients with candidaemia and a limited number of patients with deep tissue
Candida
infections. A total of 204 patients received the recommended daily dose of 100 mg; the mean duration
of intravenous treatment in these patients was 13.5 days (range, 1 to 38 days). One hundred and
nineteen patients received ≥ 14 days of anidulafungin. Adverse reactions were typically mild to
moderate and seldom led to discontinuation.
Infusion-related adverse reactions have been reported with anidulafungin; in the pivotal ICC study,
these included flushing/hot flush (2.3%), pruritus (2.3%), rash (1.5%), and urticaria (0.8%). Other
treatment-related adverse reactions that occurred in ≥ 1% of patients in the pivotal study included
hypokalaemia (3.1%), diarrhoea (3.1%), ALT increased (2.3%), hepatic enzyme increased (1.5%),
blood alkaline phosphatase increased (1.5%), and blood bilirubin increased (1.5%).
The following table includes the drug-related adverse reactions (MedDRA terms) from the 100 mg
ICC database (N = 20 4), with frequency corresponding to Common (≥1/100 to <1/10) or Uncommon
(≥1/1,000 to <1/100) and from spontaneous reports with frequency Not Known (cannot be estimated
from the available data). Within each frequency grouping, undesirable effects are presented in order
of decreasing seriousness.
4
Table of Adverse Reactions
MedDRA System Organ Class
Frequency of Reported MedDRA Preferred Term
Common
Uncommon
Not Known^
Blood and lymphatic system
disorders
Coagulopathy
-
-
Metabolism and nutrition
disorders
Hypokalaemia
Hyperglycaemia
-
Nervous system disorders
Convulsion, headache
-
-
Vascular disorders
Flushing
Hypertension, hot
flush
Hypotension
Respiratory , thoracic and
mediastinal disorders
-
-
Bronchospasm,
dyspnoea
Gastrointestinal disorders
Diarrhoea, vomiting, nausea
Abdominal pain
upper
-
Hepatobiliary disorders
Alanine aminotransferase
increased, blood alkaline
phosphatase increased,
aspartate aminotransferase
increased, blood bilirubin
increased, gamma-
glutamyltransferase increased
Cholestasis
-
Skin and subcutaneous tissue
disorders
Rash, pruritus
Urticaria
-
Renal and urinary disorders
Blood creatinine increased
-
-
General disorders and
administration site conditions
-
Infusion site pain
-
^ Frequency cannot be estimated from the available data
4.9
As with any overdose, general supportive measures should be utilised as necessary. In case of
overdose, adverse reactions may occur as mentioned in section 4.8.
During clinical trials, a single 400 mg dose of anidulafungin was inadvertently administered as a
loading dose. No clinical adverse reactions were reported. No dose limiting toxicity was observed in
a study of 10 healthy subjects administered a loading dose of 260 mg followed by 130 mg daily; 3 of
the 10 subjects experienced transient, asymptomatic transaminase elevations (≤3 x Upper Limit of
Normal (ULN)).
ECALTA is not dialysable.
5.
5.1
Pharmacodynamic properties
General properties
Pharmacotherapeutic group: Other antimycotics for systemic use, ATC code: JO2AX06
Anidulafungin is a semi-synthetic echinocandin, a lipopeptide synthesised from a fermentation product
of
Aspergillus nidulans
.
Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not
mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential
5
component of the fungal cell wall. Anidulafungin has shown fungicidal activity against
Candida
species and activity against regions of active cell growth of the hyphae of
Aspergillus fumigatus
.
Activity
in vitro
Anidulafungin exhibited
in-vitro
activity against
C. albicans, C. glabrata, C. parapsilosis,
and
C.
tropicalis.
Susceptibility breakpoints for 1,3- β-D-glucan synthesis inhibitors have not been
established. For the clinical relevance of these findings see below under clinical studies.
Minimum inhibitory concentration (MIC) determinations were performed according to the Clinical
and Laboratory Standards Institute methods M27. There have been reports of
Candida
isolates with
reduced susceptibility to echinocandins including anidulafungin, but the clinical significance of this
observation is unknown.
Activity
in vivo
Parenterally administered anidulafungin was effective against
Candida
spp. in immunocompetent and
immunocompromised mouse and rabbit models. Anidulafungin treatment prolonged survival and also
reduced the organ burden of
Candida
spp., when determined at intervals from 24 to 96 hours after the
last treatment.
Experimental infections included disseminated
C. albicans
infection in neutropenic rabbits,
oesophageal/oropharyngeal infection of neutropenic rabbits with fluconazole-resistant
C. albicans
and
disseminated infection of neutropenic mice with fluconazole-resistant
C. glabrata.
Information from clinical studies
Candidaemia and other forms of Invasive Candidiasis
The safety and efficacy of anidulafungin were evaluated in a pivotal Phase 3, randomised, double-
blind, multicentre, multinational study of primarily non-neutropenic patients with candidaemia and a
limited number of patients with deep tissue Candida infections or with abscess-forming disease.
[Patients with
Candida
endocarditis, osteomyelitis or meningitis, or those with infection due to
C.
krusei
, were specifically excluded from the study]. Patients were randomised to receive either
anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) or
fluconazole (800 mg intravenous loading dose followed by 400 mg intravenous daily), and were
stratified by APACHE II score (≤20 and >20) and the presence or absence of neutropenia. Treatment
was administered for at least 14 and not more than 42 days. Patients in both study arms were
permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they
were able to tolerate oral medication and were afebrile for at least 24 hours, and that the most recent
blood cultures were negative for
Candida
species.
Patients who received at least one dose of study medication and who had a positive culture for
Candida
species from a normally sterile site before study entry were included in the modified intent-
to-treat (MITT) population. In the primary efficacy analysis, global response in the MITT populations
at the end of intravenous therapy, anidulafungin was compared to fluconazole in a pre-specified two-
step statistical comparison (non-inferiority followed by superiority). A successful global response
required clinical improvement and microbiological eradication. Patients were followed for six weeks
beyond the end of all therapy.
Two hundred and fifty-six patients, ranging from 16 to 91 years in age, were randomised to treatment
and received at least one dose of study medication. The most frequent species isolated at baseline
were
C. albicans
(63.8% anidulafungin, 59.3% fluconazole), followed by
C. glabrata
(15.7%, 25.4%),
C. parapsilosis
(10.2%, 13.6%) and
C. tropicalis
(11.8%, 9.3%) - with 20, 13 and 15 isolates of the
last 3 species, respectively, in the anidulafungin group. The majority of patients had Apache II scores
≤ 20 and very few were neutropenic.
Efficacy data, both overall and by various subgroups, are presented below in Table 1.
6
Table 1.
Global success in the MITT population: pri
mary and secondary
endpoints
Anidulafungin
Fluconazole
Between group
difference
a
( 95% CI)
End of IV Therapy (1º endpoint)
96/127 (75.6%)
71/118 (60.2%)
15.42 (3.9, 27.0)
Candidaemia only
88/116 (75.9%)
63/103 (61.2%)
14.7 (2.5, 26.9)
Other sterile sites
b
8/11 (72.7%)
8/15 (53.3%)
-
Peritoneal fluid/IA
c
abscess
6/8
5/8
Other
2/3
3/7
C. albicans
d
60/74 (81.1%)
38/61 (62.3%)
-
Non-
albicans
species
d
32/45 (71.1%)
27/45 (60.0%)
-
Apache II score ≤ 20
82/101 (81.2%)
60/98 (61.2%)
-
Apache II score > 20
14/26 (53.8%)
11/20 (55.0%)
-
Non-neutropenic
(ANC, cells/mm
3
>
500)
94/124 (75.8%)
69/114 (60.5%)
-
Neutropenic
(ANC, cells/mm
3
≤ 500)
2/3
2/4
-
At Other Endpoints
End of All Therapy
94/127 (74.0%)
67/118 (56.8%)
17.24 (2.9, 31.6)
e
2 Week Follow-up
82/127 (64.6%)
58/118 (49.2%)
15.41 (0.4, 30.4)
e
6 Week Follow-up
71/127 (55.9%)
52/118 (44.1%)
11.84 (-3.4, 27.0)
e
a
Calculated as anidulafungin minus fluconazole
b
With or without concurrent candidaemia
c
Intra-abdominal
d
Data presented for patients with a single baseline pathogen.
e
98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points.
Mortality rates in both the anidulafungin and fluconazole arms are presented below in Table 2:
Table 2.
Mortality
Anidulafungin
Fluconazole
Overall study mortality
29/127 (22.8%)
37/118 (31.4%)
Mortality during study therapy
10/127 (7.9%)
17/118 (14.4%)
Mortality attributed to
Candida
infection
2/127 (1.6%)
5/118 (4.2%)
5.2
Pharmacokinetic properties
General pharmacokinetic characteristics
The pharmacokinetics of anidulafungin have been characterised in healthy subjects, special
populations and patients. A low intersubject variability in systemic exposure (coefficient of variation
~25%) was observed. The steady state was achieved on the first day after a loading dose (twice the
daily maintenance dose).
Distribution
The pharmacokinetics of anidulafungin are characterised by a rapid distribution half-life (0.5-1 hour)
and a volume of distribution, 30-50 l, which is similar to total body fluid volume. Anidulafungin is
extensively bound (>99%) to human plasma proteins. No specific tissue distribution studies of
anidulafungin have been done in humans. Therefore, no information is available about the penetration
of anidulafungin into the cerebrospinal fluid (CSF) and/or across the blood-brain barrier.
7
Biotransformation
Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant
substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. It is unlikely that anidulafungin will
have clinically relevant effects on the metabolism of drugs metabolised by cytochrome P450
isoenzymes.
Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-
opened peptide that lacks antifungal activity. The
in vitro
degradation half-life of anidulafungin under
physiologic conditions is approximately 24 hours.
In vivo
, the ring-opened product is subsequently
converted to peptidic degradants and eliminated mainly through biliary excretion.
Elimination
The clearance of anidulafungin is about 1 l/h. Anidulafungin has a predominant elimination half-life of
approximately 24 hours that characterizes the majority of the plasma concentration-time profile, and a
terminal half-life of 40-50 hours that characterises the terminal elimination phase of the profile.
In a single-dose clinical study, radiolabeled (
14
C)
anidulafungin (~88 mg) was administered to healthy
subjects. Approximately 30% of the administered radioactive dose was eliminated in the faeces over 9
days, of which less than 10% was intact drug. Less than 1% of the administered radioactive
dose was
excreted in the urine, indicating negligible renal clearance. Anidulafungin concentrations fell below
the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity
were recovered in blood, urine, and faeces 8 weeks post-dose.
Linearity
Anidulafungin displays linear pharmacokinetics across a wide range of once daily doses (15-130 mg).
Special populations
Patients with fungal infections
The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those
observed in healthy subjects based on population pharmacokinetic analyses. With the 200/100 mg
daily dose regimen at an infusion rate of 1.1 mg/min, the steady state C
max
and trough
concentrations (C
min
) could reach approximately 7 and 3 mg/l, respectively, with an average
steady state AUC of approximately 110 mg⋅h/l.
Weight
Although weight was identified as a source of variability in clearance in the population
pharmacokinetic analysis, weight has little clinical relevance on the pharmacokinetics of
anidulafungin.
Gender
Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose
patient studies, drug clearance was slightly faster (approximately 22%) in men.
Elderly
The population pharmacokinetic analysis showed that median clearance differed slightly between the
elderly group (patients ≥ 65, median CL = 1.07 l/h) and the non-elderly group (patients < 65, median
CL = 1.22 l/h), however the range of clearance was similar.
Ethnicity
Anidulafungin pharmacokinetics were similar among Caucasians, Blacks, Asians, and Hispanics.
HIV positivity
Dosage adjustments are not required based on HIV positivity, irrespective of concomitant anti-
retroviral therapy.
8
Hepatic insufficiency
Anidulafungin is not hepatically metabolised. Anidulafungin pharmacokinetics were examined in
subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were
not increased in subjects with any degree of hepatic insufficiency. Although a slight decrease in AUC
was observed in patients with Child-Pugh C hepatic insufficiency, the decrease was within the range
of population estimates noted for healthy subjects.
Renal insufficiency
Anidulafungin has negligible renal clearance (<1%). In a clinical study of subjects with mild,
moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin
pharmacokinetics were similar to those observed in subjects with normal renal function.
Anidulafungin is not dialysable and may be administered without regard to the timing of
hemodialysis.
Paediatric
The pharmacokinetics of anidulafungin after at least 5 daily doses were investigated in 24
immunocompromised paediatric (2 to 11 years old) and adolescent (12 to 17 years old) patients with
neutropenia. Steady state was achieved on the first day after a loading dose (twice the maintenance
dose), and steady state C
max
and AUC
ss
increase in a dose-proportional manner. Systemic
exposure
following daily maintenance dose of 0.75 and 1.5 mg/kg/day in this population were comparable to
those observed in adults following 50 and 100 mg/day, respectively. Both regimens were well-
tolerated by these patients.
5.3
Preclinical safety data
In 3 month studies, evidence of liver toxicity, including elevated enzymes and morphologic
alterations, was observed in both rats and monkeys at doses 4- to 6-fold higher than the anticipated
clinical therapeutic exposure.
In vitro
and
in vivo
genotoxicity studies with anidulafungin provided no
evidence of genotoxic potential. Long-term studies in animals have not been conducted to evaluate
the carcinogenic potential of anidulafungin.
Administration of anidulafungin to rats did not indicate any effects on reproduction, including male
and female fertility.
Anidulafungin crossed the placental barrier in rats and was detected in foetal plasma.
Embryo-foetal development studies were conducted with doses between 0.2- and 2-fold (rats) and
between 1- and 4-fold (rabbits) the proposed therapeutic maintenance dose of 100 mg/day.
Anidulafungin did not produce any drug-related developmental toxicity in rats at the highest dose
tested. Developmental effects observed in rabbits (slightly reduced foetal weights) occurred only at
the highest dose tested, a dose that also produced maternal toxicity.
Crossing of the blood-brain barrier by anidulafungin was limited in healthy rats; however, in rabbits
with disseminated candidiasis, anidulafungin has been shown to cross the blood-brain barrier and
reduce fungal burden in the brain.
Rats were dosed with anidulafungin at three dose levels and anesthetised within one hour using a
combination of ketamine and xylazine. Rats in the high dose group experienced infusion-related
reactions that were exacerbated by anaesthesia. Some rats in the mid dose group experienced similar
reactions but only after administration of anaesthesia. There were no adverse reactions in the low-
dose animals in the presence or absence of anaesthesia, and no infusion-related reactions in the mid-
dose group in the absence of anaesthesia.
9
6.
6.1
List of excipients
Powder
:
Fructose
Mannitol
Polysorbate 80
Tartaric acid
Sodium hydroxide (for pH-adjustment)
Hydrochloric acid (for pH-adjustment)
Solvent
:
Ethanol anhydrous
Water for injections
6.2
Incompatibilities
This medicinal product must not be mixed with other medicinal products or electrolytes except those
mentioned in section 6.6.
6.3
Shelf life
Powder and solvent:
3 years
Reconstituted solution
:
The reconstituted solution should be further diluted within an hour. Chemical and physical in-use
stability of the reconstituted solution has been demonstrated for 3 hours at 25ºC and for 2 hours at
5°C.
Infusion solution
:
Chemical and physical in-use stability of the infusion solution has been demonstrated for 24 hours at
25ºC.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions are the responsibility of the user.
6.4
Special precautions for storage
Powder and solvent:
Do not store above 25ºC.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5
Nature and contents of container
Powder
:
30 ml Type 1 glass vial with an elastomeric stopper and aluminium seal with flip-off cap.
Solvent
:
30 ml of 20 % (w/w) ethanol anhydrous in water for injections in a Type 1 glass vial with an
elastomeric stopper and aluminium seal with flip-off cap.
ECALTA will be available as a box containing 1 vial of 100 mg powder and 1 vial of 30 ml solvent.
10
6.6
Special precautions for disposal and other handling
ECALTA must be reconstituted with the solvent (20% (w/w) ethanol anhydrous in water for
injections) and subsequently diluted with ONLY 9 mg/ml (0.9%) sodium chloride for infusion or
50 mg/ml (5%) glucose for infusion. The compatibility of reconstituted ECALTA with intravenous
substances, additives, or medicines other than 9 mg/ml (0.9%) sodium chloride for infusion or
50 mg/ml (5%) glucose for infusion has not been established.
Reconstitution
Aseptically reconstitute each vial with the solvent (20% (w/w) ethanol anhydrous in water for
injections) to provide a concentration of 3.33 mg/ml. The reconstitution time can be up to 5 minutes.
The reconstituted solution should be clear and free from visible particulates. After subsequent dilution,
the solution is to be discarded if particulate matter or discoloration is identified.
The reconstituted solution must be further diluted within an hour and administered within 24 hours.
Dilution
and infusion
Aseptically transfer the contents of the reconstituted vial(s) into an intravenous bag (or bottle)
containing either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion
obtaining an anidulafungin concentration of 0.36 mg/ml. The table below provides the volumes
required for each dose.
Dilution requirements for ECALTA administration
Dose
Number
of boxes
Total
reconstituted
volume
Infusion
volume
A
Total infusion
volume
Infusion solution
concentration
Rate of
infusion
100 mg
1
30 ml (1 box)
250 ml
280 ml
0.36 mg/ml
3.0 ml/min
200 mg
2
60 ml (2 boxes)
500 ml
560 ml
0.36 mg/ml
3.0 ml/min
A
Either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. If either particulate matter or
discolouration are identified, discard the solution.
For single use only. Waste materials should be disposed of in accordance with local requirements.
7.
Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom.
8.
EU/1/07/416/001
9.
20 September 2007
10.
11
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/.
12
1.
ECALTA 100 mg powder for concentrate for solution for infusion.
2.
Each vial contains 100 mg anidulafungin
The reconstituted solution contains 3.33 mg/ml anidulafungin and the diluted solution contains 0.77
mg/ml anidulafungin.
Excipients: Fructose 102.5 mg per vial
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
White to off-white lyophilised solid.
The reconstituted solution has a pH of 3.5 to 5.5.
4.
Treatment of invasive candidiasis in adult non-neutropenic patients.
ECALTA has been studied primarily in patients with candidaemia and only in a limited number of
patients with deep tissue
Candida
infections or with abscess-forming disease
(see section 4.4 and
section 5.1).
4.2
Treatment with ECALTA should be initiated by a physician experienced in the management of
invasive fungal infections.
Specimens for fungal culture should be obtained prior to therapy. Therapy
may be initiated before culture results are known and can be adjusted accordingly once they are
available.
A single 200 mg loading dose should be administered on Day 1, followed by 100 mg daily thereafter.
Duration of treatment should be based on the patient’s clinical response. In general, antifungal
therapy should continue for at least 14 days after the last positive culture.
ECALTA should be reconstituted with water for injections to a concentration of 3.33 mg/ml and
subsequently diluted to a concentration of 0.77 mg/ml before use according to the instructions given in
section 6.6.
It is recommended that ECALTA be administered at a rate of infusion that does not exceed
1.1 mg/minute (equivalent to 1.4 ml/minute when reconstituted and diluted per instructions).
Infusion associated reactions are infrequent when the rate of anidulafungin infusion does not
exceed 1.1 mg/minute.
ECALTA should not be administered as a bolus injection.
13
Renal and hepatic impairment
No dosing adjustments are required for patients with mild, moderate, or severe hepatic impairment.
No dosing adjustments are required for patients with any degree of renal insufficiency, including those
on dialysis. ECALTA can be given without regard to the timing of haemodialysis (see section 5.2).
Duration of treatment
There are insufficient data to support the 100 mg dose for longer than 35 days of treatment.
Other special populations
No dosing adjustments are required for adult patients based on gender, weight, ethnicity, HIV
positivity, or geriatric status (see section 5.2).
Children and adolescents
ECALTA is not recommended for use in children below 18 due to insufficient data on safety and
efficacy (see section 5.2).
4.3
Hypersensitivity to the active substance, or to any of the excipients.
Hypersensitivity to other medicinal products of the echinocandin class.
4.4
The efficacy of ECALTA in neutropenic patients with candidaemia and in patients with deep tissue
Candida
infections or intra-abdominal abscess and peritonitis has not been established.
Clinical efficacy has been evaluated primarily in non-neutropenic patients with
C. albicans
infections
and in a smaller number of patients infected with non-albicans, mainly
C. glabrata
,
C. parapsilosis
and
C. tropicalis.
Patients with candida endocarditis, osteomyelitis or meningitis and known
C.krusei
infection have not been studied.
Hepatic effects
Increased levels of hepatic enzymes have been seen in healthy subjects and patients treated with
anidulafungin. In some patients with serious underlying medical conditions who were receiving
multiple concomitant medicines along with anidulafungin, clinically significant hepatic abnormalities
have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or hepatic failure have been
reported. Patients with increased hepatic enzymes during anidulafungin therapy should be monitored
for evidence of worsening hepatic function and evaluated for risk/benefit of continuing anidulafungin
therapy.
Infusion-related reactions
Exacerbation of infusion-related reactions by coadministration of anaesthetics has been seen in a non-
clinical (rat) study (see section 5.3). The clinical relevance of this is unknown. Nevertheless, care
should be taken when co-administering anidulafungin and anaesthetic agents.
Fructose content
Patients with rare hereditary problems of fructose intolerance should not take this medicine
.
4.5
Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450
isoenzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A). Of note,
in vitro
studies do not fully exclude
possible
in vivo
interactions.
Drug interaction studies were performed with anidulafungin and other medicinal products likely to be
co-administered. No dosage adjustment of either medicinal product is recommended when
14
anidulafungin is co-administered with ciclosporin, voriconazole or tacrolimus, and no dosage
adjustment for anidulafungin is recommended when co-administered with amphotericin B or
rifampicin.
4.6
There are no data regarding the use of anidulafungin in pregnant women. Slight developmental effects
have been observed in rabbits administered anidulafungin during pregnancy, in the presence of
maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore anidulafungin
is not recommended in pregnancy.
Animal studies have shown excretion of anidulafungin in breast milk. It is not known whether
anidulafungin is excreted in human breast milk. A decision on whether to continue/discontinue breast-
feeding or therapy with anidulafungin should be made taking into account the benefit of breast-feeding
to the child and the benefit of anidulafungin to the mother.
4.7
No studies on the effects on the ability to drive and use machines have been performed.
4.8
Nine hundred and twenty-nine (929) subjects received single or multiple doses of intravenous
anidulafungin in clinical trials: 672 in Phase 2/3 trials (287 patients with candidaemia/invasive
candidiasis, 355 patients with oral/oesophageal candidiasis, 30 patients with invasive aspergillosis),
and 257 in Phase I studies.
Three studies (one comparative vs fluconazole, two non-comparative) assessed the efficacy of
anidulafungin in patients with candidaemia and a limited number of patients with deep tissue
Candida
infections. A total of 204 patients received the recommended daily dose of 100 mg; the mean duration
of intravenous treatment in these patients was 13.5 days (range, 1 to 38 days). One hundred and
nineteen patients received ≥ 14 days of anidulafungin. Adverse reactions were typically mild to
moderate and seldom led to discontinuation.
Infusion-related adverse reactions have been reported with anidulafungin; in the pivotal ICC study,
these included flushing/hot flush (2.3%), pruritus (2.3%), rash (1.5%), and urticaria (0.8%). Other
treatment-related adverse reactions that occurred in ≥ 1% of patients in the pivotal study included
hypokalaemia (3.1%), diarrhoea (3.1%), ALT increased (2.3%), hepatic enzyme increased (1.5%),
blood alkaline phosphatase increased (1.5%), and blood bilirubin increased (1.5%).
The following table includes, the drug-related adverse reactions (MedDRA terms) from the 100 mg
ICC database (N = 204), with frequency corresponding to Common (≥1/100 to <1/10) or Uncommon
(≥1/1,000 to <1/100) and from spontaneous reports with frequency Not Known (cannot be estimated
from the available data). Within each frequency grouping, undesirable effects are presented in order
of decreasing seriousness.
15
Table of Adverse Reactions
MedDRA System Organ Class
Frequency of Reported MedDRA Preferred Term
Common
Uncommon
Not Known^
Blood and lymphatic system
disorders
Coagulopathy
-
-
Metabolism and nutrition
disorders
Hypokalaemia
Hyperglycaemia
-
Nervous system disorders
Convulsion, headache
-
-
Vascular disorders
Flushing
Hypertension, hot
flush
Hypotension
Respiratory , thoracic and
mediastinal disorders
-
-
Bronchospasm,
dyspnoea
Gastrointestinal disorders
Diarrhoea, vomiting, nausea
Abdominal pain
upper
-
Hepatobiliary disorders
Alanine aminotransferase
increased, blood alkaline
phosphatase increased,
aspartate aminotransferase
increased, blood bilirubin
increased, gamma-
glutamyltransferase increased
Cholestasis
-
Skin and subcutaneous tissue
disorders
Rash, pruritus
Urticaria
-
Renal and urinary disorders
Blood creatinine increased
-
-
General disorders and
administration site conditions
-
Infusion site pain
-
^ Frequency cannot be estimated from the available data
4.9
As with any overdose, general supportive measures should be utilised as necessary. In case of
overdose, adverse reactions may occur as mentioned in section 4.8.
During clinical trials, a single 400 mg dose of anidulafungin was inadvertently administered as a
loading dose. No clinical adverse reactions were reported. No dose limiting toxicity was observed in
a study of 10 healthy subjects administered a loading dose of 260 mg followed by 130 mg daily; 3 of
the 10 subjects experienced transient, asymptomatic transaminase elevations (≤3 x Upper Limit of
Normal (ULN)).
ECALTA is not dialysable.
5.
5.1
Pharmacodynamic properties
General properties
Pharmacotherapeutic group: Other antimycotics for systemic use, ATC code: JO2AX06
Anidulafungin is a semi-synthetic echinocandin, a lipopeptide synthesised from a fermentation product
of
Aspergillus nidulans
.
Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not
mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential
component of the fungal cell wall. Anidulafungin has shown fungicidal activity against
Candida
species and activity against regions of active cell growth of the hyphae of
Aspergillus fumigatus
.
16
Activity
in vitro
Anidulafungin exhibited
in-vitro
activity against
C. albicans, C. glabrata, C. parapsilosis,
and
C.
tropicalis.
Susceptibility breakpoints for 1,3- β-D-glucan synthesis inhibitors have not been
established. For the clinical relevance of these findings see below under clinical studies.
Minimum inhibitory concentration (MIC) determinations were performed according to the Clinical
and Laboratory Standards Institute methods M27. There have been reports of
Candida
isolates with
reduced susceptibility to echinocandins including anidulafungin, but the clinical significance of this
observation is unknown
.
Activity
in vivo
Parenterally administered anidulafungin was effective against
Candida
spp. in immunocompetent and
immunocompromised mouse and rabbit models. Anidulafungin treatment prolonged survival and also
reduced the organ burden of
Candida
spp., when determined at intervals from 24 to 96 hours after the
last treatment.
Experimental infections included disseminated
C. albicans
infection in neutropenic rabbits,
oesophageal/oropharyngeal infection of neutropenic rabbits with fluconazole-resistant
C. albicans
and
disseminated infection of neutropenic mice with fluconazole-resistant
C. glabrata.
Information from clinical studies
Candidaemia and other forms of Invasive Candidiasis
The safety and efficacy of anidulafungin were evaluated in a pivotal Phase 3, randomised, double-
blind, multicentre, multinational study of primarily non-neutropenic patients with candidaemia and a
limited number of patients with deep tissue Candida infections or with abscess-forming disease.
[Patients with
Candida
endocarditis, osteomyelitis or meningitis, or those with infection due to
C.
krusei
, were specifically excluded from the study]. Patients were randomised to receive either
anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) or
fluconazole (800 mg intravenous loading dose followed by 400 mg intravenous daily), and were
stratified by APACHE II score (≤20 and >20) and the presence or absence of neutropenia. Treatment
was administered for at least 14 and not more than 42 days. Patients in both study arms were
permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they
were able to tolerate oral medication and were afebrile for at least 24 hours, and that the most recent
blood cultures were negative for
Candida
species.
Patients who received at least one dose of study medication and who had a positive culture for
Candida
species from a normally sterile site before study entry were included in the modified intent-
to-treat (MITT) population. In the primary efficacy analysis, global response in the MITT populations
at the end of intravenous therapy, anidulafungin was compared to fluconazole in a pre-specified two-
step statistical comparison (non-inferiority followed by superiority). A successful global response
required clinical improvement and microbiological eradication. Patients were followed for six weeks
beyond the end of all therapy.
Two hundred and fifty-six patients, ranging from 16 to 91 years in age, were randomised to treatment
and received at least one dose of study medication. The most frequent species isolated at baseline
were
C. albicans
(63.8% anidulafungin, 59.3% fluconazole), followed by
C. glabrata
(15.7%, 25.4%),
C. parapsilosis
(10.2%, 13.6%) and
C. tropicalis
(11.8%, 9.3%) - with 20, 13 and 15 isolates of the
last 3 species, respectively, in the anidulafungin group. The majority of patients had Apache II scores
≤ 20 and very few were neutropenic.
Efficacy data, both overall and by various subgroups, are presented below in Table 1.
17
Table 1.
Global success in the MITT population: pri
mary and secondary
endpoints
Anidulafungin
Fluconazole
Between group
difference
a
( 95% CI)
End of IV Therapy (1º endpoint)
96/127 (75.6%)
71/118 (60.2%)
15.42 (3.9, 27.0)
Candidaemia only
88/116 (75.9%)
63/103 (61.2%)
14.7 (2.5, 26.9)
Other sterile sites
b
8/11 (72.7%)
8/15 (53.3%)
-
Peritoneal fluid/IA
c
abscess
6/8
5/8
Other
2/3
3/7
C. albicans
d
60/74 (81.1%)
38/61 (62.3%)
-
Non-
albicans
species
d
32/45 (71.1%)
27/45 (60.0%)
-
Apache II score ≤ 20
82/101 (81.2%)
60/98 (61.2%)
-
Apache II score > 20
14/26 (53.8%)
11/20 (55.0%)
-
Non-neutropenic
(ANC, cells/mm
3
>
500)
94/124 (75.8%)
69/114 (60.5%)
-
Neutropenic
(ANC, cells/mm
3
≤ 500)
2/3
2/4
-
At Other Endpoints
End of All Therapy
94/127 (74.0%)
67/118 (56.8%)
17.24 (2.9, 31.6)
e
2 Week Follow-up
82/127 (64.6%)
58/118 (49.2%)
15.41 (0.4, 30.4)
e
6 Week Follow-up
71/127 (55.9%)
52/118 (44.1%)
11.84 (-3.4, 27.0)
e
a
Calculated as anidulafungin minus fluconazole
b
With or without concurrent candidaemia
c
Intra-abdominal
d
Data presented for patients with a single baseline pathogen.
e
98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points.
Mortality rates in both the anidulafungin and fluconazole arms are presented below in Table 2:
Table 2.
Mortality
Anidulafungin
Fluconazole
Overall study mortality
29/127 (22.8%)
37/118 (31.4%)
Mortality during study therapy
10/127 (7.9%)
17/118 (14.4%)
Mortality attributed to
Candida
infection
2/127 (1.6%)
5/118 (4.2%)
5.2
Pharmacokinetic properties
General pharmacokinetic characteristics
The pharmacokinetics of anidulafungin have been characterised in healthy subjects, special
populations and patients. A low intersubject variability in systemic exposure (coefficient of variation
~25%) was observed. The steady state was achieved on the first day after a loading dose (twice the
daily maintenance dose).
Distribution
The pharmacokinetics of anidulafungin are characterised by a rapid distribution half-life (0.5-1 hour)
and a volume of distribution, 30-50 l, which is similar to total body fluid volume. Anidulafungin is
extensively bound (>99%) to human plasma proteins. No specific tissue distribution studies of
anidulafungin have been done in humans. Therefore, no information is available about the penetration
of anidulafungin into the cerebrospinal fluid (CSF) and/or across the blood-brain barrier.
18
Biotransformation
Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant
substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. It is unlikely that anidulafungin will
have clinically relevant effects on the metabolism of drugs metabolised by cytochrome P450
isoenzymes.
Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-
opened peptide that lacks antifungal activity. The
in vitro
degradation half-life of anidulafungin under
physiologic conditions is approximately 24 hours.
In vivo
, the ring-opened product is subsequently
converted to peptidic degradants and eliminated mainly through biliary excretion.
Elimination
The clearance of anidulafungin is about 1 l/h. Anidulafungin has a predominant elimination half-life of
approximately 24 hours that characterizes the majority of the plasma concentration-time profile, and a
terminal half-life of 40-50 hours that characterises the terminal elimination phase of the profile.
In a single-dose clinical study, radiolabeled (
14
C)
anidulafungin (~88 mg) was administered to healthy
subjects. Approximately 30% of the administered radioactive dose was eliminated in the faeces over 9
days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was
excreted in the urine, indicating negligible renal clearance. Anidulafungin concentrations fell below
the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity
were recovered in blood, urine, and faeces 8 weeks post-dose.
Linearity
Anidulafungin displays linear pharmacokinetics across a wide range of once daily doses (15-130 mg).
Special populations
Patients with fungal infections
The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those
observed in healthy subjects based on population pharmacokinetic analyses. With the 200/100 mg
daily dose regimen at an infusion rate of 1.1 mg/min, the steady state C
max
and trough
concentrations (C
min
) could reach approximately 7 and 3 mg/l, respectively, with an average
steady state AUC of approximately 110 mg⋅h/l.
Weight
Although weight was identified as a source of variability in clearance in the population
pharmacokinetic analysis, weight has little clinical relevance on the pharmacokinetics of
anidulafungin.
Gender
Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose
patient studies, drug clearance was slightly faster (approximately 22%) in men.
Elderly
The population pharmacokinetic analysis showed that median clearance differed slightly between the
elderly group (patients ≥ 65, median CL = 1.07 l/h) and the non-elderly group (patients < 65, median
CL = 1.22 l/h), however the range of clearance was similar.
Ethnicity
Anidulafungin pharmacokinetics were similar among Caucasians, Blacks, Asians, and Hispanics.
HIV positivity
Dosage adjustments are not required based on HIV positivity, irrespective of concomitant anti-
retroviral therapy.
19
Hepatic insufficiency
Anidulafungin is not hepatically metabolised. Anidulafungin pharmacokinetics were examined in
subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were
not increased in subjects with any degree of hepatic insufficiency. Although a slight decrease in AUC
was observed in patients with Child-Pugh C hepatic insufficiency, the decrease was within the range
of population estimates noted for healthy subjects.
Renal insufficiency
Anidulafungin has negligible renal clearance (<1%). In a clinical study of subjects with mild,
moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin
pharmacokinetics were similar to those observed in subjects with normal renal function.
Anidulafungin is not dialysable and may be administered without regard to the timing of
hemodialysis.
Paediatric
The pharmacokinetics of anidulafungin after at least 5 daily doses were investigated in 24
immunocompromised paediatric (2 to 11 years old) and adolescent (12 to 17 years old) patients with
neutropenia. Steady state was achieved on the first day after a loading dose (twice the maintenance
dose), and steady state C
max
and AUC
ss
increase in a dose-proportional manner. Systemic exposure
following daily maintenance dose of 0.75 and 1.5 mg/kg/day in this population were comparable to
those observed in adults following 50 and 100 mg/day, respectively. Both regimens were well-
tolerated by these patients.
5.3
Preclinical safety data
In 3 month studies, evidence of liver toxicity, including elevated enzymes and morphologic
alterations, was observed in both rats and monkeys at doses 4- to 6-fold higher than the anticipated
clinical therapeutic exposure.
In vitro
and
in vivo
genotoxicity studies with anidulafungin provided no
evidence of genotoxic potential. Long-term studies in animals have not been conducted to evaluate
the carcinogenic potential of anidulafungin.
Administration of anidulafungin to rats did not indicate any effects on reproduction, including male
and female fertility.
Anidulafungin crossed the placental barrier in rats and was detected in foetal plasma.
Embryo-foetal development studies were conducted with doses between 0.2- and 2-fold (rats) and
between 1- and 4-fold (rabbits) the proposed therapeutic maintenance dose of 100 mg/day.
Anidulafungin did not produce any drug-related developmental toxicity in rats at the highest dose
tested. Developmental effects observed in rabbits (slightly reduced foetal weights) occurred only at
the highest dose tested, a dose that also produced maternal toxicity.
Crossing of the blood-brain barrier by anidulafungin was limited in healthy rats; however, in rabbits
with disseminated candidiasis, anidulafungin has been shown to cross the blood-brain barrier and
reduce fungal burden in the brain.
Rats were dosed with anidulafungin at three dose levels and anesthetised within one hour using a
combination of ketamine and xylazine. Rats in the high dose group experienced infusion-related
reactions that were exacerbated by anaesthesia. Some rats in the mid dose group experienced similar
reactions but only after administration of anaesthesia. There were no adverse reactions in the low-
dose animals in the presence or absence of anaesthesia, and no infusion-related reactions in the mid-
dose group in the absence of anaesthesia.
20
6
6.1
List of excipients
Fructose
Mannitol
Polysorbate 80
Tartaric acid
Sodium hydroxide (for pH-adjustment)
Hydrochloric acid (for pH-adjustment)
6.2
Incompatibilities
This medicinal product must not be mixed with other medicinal products or electrolytes except those
mentioned in section 6.6.
6.3
Shelf life
3 years
Reconstituted solution
:
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 1 hour
at 5ºC.
If not further diluted immediately, the reconstituted solution should be stored at 2°C – 8°C and diluted
within an hour of reconstitution.
Do not freeze.
Infusion solution
:
Chemical and physical in-use stability of the infusion solution has been demonstrated for 24 hours at
5ºC.
Do not freeze.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions are the responsibility of the user.
6.4
Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5
Nature and contents of container
30 ml Type 1 glass vial with an elastomeric stopper (butyl rubber with an inert polymer coating on the
product contact surface and lubricant on the top surface for easier machinability) and aluminium seal
with flip-off cap.
ECALTA will be available as a box containing 1 vial of 100 mg powder.
6.6
Special precautions for disposal and other handling
ECALTA must be reconstituted with water for injections and subsequently diluted with ONLY
9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion. The
compatibility of reconstituted ECALTA with intravenous substances, additives, or medicines other
than 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion has not been
established.
21
Reconstitution
Aseptically reconstitute each vial with 30 ml water for injections to provide a concentration of
3.33 mg/ml. The reconstitution time can be up to 5 minutes. The reconstituted solution should be clear
and free from visible particulates. After subsequent dilution, the solution is to be discarded if
particulate matter or discoloration is identified.
If not further diluted immediately, the reconstituted solution should be stored at 2°C – 8°C and diluted
within an hour of reconstitution.
Dilution
and infusion
Aseptically transfer the contents of the reconstituted vial(s) into an intravenous bag (or bottle)
containing either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion
obtaining an anidulafungin concentration of 0.77 mg/ml. The table below provides the volumes
required for each dose.
Dilution requirements for ECALTA administration
Dose
Number
of vials of
powder
Total
reconstituted
volume
Infusion
volume
A
Total
infusion
volume
B
Rate of
infusion
Minimum
duration of
infusion
100 mg
1
30 ml
100 ml
130 ml
1.4 ml/
min
90 min
200 mg
2
60 ml
200 ml
260 ml
1.4 ml
/min
180 min
A
Either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion.
B
Infusion solution concentration is 0.77 mg/ml
The rate of infusion should not exceed 1.1 mg/minute (equivalent to 1.4 ml/minute when reconstituted
and diluted per instructions).
Parenteral medicinal products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. If either particulate matter or
discolouration are identified, discard the solution.
For single use only. Waste materials should be disposed of in accordance with local requirements.
7.
Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom.
8.
EU/1/07/416/002
9.
20 September 2007
10.
22
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/.
23
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING
AUTHORISATION
24
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Pfizer Manufacturing Belgium NV
Rijksweg 12
2870 Puurs
Belgium
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 Marketing Authorisation Holder (MAH) shall ensure that prior to the launch of the new product
formulation Ecalta (100 mg powder for concentrate for solution for infusion), the awareness campaign
to prevent a risk of medical errors will be delivered as specified in the Risk Management Plan version
4.0 dated 21 September 2009 and any subsequent updates of the RMP agreed by the CHMP.
It includes:
-
A Dear Healthcare Professional letter to prescribers and pharmacists
-
Information to wholesalers and distributors
-
The evaluation of effectiveness of the awareness campaign
The awareness campaign should deliver the following key messages:
-
Change in the reconstitution procedure using sterile water for injection
s
-
Change in the dilution procedure using 100 ml of infusion solution (per powder vial) only
-
Change in the concentration of the infusion solution to 0.77 mg/ml
-
Maintained infusion rate at 1.1 mg/min (equivalent to 1.4 ml/minute when reconstituted
and diluted per instructions).
-
Need to store and distribute the product in refrigerator (temperature between 2 °C and 8
°C)
-
New packaging design and content
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.0 (9 February
2009 and included in variation EMA/H/C/788/II/10)
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.
25
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 4.0 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.
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 European Medicines Agency
26
ANNEX III
LABELLING AND PACKAGE LEAFLET
27
A. LABELLING
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Carton- ECALTA 100 mg powder and solvent for concentrate for solution for infusion
1.
ECALTA 100 mg powder and solvent for concentrate for solution for infusion
Anidulafungin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 100 mg anidulafungin.
The reconstituted solution contains 3.33 mg/ml anidulafungin and the diluted solution contains
0.36 mg/ml anidulafungin.
3.
LIST OF EXCIPIENTS
Powder for concentrate for solution for infusion:
Excipients: fructose, mannitol, polysorbate 80, tartaric acid and NaOH and/or HCl for pH adjustment.
Solvent for concentrate for solution for infusion:
Contains ethanol anhydrous and water for injections.
4.
1 vial of 100 mg powder
1 vial of 30 ml solvent
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Reconstitute and dilute before use –
read the package leaflet before use.
For intravenous use only.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF REACH AND SITE OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MONTH – YYYY}
29
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Ltd
Ramsgate Road
Sandwich
KENT
CT13 9NJ United-Kingdom
EU/1/07/416/001
13. BATCH NUMBER
Lot: {number}
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.]
30
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial label - ECALTA 100 mg powder and solvent for concentrate for solution for infusion
1.
ECALTA 100 mg powder for concentrate for solution for infusion
Anidulafungin
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP: {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
100 mg
6.
OTHER
31
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Solvent Vial label - ECALTA 100 mg powder and solvent for concentrate for solution for
infusion
1.
Solvent for concentrate for solution for infusion for ECALTA
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP: {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 ml
6.
OTHER
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Carton - ECALTA 100 mg powder for concentrate for solution for infusion
1.
ECALTA 100 mg powder for concentrate for solution for infusion
Anidulafungin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 100 mg anidulafungin.
The reconstituted solution contains 3.33 mg/ml anidulafungin and the diluted solution contains
0.77 mg/ml anidulafungin.
3.
LIST OF EXCIPIENTS
Excipients: fructose, mannitol, polysorbate 80, tartaric acid and NaOH and/or HCl for pH adjustment.
4.
1 vial of 100 mg powder for concentrate for solution for infusion
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Reconstitute the contents with water for injections and dilute before use –
read the package leaflet
before use.
For intravenous use only.
Rate of infusion should not exceed 1.1 mg/minute
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF REACH AND SITE OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MONTH – YYYY}
33
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C). Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Ltd
Ramsgate Road
Sandwich
KENT
CT13 9NJ United-Kingdom
EU/1/07/416/002
13. BATCH NUMBER
Lot {number}
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 label - ECALTA 100 mg powder for concentrate for solution for infusion
1.
ECALTA 100 mg powder for concentrate
Anidulafungin
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
100 mg
6.
OTHER
Store in a refrigerator (2°C – 8°C). Do not freeze.
35
B. PACKAGE LEAFLET
36
PACKAGE LEAFLET: INFORMATION FOR THE USER
ECALTA 100 mg powder and solvent for concentrate for solution for infusion
Anidulafungin
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
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 ECALTA is and what it is used for
2.
What you should know before you are treated with ECALTA
4.
Possible side effects
5.
How to store ECALTA
6.
Further information
1.
WHAT ECALTA IS AND WHAT IT IS USED FOR
ECALTA is prescribed to treat a type of fungal infection of the blood called candidaemia. The
infection is caused by fungal cells (yeasts) called
Candida
.
ECALTA belongs to a group of medicines called echinocandins. These medicines are used to treat
serious fungal infections.
ECALTA prevents normal development of fungal cell walls. In the presence of ECALTA, fungal cells
have incomplete or defective cell walls, making them fragile or unable to grow.
2.
WHAT YOU SHOULD KNOW BEFORE YOU ARE TREATED WITH ECALTA
You should not be treated with ECALTA
-
if you are allergic (hypersensitive) to anidulafungin, other echinocandins (e.g. CANCIDAS), or
any of the other ingredients of ECALTA
Take special care with ECALTA
-
if you develop liver problems during your treatment. If this happens, your doctor may decide to
monitor your liver function more closely.
-
if you are given anaesthetics during your treatment with ECALTA.
Children
ECALTA should not be given to patients under 18 years of age.
Taking 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.
37
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to use ECALTA
Do not start or stop any other medicines without your doctor’s or pharmacist’s approval.
Pregnancy and breast-feeding
The effect of ECALTA in pregnant women is not known. Therefore ECALTA is not recommended
during pregnancy.
Effective contraception should be used in women of childbearing age. Contact your
doctor immediately if you become pregnant while taking ECALTA.
The effect of ECALTA in breast-feeding women is not known. Ask your doctor or pharmacist for
advice before taking ECALTA while breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicines.
Driving and using machines
No studies on the effect on the ability to drive and use machines have been performed.
Important information about some of the ingredients of ECALTA
This medicinal product contains fructose (a type of sugar). If you have been told by your doctor that
you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
This medicinal product contains 24 vol% ethanol (alcohol), i.e. up to 6 g per dose consumed over a 1.5
–hour period (12 g loading dose consumed over a 3-hour period); this is equivalent to 144 ml beer
(288 ml beer for the loading dose) or 60 ml wine (120 ml wine for the loading dose). Harmful for
those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women,
children, and in high-risk groups such as those with liver disease or epilepsy.
The amount of alcohol in this medicinal product may alter the effects of other medicines.
The amount of alcohol in this medicinal product may impair your ability to drive or use machines.
3.
HOW TO USE ECALTA
ECALTA will always be prepared and given to you by a doctor or a healthcare professional (there is
more information about the method of preparation at the end of the leaflet in the section for medical
and healthcare professionals only).
The treatment starts with 200 mg on the first day (loading dose). This will be followed by a daily dose
of 100 mg (maintenance dose).
ECALTA should be given to you once a day, by slow infusion (a drip) into your vein. This will take at
least 1.5 hours for the maintenance dose and 3 hours for the loading dose.
Your doctor will determine the duration of your treatment and how much ECALTA you will receive
each day and will monitor your response and condition.
In general, your treatment should continue for at least 14 days after the last day
Candida
was found in
your blood.
If you receive more ECALTA than you should
If you are concerned that you may have been given too much ECALTA, tell your doctor or another
healthcare professional immediately.
38
If a dose of ECALTA has been forgotten
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be
missed. However tell your doctor or pharmacist if you think that a dose has been forgotten.
Do not take a double dose to make up for a forgotten dose.
Effects when treatment with ECALTA is stopped
You should not experience any effects from ECALTA if your doctor stops ECALTA treatment.
Your doctor may prescribe another medicine following your treatment with ECALTA to continue
treating your fungal infection or prevent it from returning.
If your original symptoms come back, tell your doctor or another healthcare professional immediately.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ECALTA can cause side effects, although not everybody gets them.
The frequency of possible side effects is listed below is defined using the following convention:
very common (affects more than 1 user in 10), common (affects 1 to 10 users in 100), uncommon
(affects 1 to 10 users in 1,000), rare (affects 1 to 10 users in 10,000), not known (frequency cannot be
estimated from the available data).
Common side effects
-
Disorder of blood clotting system
-
Low blood potassium (hypokalaemia)
-
Convulsion (seizure)
-
Headache
-
Flushing
-
Diarrhoea, vomiting, nausea
-
Changes in blood tests of liver function
-
Rash, pruritis (itching)
-
Changes in blood tests of kidney function
Uncommon side effects
-
High blood sugar
-
High blood pressure
-
Hot flush
-
Stomach pain
-
Abnormal flow of bile from the gallbladder into the intestine
(cholestasis)
-
Hives
-
Pain at injection site
Not known
-
Low blood pressure
-
Sudden contraction of the muscles around the airways resulting in wheezing or coughing
-
Difficulty of breathing
If any of the side effects you experience are severe, or if you notice any side effects not listed in this
leaflet, please tell your doctor or pharmacist.
39
5.
HOW TO STORE ECALTA
Keep out of the reach and sight of children.
Do not use ECALTA after the expiry date which is stated on the label. The expiry data refers to the
last day of that month.
Do not store ECALTA above 25ºC.
The reconstituted solution should not be stored above 25ºC. Do not freeze.
The infusion solution should not be stored above 25ºC. Do not refrigerate or freeze.
Medicines should not be disposed of via wastewater or household waste.
6.
FURTHER INFORMATION
What ECALTA contains
-
The active substance is anidulafungin. Each vial of powder contains 100 mg anidulafungin.
-
The other ingredients are
Powder:
fructose, mannitol, polysorbate 80, tartaric acid, sodium hydroxide (for pH-adjustment),
hydrochloric acid (for pH-adjustment)
Solvent:
ethanol anhydrous, water for injections
What ECALTA looks like and contents of the pack
ECALTA is supplied as a box containing 1 vial of 100 mg powder for concentrate for solution for
infusion and 1 vial of 30 ml solvent.
The powder for concentrate for solution for infusion is white to off-white. The solvent is a clear
colourless solution.
Marketing Authorisation Holder and Manufacturer
The marketing authorisation for ECALTA is held by:
Pfizer Limited, Ramsgate Rd, Sandwich, Kent, CT13 9NJ, United Kingdom
Manufacturer
Pfizer Manufacturing Belgium NV, Rijksweg 12, 2870 Puurs, Belgium
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België /Belgique/Belgien Luxembourg/Luxemburg
Pfizer S.A./N.V. Pfizer S.A.
Tél/Tel: +32 (0)2 554 62 11 Tél: +32 (0)2 554 62 11
България Magyarország
Пфайзер Люксембург САРЛ, Клон България Pfizer Kft.
Тел.: +359 2 970 4333
Tel. + 36 1 488 37 00
Česká republika
V.J. Salomone Pharma Ltd.
Tel: +420-283-004-111
Tel : +356 21 22 01 74
Danmark
Nederland
Tlf: +45 44 20 11 00
Tel: +31 (0)10 406 43 01
40
Pfizer s.r.o.
Malta
Pfizer ApS
Pfizer bv
Deutschland
Norge
Pfizer Pharma GmbH
Pfizer AS
Tel: +49 (0) 30 550055-51000
Tlf: +47 67 52 61 00
Pfizer Luxembourg SARL Eesti filiaal
Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 6 405 328
Tel: +43 (0)1 521 15-0
Pfizer Hellas A.E.
Pfizer Polska Sp. z o.o.,
Τηλ: +30 210 6785 800
Tel.: +48 22 335 61 00
España
Portugal
Tel: +34 91 490 99 00
Laboratórios Pfizer, Lda.
France
Pfizer România S.R.L
Tél: +33 (0)1 58 07 34 40
Tel: +40 (0)21 207 28 00
Pfizer Healthcare Ireland
Pfizer Luxembourg SARL
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: 1800 633 363 (toll free)
Tel: +44 (0)1304 616161
Tel: + 386 (0)1 52 11 400
Ísland
Slovenská republika
Vistor hf.,
Pfizer Luxembourg SARL, organizačná zložka
Sími: + 354 535 7000
Tel: +421-2-3355 5500
Pfizer Italia S.r.l.
Suomi/Finland
Tel: +39 06 33 18 21
Puh/Tel: +358(0)9 43 00 40
GEO. PAVLIDES & ARAOUZOS LTD,
Pfizer AB
Τηλ: +35722818087
Tel: +46 (0)8 5505 2000
Latvija
United Kingdom
Pfizer Luxembourg SARL
Filiāle Latvijā
Pfizer Limited
Tel: +371 670 35 775
Tel: +44 (0)1304 616161
Pfizer Luxembourg SARL
filialas Lietuvoje
Tel. +3705 2514000
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/.
<---------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
41
Eesti
Österreich
Ελλάδα
Polska
Pfizer S.A.
Tel: + 351 214 235 500
Pfizer
România
Ireland
Slovenija
Italia
Pfizer Oy
Κύπρος
Sverige
Lietuva
ECALTA must be reconstituted with the solvent (20% (w/w) ethanol anhydrous in water for
injections) and subsequently diluted with ONLY 9 mg/ml (0.9%) sodium chloride for infusion or
50 mg/ml (5%) glucose for infusion. The compatibility of reconstituted ECALTA with intravenous
substances, additives, or medicines other than 9 mg/ml (0.9%) sodium chloride for infusion or
50 mg/ml (5%) glucose for infusion has not been established.
Reconstitution
Aseptically reconstitute each vial with the solvent (20% (w/w) ethanol anhydrous in water for
injections) to provide a concentration of 3.33 mg/ml. The reconstitution time can be up to 5 minutes.
The reconstituted solution should be clear and free from visible particulates. After subsequent dilution,
the solution is to be discarded if particulate matter or discoloration is identified.
The reconstituted solution must be further diluted within an hour and administered within 24 hours.
Dilution
and infusion
Aseptically transfer the contents of the reconstituted vial(s) into an intravenous bag (or bottle)
containing either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion
obtaining an anidulafungin concentration of 0.36 mg/ml. The table below provides the volumes
required for each dose.
Dilution requirements for ECALTA administration
Dose
Number
of boxes
Total
reconstituted
volume
Infusion
volume
A
Total infusion
volume
Infusion solution
concentration
Rate of
infusion
100 mg
1
30 ml (1 box)
250 ml
280 ml
0.36 mg/ml
3.0 ml/min
200 mg
2
60 ml (2 boxes)
500 ml
560 ml
0.36 mg/ml
3.0 ml/min
A
Either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. If either particulate matter or
discolouration are identified, discard the solution.
For single use only. Waste materials should be disposed of in accordance with local requirements.
42
PACKAGE LEAFLET: INFORMATION FOR THE USER
ECALTA 100 mg powder for concentrate for solution for infusion
Anidulafungin
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
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 ECALTA is and what it is used for
2.
What you should know before you are treated with ECALTA
4.
Possible side effects
5.
How to store ECALTA
6.
Further information
1.
WHAT ECALTA IS AND WHAT IT IS USED FOR
ECALTA is prescribed to treat a type of fungal infection of the blood called candidaemia. The
infection is caused by fungal cells (yeasts) called
Candida
.
ECALTA belongs to a group of medicines called echinocandins. These medicines are used to treat
serious fungal infections.
ECALTA prevents normal development of fungal cell walls. In the presence of ECALTA, fungal cells
have incomplete or defective cell walls, making them fragile or unable to grow.
2.
WHAT YOU SHOULD KNOW BEFORE YOU ARE TREATED WITH ECALTA
You should not be treated with ECALTA
-
if you are allergic (hypersensitive) to anidulafungin, other echinocandins (e.g. CANCIDAS), or
any of the other ingredients of ECALTA
Take special care with ECALTA
-
if you develop liver problems during your treatment. If this happens, your doctor may decide to
monitor your liver function more closely.
-
if you are given anaesthetics during your treatment with ECALTA.
Children
ECALTA should not be given to patients under 18 years of age.
Taking 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.
43
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to use ECALTA
Do not start or stop any other medicines without your doctor’s or pharmacist’s approval.
Pregnancy and breast-feeding
The effect of ECALTA in pregnant women is not known. Therefore ECALTA is not recommended
during pregnancy.
Effective contraception should be used in women of childbearing age. Contact your
doctor immediately if you become pregnant while taking ECALTA.
The effect of ECALTA in breast-feeding women is not known. Ask your doctor or pharmacist for
advice before taking ECALTA while breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicines.
Driving and using machines
No studies on the effect on the ability to drive and use machines have been performed.
Important information about some of the ingredients of ECALTA
This medicinal product contains fructose (a type of sugar). 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 ECALTA
ECALTA will always be prepared and given to you by a doctor or a healthcare professional (there is
more information about the method of preparation at the end of the leaflet in the section for medical
and healthcare professionals only).
The treatment starts with 200 mg on the first day (loading dose). This will be followed by a daily dose
of 100 mg (maintenance dose).
ECALTA should be given to you once a day, by slow infusion (a drip) into your vein. This will take at
least
1.5 hours for the maintenance dose and 3 hours for the loading dose.
Your doctor will determine the duration of your treatment and how much ECALTA you will receive
each day and will monitor your response and condition.
In general, your treatment should continue for at least 14 days after the last day
Candida
was found in
your blood.
If you receive more ECALTA than you should
If you are concerned that you may have been given too much ECALTA, tell your doctor or another
healthcare professional immediately.
If a dose of ECALTA has been forgotten
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be
missed. However tell your doctor or pharmacist if you think that a dose has been forgotten.
Do not take a double dose to make up for a forgotten dose.
Effects when treatment with ECALTA is stopped
You should not experience any effects from ECALTA if your doctor stops ECALTA treatment.
Your doctor may prescribe another medicine following your treatment with ECALTA to continue
treating your fungal infection or prevent it from returning.
44
If your original symptoms come back, tell your doctor or another healthcare professional immediately.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ECALTA can cause side effects, although not everybody gets them.
The frequency of possible side effects is listed below is defined using the following convention:
very common (affects more than 1 user in 10), common (affects 1 to 10 users in 100), uncommon
(affects 1 to 10 users in 1,000), rare (affects 1 to 10 users in 10,000), not known (frequency cannot be
estimated from the available data).
Common side effects
-
Disorder of blood clotting system
-
Low blood potassium (hypokalaemia)
-
Convulsion (seizure)
-
Headache
-
Flushing
-
Diarrhoea, vomiting, nausea
-
Changes in blood tests of liver function
-
Rash, pruritis (itching)
-
Changes in blood tests of kidney function
Uncommon side effects
-
High blood sugar
-
High blood pressure
-
Hot flush
-
Stomach pain
-
Abnormal flow of bile from the gallbladder into the intestine
(cholestasis)
-
Hives
-
Pain at injection site
Not known
-
Low blood pressure
-
Sudden contraction of the muscles around the airways resulting in wheezing or coughing
-
Difficulty of breathing
If any of the side effects you experience are severe, or if you notice any side effects not listed in this
leaflet, please tell your doctor or pharmacist.
5.
HOW TO STORE ECALTA
Keep out of the reach and sight of children.
Do not use ECALTA after the expiry date which is stated on the label. The expiry data refers to the
last day of that month.
Store in a refrigerator (2°C – 8°C). Do not freeze.
The reconstituted solution should be stored in a refrigerator (2°C – 8°C), for up to one hour. Do not
freeze.
The infusion solution should be stored in a refrigerator (2°C – 8°C), and should be administered within
24 hours. Do not freeze.
Medicines should not be disposed of via wastewater or household waste.
45
6.
FURTHER INFORMATION
What ECALTA contains
-
The active substance is anidulafungin. Each vial of powder contains 100 mg anidulafungin.
-
The other ingredients are: fructose, mannitol, polysorbate 80, tartaric acid, sodium hydroxide
(for pH-adjustment), hydrochloric acid (for pH-adjustment)
What ECALTA looks like and contents of the pack
ECALTA is supplied as a box containing 1 vial of 100 mg powder for concentrate for solution for
infusion.
The powder is white to off-white.
Marketing Authorisation Holder and Manufacturer
The marketing authorisation for ECALTA is held by:
Pfizer Limited, Ramsgate Rd, Sandwich, Kent, CT13 9NJ, United Kingdom
Manufacturer
Pfizer Manufacturing Belgium NV, Rijksweg 12, 2870 Puurs, Belgium
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België /Belgique/Belgien Luxembourg/Luxemburg
Pfizer S.A./N.V. Pfizer S.A.
Tél/Tel: +32 (0)2 554 62 11 Tél: +32 (0)2 554 62 11
България Magyarország
Пфайзер Люксембург САРЛ, Клон България Pfizer Kft.
Тел.: +359 2 970 4333
Tel. + 36 1 488 37 00
Česká republika
Malta
Tel: +420-283-004-111
V.J. Salomone Pharma Ltd.
Pfizer ApS
Nederland
Tlf: +45 44 20 11 00
Tel: +31 (0)10 406 43 01
Deutschland
Norge
Tel: +49 (0) 30 550055-51000
Tlf: +47 67 52 61 00
Pfizer Luxembourg SARL Eesti filiaal
Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 6 405 328
Tel: +43 (0)1 521 15-0
Pfizer Hellas A.E.
Pfizer Polska Sp. z o.o.,
Τηλ: +30 210 6785 800
Tel.: +48 22 335 61 00
46
Pfizer s.r.o.
Tel : +356 21 22 01 74
Danmark
Pfizer bv
Pfizer Pharma GmbH
Pfizer AS
Eesti
Österreich
Ελλάδα
Polska
Pfizer S.A.
Laboratórios Pfizer, Lda.
Tel: +34 91 490 99 00
Tel: + 351 214 235 500
France
România
Tél: +33 (0)1 58 07 34 40
Tel: +40 (0)21 207 28 00
Pfizer Healthcare Ireland
Pfizer Luxembourg SARL
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: + 386 (0)152 11 400
Tel: 1800 633 363 (toll free)
Tel: +44 (0)1304 616161
Ísland
Slovenská republika
Sími: + 354 535 7000
Pfizer Luxembourg SARL, organizačná zložka
Pfizer Italia S.r.l.
Suomi/Finland
Tel: +39 06 33 18 21
Puh/Tel: +358(0)9 43 00 40
GEO. PAVLIDES & ARAOUZOS LTD,
Pfizer AB
Τηλ: +35722818087
Tel: +46 (0)8 5505 2000
Latvija
United Kingdom
Pfizer Luxembourg SARL
Filiāle Latvijā
Pfizer Limited
Tel: +371 670 35 775
Tel: +44 (0)1304 616161
Lietuva
Pfizer Luxembourg SARL
filialas Lietuvoje
Tel. +3705 2514000
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/.
<--------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only and applies only to
the single vial ECALTA 100 mg powder for concentrate for solution for infusion presentation
:
The contents of the vial must be reconstituted with water for injections and subsequently diluted with
ONLY 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion. The
compatibility of reconstituted ECALTA with intravenous substances, additives, or medicines other
than 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion has not been
established.
47
España
Portugal
Pfizer
Pfizer România S.R.L
Ireland
Slovenija
Vistor hf.,
Tel: +421-2-3355 5500
Italia
Pfizer Oy
Κύπρος
Sverige
Reconstitution
Aseptically reconstitute each vial with 30 ml water for injections to provide a concentration of
3.33 mg/ml. The reconstitution time can be up to 5 minutes. The reconstituted solution should be clear
and free from visible particulates. After subsequent dilution, the solution is to be discarded if
particulate matter or discoloration is identified.
If not further diluted immediately, the reconstituted solution should be stored at 2°C – 8°C and diluted
within an hour of reconstitution.
Dilution
and infusion
Aseptically transfer the contents of the reconstituted vial(s) into an intravenous bag (or bottle)
containing either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion
obtaining an anidulafungin concentration of 0.77 mg/ml. The table below provides the volumes
required for each dose.
Dilution requirements for ECALTA administration
Dose
Number
of vials of
powder
Total
reconstituted
volume
Infusion
volume
A
Total
infusion
volume
B
Rate of
infusion
Minimum
duration of
infusion
100 mg
1
30 ml
100 ml
130 ml
1.4 ml/
min
90 min
200 mg
2
60 ml
200 ml
260 ml
1.4 ml/
min
180 min
A
Either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion.
B
Infusion solution concentration is 0.77 mg/ml
The rate of infusion should not exceed 1.1 mg/minute (equivalent to 1.4 ml/minute when reconstituted
and diluted per instructions).
Parenteral medicinal products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit. If either
particulate matter or discolouration are identified, discard the solution.
For single use only. Waste materials should be disposed of in accordance with local requirements.
48
Source: European Medicines Agency
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