ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Cubicin 350 mg powder for solution for injection or infusion
2.
Each vial contains 350 mg daptomycin.
One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml
(0.9%) solution.
For a full list of excipients, see section 6.1.
3.
Powder for solution for injection or infusion
A pale yellow to light brown lyophilised powder.
4.
Cubicin is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1).
-
Complicated skin and soft-tissue infections (cSSTI).
-
Right-sided infective endocarditis (RIE) due to
Staphylococcus aureus.
It is recommended that
the decision to use daptomycin should take into account the antibacterial susceptibility of the
organism and should be based on expert advice. See sections 4.4 and 5.1.
-
Staphylococcus aureus
bacteraemia (SAB) when associated with RIE or with cSSTI.
Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where
Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-
administered with appropriate antibacterial agent(s).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical
experience in patients with the administration of daptomycin as an injection over 2 minutes. This
mode of administration was only studied in healthy subjects. However, when compared with the same
doses given as intravenous infusions over 30 minutes there were no clinically important differences in
the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).
Posology
-
cSSTI without concurrent
Staphylococcus aureus
bacteraemia: Cubicin 4 mg/kg is administered
once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).
-
cSSTI with concurrent
Staphylococcus aureus
bacteraemia: Cubicin 6 mg/kg is administered
once every 24 hours. See below for dose adjustments in patients with renal insufficiency. The
duration of therapy may need to be longer than 14 days in accordance with the perceived risk of
complications in the individual patient.
2
-
Known or suspected right-sided infective endocarditis due to
Staphylococcus aureus
: Cubicin
6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with
renal insufficiency. The duration of therapy should be in accordance with available official
recommendations.
Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not
be used more frequently than once a day.
Renal insufficiency
Daptomycin is eliminated primarily by the kidney
.
Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in
patients with any degree of renal insufficiency (CrCl < 80 ml/min) when it is considered that the
expected clinical benefit outweighs the potential risk. The response to treatment, renal function and
creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of
renal insufficiency (see also sections 4.4 and 5.2)
.
Dose adjustments in patients with renal insufficiency by indication and creatinine clearance
Indication for use
Creatinine clearance
Dose recommendation
Comments
cSSTI without
S.
aureus
bacteraemia
30 ml/min
4 mg/kg once daily
See section 5.1
< 30 ml/min
4 mg/kg every 48 hours
(1, 2)
RIE or cSSTI
associated with
S.
aureus
bacteraemia
30 ml/min
6 mg/kg once daily
See section 5.1
< 30 ml/min
6 mg/kg every 48 hours
(1, 2)
(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled
clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see
sections 4.4 and 5.2).
(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK
modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory
peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the
completion of dialysis on dialysis days (see section 5.2).
Hepatic insufficiency
No dose adjustment is necessary when administering Cubicin to patients with mild or moderate
hepatic insufficiency (Child-Pugh Class B) (see section 5.2). No data are available in patients with
severe hepatic insufficiency (Child-Pugh Class C). Therefore caution should be exercised if Cubicin
is given to such patients.
Elderly patients
The recommended doses should be used in elderly patients except those with severe renal
insufficiency (see above and section 4.4). However, there are limited data on the safety and efficacy
of daptomycin in patients aged > 65 years and caution should be exercised if Cubicin is given to such
patients.
3
Children and adolescents
Cubicin is not recommended for use in children and adolescents below the age of 18 years due to a
lack of data on safety and efficacy (see section 5.2).
Method of administration
Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period
or by intravenous injection (see section 6.6) and administered over a 2-minute period.
Hypersensitivity to the active substance or to any of the excipients.
If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy
consideration should be given to instituting alternative antibacterial therapy that has been
demonstrated to be efficacious in the treatment of the specific type of infection(s) present.
Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to
Cubicin occurs, discontinue use and institute appropriate therapy.
It has been demonstrated in clinical studies that
Cubicin is not effective in the treatment of
pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.
Clinical data on the use of Cubicin to treat RIE due to
Staphylococcus aureus
are limited to
19 patients (see “Information from clinical trials” in section 5.1).
The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective
endocarditis due to
Staphylococcus aureus
has not been demonstrated.
Patients with deep-seated infections should receive any required surgical interventions (e.g.
debridement, removal of prosthetic devices, valve replacement surgery) without delay.
There is insufficient evidence to be able to draw any conclusions regarding the possible clinical
efficacy of Cubicin against infections due to enterococci, including
Enterococcus faecalis
and
Enterococcus faecium
. In addition, dose regimens of daptomycin that might be appropriate for the
treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures
with daptomycin in the treatment of enterococcal infections that were mostly accompanied by
bacteraemia have been reported. In some instances treatment failure has been associated with the
selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).
The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If
superinfection occurs during therapy, appropriate measures should be taken.
Clostridium difficile
-associated diarrhoea (CDAD) has been reported with Cubicin. If CDAD is
suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as
clinically indicated.
False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR)
have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see
also section 4.5).
4
Creatine phosphokinase and myopathy
Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular
pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been
reported during therapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked
increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred
more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%).
Therefore, it is recommended that:
Plasma CPK should be measured at baseline and at regular intervals (at least once weekly)
during therapy in all patients.
CPK should be measured more frequently (e.g. every 2-3 days at least during the first two
weeks of treatment) in patients who are at higher risk of developing myopathy. For example,
patients with any degree of renal insufficiency (creatinine clearance < 80 ml/min; see also
section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal
products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates
and ciclosporin).
It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at
baseline may be at increased risk of further increases during daptomycin therapy. This should
be taken into account when initiating daptomycin therapy and, if daptomycin is given, these
patients should be monitored more frequently than once weekly.
Cubicin should not be administered to patients who are taking other medicinal products
associated with myopathy unless it is considered that the benefit to the patient outweighs the
risk.
Patients should be reviewed regularly while on therapy for any signs or symptoms that might
represent myopathy.
Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should
have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of
unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of
normal.
Peripheral neuropathy
Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy
with Cubicin should be investigated and consideration should be given to discontinuation of
daptomycin (see sections 4.8 and 5.3).
Renal insufficiency
Renal insufficiency has been reported during treatment with Cubicin. Severe renal insufficiency may
in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of
development of myopathy (see above).
Dose adjustment is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2
and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled
clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin
should only be used in such patients when it is considered that the expected clinical benefit outweighs
the potential risk.
Caution is advised when administering Cubicin to patients who already have some degree of renal
insufficiency (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular
monitoring of renal function is advised (see also section 5.2).
In addition, regular monitoring of renal function is advised during concomitant administration of
potentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see also section
4.5).
5
Obesity
In obese subjects with Body Mass Index (BMI) > 40 kg/m
2
but with creatinine clearance > 70 ml/min,
the AUC
0-∞
daptomycin was significantly increased (mean 42% higher) compared with non-obese
matched controls. There is limited information on the safety and efficacy of daptomycin in the very
obese and so caution is recommended. However, there is currently no evidence that a dose reduction
is required (see section 5.2).
Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely
that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450
system.
Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid.
Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal
products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not
significantly altered by aztreonam.
Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during
coadministration using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The
interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown.
Caution is warranted when Cubicin is co-administered with tobramycin.
Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of
Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in
patients receiving Cubicin and warfarin should be monitored for the first several days after therapy
with Cubicin is initiated.
There is limited experience regarding concomitant administration of daptomycin with other medicinal
products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of
marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these
medicinal products at the same time as Cubicin. It is recommended that other medicinal products
associated with myopathy should if possible be temporarily discontinued during treatment with
Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration
cannot be avoided, CPK levels should be measured more frequently than once weekly and patients
should be closely monitored for any signs or symptoms that might represent myopathy. See sections
4.4, 4.8 and 5.3.
Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-
administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2
inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-
administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-
administered with any other medicinal product known to reduce renal filtration.
During post–marketing surveillance, cases of interference between daptomycin and particular reagents
used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported.
This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities
of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in
vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by
drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin.
6
No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or
indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition
or postnatal development (see section 5.3).
Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the potential benefit
outweighs the possible risk.
In a single case study, Cubicin was administered daily for 28 days to a nursing mother at a dose of
500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27.
The highest measured concentration of daptomycin in the breast milk was 0.045 µg/ml, which is a low
concentration. Therefore, until more experience is gained, breast-feeding should be discontinued
when Cubicin is administered to nursing women.
No studies on the effects on the ability to drive and use machines have been performed.
On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an
effect on the ability to drive or use machinery.
In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a
daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects
received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers.
Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to
the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.
The following adverse reactions were reported during therapy and during follow-up with frequencies
corresponding to common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to
< 1/1,000); very rare (< 1/10,000):
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1
Adverse reactions from clinical studies and post-marketing reports
System organ class
Frequency
Adverse reactions
Infections and infestations
Common:
Fungal infections, urinary tract infection, candida
infection
Uncommon:
Fungaemia
Not known*:
Clostridium difficile
-associated diarrhoea
Blood and lymphatic system
disorders
Common:
Anaemia
Uncommon:
Thrombocythaemia, eosinophilia, international
normalised ratio (INR) increased
Rare:
Prothrombin time (PT) prolonged
7
Immune system disorders
Not known*:
Hypersensitivity, manifested by isolated spontaneous
reports including, but not limited to pulmonary
eosinophilia, vesicobullous rash with mucous
membrane involvement and sensation of
oropharyngeal swelling
Not known*:
Anaphylaxis
Not known*:
Infusion reactions including the following symptoms:
tachycardia, wheezing, pyrexia, rigors, systemic
flushing, vertigo, syncope and metallic taste
Metabolism and nutrition
disorders
Uncommon:
Decreased appetite, hyperglycaemia, electrolyte
imbalance
Psychiatric disorders
Common:
Anxiety, insomnia
Nervous system disorders
Common:
Dizziness, headache
Uncommon:
Paraesthesia, taste disorder, tremor
Not known*:
Peripheral neuropathy
Ear and labyrinth disorders
Uncommon:
Vertigo
Cardiac disorders
Uncommon:
Supraventricular tachycardia, extrasystole
Vascular disorders
Common:
Hypertension, hypotension
Uncommon:
Flushes
Gastrointestinal disorders
Common:
Gastrointestinal and abdominal pain, nausea,
vomiting, constipation, diarrhoea, flatulence,
bloating and distension
Uncommon:
Dyspepsia, glossitis
Hepatobiliary disorders
Common:
Liver function tests abnormal
1
(increased alanine
aminotransferase (ALT), aspartate aminotransferase
(AST) or alkaline phosphatase (ALP))
Rare:
Jaundice
Skin and subcutaneous tissue
disorders
Common:
Rash, pruritus
Uncommon:
Urticaria
Musculoskeletal and
connective tissue disorders
Common:
Limb pain, serum creatine phosphokinase (CPK)
1
increased
Uncommon:
Myositis, increased myoglobin, muscular weakness,
muscle pain, arthralgia, serum lactate dehydrogenase
(LDH) increased
Not known*:
Rhabdomyolysis
2
Renal and urinary disorders
Uncommon:
Renal insufficiency, including renal impairment and
renal failure, serum creatinine increased
Reproductive system and
breast disorders
Uncommon:
Vaginitis
General disorders and
administration site conditions
Common:
Infusion site reactions, pyrexia, asthenia
Uncommon:
Fatigue, pain
*
Based on post-marketing reports. Since these reports are from a population of uncertain size
and are subject to confounding factors, it is not possible to reliably estimate their frequency or
establish a causal relationship to exposure to the medicinal product.
1
In some cases of myopathy involving raised CPK and muscle symptoms, the patients also
presented with elevated transaminases. These transaminase increases were likely to be related
to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3
toxicity and resolved upon discontinuation of treatment.
2
When clinical information on the patients was available to make a judgement, approximately
50% of the cases occurred in patients with pre-existing renal insufficiency, or in those receiving
concomitant medicinal products known to cause rhabdomyolysis.
8
The safety data for the administration of daptomycin via 2-minute intravenous injection are derived
from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods
of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous
infusion, had a similar safety and tolerability profile. There was no relevant difference in local
tolerability or in the nature and frequency of adverse reactions.
In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by
haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal
dialysis (approximately 11% of the administered dose is removed over 48 hours).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code:
J01XX09
Mode of action
Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.
The mechanism of action involves binding
(in the presence of calcium ions) to bacterial membranes
of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of
protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.
PK/PD relationship
Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive
organisms
in vitro
and in
in vivo
animal models. In animal models AUC/MIC and C
max
/MIC correlate
with efficacy and predicted bacterial kill
in vivo
at single doses equivalent to human doses of 4 mg/kg
and 6 mg/kg once daily.
Mechanisms of resistance
Strains with decreased susceptibility to daptomycin have been reported especially during the
treatment of patients with difficult-to-treat infections and/or following administration for prolonged
periods. In particular, there have been reports of treatment failures in patients infected with
Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium,
including bacteraemic
patients, that have been associated with the selection of organisms with reduced susceptibility or frank
resistance to daptomycin during therapy.
The mechanism of resistance to daptomycin has not yet been identified.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except
S.
pneumoniae
) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.
Susceptibility
The prevalence of resistance may vary geographically and over time for selected species and local
information on resistance is desirable, particularly when treating severe infections. As necessary,
expert advice should be sought when the local prevalence of resistance is such that the utility of the
agent in at least some types of infections is questionable.
9
Commonly Susceptible Species
Staphylococcus aureus
*
Staphylococcus haemolyticus
Coagulase negative staphylococci
Streptococcus agalactiae
*
Streptococcus dysgalactiae
subsp
equisimilis
*
Streptococcus pyogenes
*
Group G streptococci
Clostridium perfringens
Peptostreptococcus spp
Inherently resistant organisms
Gram negative organisms
*
denotes species against which it is considered that activity has been satisfactorily demonstrated in
clinical studies.
Information from clinical trials
In two clinical trials in complicated skin and soft tissues infections, 36% of patients treated with
Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common
type of infection treated was wound infection (38% of patients), while 21% had major abscesses.
These limitations of the patients population treated should be taken into account when deciding to use
Cubicin.
In a randomised controlled open-label study in 235 patients with
Staphylococcus aureus
bacteraemia
(i.e, at least one positive blood culture of
Staphylococcus aureus
prior to receiving the first dose) 19
of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11 were infected
with methicillin-susceptible and 8 with methicillin-resistant
Staphylococcus aureus
. The success rates
in RIE patients are shown in the table below.
Population
Daptomycin
Comparator
Differences in
Success
n/N (%)
n/N (%)
Rates (95% CI)
ITT (intention to treat) Population
RIE
8/19 (42.1%)
7/16 (43.8%)
-1.6% (-34.6, 31.3)
PP (per protocol) Population
RIE
6/12 (50.0%)
4/8 (50.0%)
0.0% (-44.7, 44.7)
Failure of treatment due to persisting or relapsing
Staphylococcus aureus
infections was observed in
19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and
2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these
failures six patients treated with Cubicin and one patient treated with vancomycin were infected with
Staphylococcus aureus
that developed increasing MICs of daptomycin on or following therapy (see
“Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing
Staphylococcus aureus
infection had deep-seated infection and did not receive necessary surgical
intervention.
5.2 Pharmacokinetic properties
Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg
administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy
volunteers. Steady-state concentrations are achieved by the third daily dose.
Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional
pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure
10
(AUC and C
max
) was demonstrated in healthy subjects following administration of daptomycin as a
30-minute intravenous infusion or as a 2-minute intravenous injection.
Animal studies showed that daptomycin is not absorbed to any significant extent after oral
administration.
Distribution
The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately
0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin
appears to only minimally penetrate the blood-brain barrier and the placental barrier following single
and multiple doses.
Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In
healthy volunteers and patients treated with daptomycin, protein binding averaged about 90%
including subjects with renal insufficiency.
Metabolism
In
in vitro
studies, daptomycin was not metabolised by human liver microsomes.
In vitro
studies with
human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following
human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that
daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450
system.
After infusion of 14C-daptomycin, the plasma radioactivity was similar to the concentration
determined by microbiological assay. Inactive metabolites were detected in urine, as determined by
the difference in total radioactive concentrations and microbiologically active concentrations. In a
separate study, no metabolites were observed in plasma, and minor amounts of three oxidative
metabolites and one unidentified compound were detected in urine. The site of metabolism has not
been identified.
Elimination
Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and
daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active
tubular secretion of daptomycin.
Following intravenous administration, plasma clearance of daptomycin is approximately 7 to
9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.
In a mass balance study using radiolabelled material, 78% of the administered dose was recovered
from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was
approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.
Special populations
Elderly
Following administration of a single 4 mg/kg intravenous dose of Cubicin, the mean total clearance of
daptomycin decreased approximately 35% and the mean AUC
0-∞
increased approximately 58% in
elderly subjects (≥ 75 years of age) compared with those in young healthy subjects (18 to 30 years of
age). There were no differences in C
max
. The differences noted are most likely due to the normal
reduction in renal function observed in the geriatric population.
No dose adjustment is necessary based on age alone. However, renal function should be assessed and
the dose should be reduced if there is evidence of severe renal insufficiency.
11
Children and adolescents (< 18 years of age)
The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three
groups of paediatric patients with proven or suspected Gram-positive infection (2-6 years, 7-11 years
and 12-17 years). The pharmacokinetics of daptomycin following a single 4 mg/kg dose in
adolescents aged 12-17 years are generally similar to those of healthy adult subjects with normal renal
function with trends towards lower AUC and C
max
in adolescents. In the younger age groups
(2-6 years and 7-11 years), exposure (C
max
and AUC) and elimination half-life for the same mg/kg
dose were reduced compared with adolescents. Efficacy was not assessed in this study.
A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single
8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to
6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard
antibiotic therapy.
The mean exposure (AUC
0-∞
) was approximately 429 and 550 μg*hr/ml after the administration of 8
and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at
steady state (495 μg*hr/ml). The pharmacokinetics of daptomycin appears to be linear in the dose
range studied. The half life, clearance and volume of distribution were similar at both dose levels.
Obesity
Relative to non-obese subjects daptomycin systemic exposure measured by AUC is increased by
about 28% in moderately obese subjects (Body Mass Index of 25-40 kg/m
2
) and by 42% in extremely
obese subjects (Body Mass Index of > 40 kg/m
2
). However, no dose adjustment is considered to be
necessary based on obesity alone.
Gender
No clinically significant gender-related differences in daptomycin pharmacokinetics have been
observed.
Renal insufficiency
Following administration of a single 4 mg/kg or 6 mg/kg dose of daptomycin to subjects with various
degrees of renal insufficiency, daptomycin clearance (CL) decreased and systemic exposure (AUC)
increased as renal function (creatinine clearance) decreased.
Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after
administration of a 6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in
patients with normal renal function who received the same dose. On the second day after
administration of a 6 mg/kg dose to HD and CAPD patients the daptomcyin AUC was approximately
1.3-fold higher than that observed after a second 6 mg/kg dose in patients with normal renal function.
On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every
48 hours at the dose recommended for the type of infection being treated (see section 4.2).
Hepatic insufficiency
The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic insufficiency
(Child-Pugh B classification of hepatic insufficiency) compared with healthy volunteers matched for
gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when
administering daptomycin in patients with moderate hepatic insufficiency. The pharmacokinetics of
daptomycin in patients with severe hepatic insufficiency (Child-Pugh C classification) have not been
evaluated.
5.3 Preclinical safety data
In studies of clinically-relevant duration (14-28 days), daptomycin administration was associated with
minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic
changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the
higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed.
12
Depending on the study duration, all muscle effects, including microscopic changes, were fully
reversible within 1-3 months following cessation of dosing. No functional or pathological changes in
smooth or cardiac muscle were observed.
The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels
of 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) for
patients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, the
safety margins for both methods of administration are very similar.
A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as
compared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animals
were primarily related to time between doses.
Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle
effects in adult rats and dogs, and were primarily related to plasma C
max
. Peripheral nerve changes
were characterised by minimal to slight axonal degeneration and were frequently accompanied by
functional changes. Reversal of both the microscopic and functional effects was complete within
6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold,
respectively, based on comparison of C
max
values at the No Observed Effect Level (NOEL) with the
C
max
achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients with
normal renal function.
The findings of
in vitro
and some
in vivo
studies designed to investigate the mechanism of
daptomycin myotoxicity indicate that the plasma membrane of differentiated spontaneously
contracting muscle cells is the target of toxicity. The specific cell surface component directly targeted
has not been identified. Mitochondrial loss/damage was also observed; however the role and
significance of this finding in the overall pathology are unknown. This finding was not associated
with an effect on muscle contraction.
In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as
compared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses
lower than those associated with skeletal muscle toxicity.
Reproductive toxicity testing showed no evidence of effects on fertility, embryofetal, or postnatal
development. However, daptomycin can cross the placenta in pregnant rats (see section 5.2).
Excretion of daptomycin into milk of lactating animals has not been studied.
Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or
clastogenic in a battery of
in vivo
and
in vitro
genotoxicity tests.
6.
6.1 List of excipients
Sodium hydroxide
6.2 Incompatibilities
Cubicin is not physically or chemically compatible with glucose-containing solutions. This medicinal
product must not be mixed with other medicinal products except those mentioned in section 6.6.
13
6.3 Shelf life
3 years
After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has
been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical
stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C –
8°C.
For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and
diluted solution in infusion bag; see section 6.6) at 25°C must not exceed 12 hours (or 24 at 2°C –
8°C).
For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see
section 6.6) at 25°C must not exceed 12 hours (or 48 at 2°C – 8°C).
However, from a microbiological point of view the product should be used immediately. No
preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage
times are the responsibility of the user and would not normally be longer than 24 hours at 2C – 8°C,
unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2C – 8C).
For storage conditions of the reconstituted or reconstituted and diluted medicinal product see section
6.3.
6.5 Nature and contents of container
Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with
yellow plastic flip off caps.
Available in packs containing 1 vial or 5 vials.
6.6 Special precautions for disposal and other handling
Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over
2 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional
dilution step as detailed below.
Cubicin given as 30-minute intravenous infusion
A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised
product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous infusion, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
14
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical
volume 50 ml).
6.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
7.
Replace needle with a new needle for the intravenous infusion.
8.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9.
The reconstituted and diluted solution should then be infused intravenously over 30 minutes as
directed in section 4.2.
The following have been shown to be compatible when added to Cubicin containing infusion
solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine,
heparin and lidocaine.
Cubicin given as 2-minute intravenous injection
Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only
be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised
product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous injection, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
6.
Replace needle with a new needle for the intravenous injection.
7.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8.
The reconstituted solution should then be injected intravenously slowly over 2 minutes as
directed in section 4.2.
15
Cubicin vials are for single-use only.
From a microbiological point of view, the product should be used immediately after reconstitution
(see section 6.3).
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/05/328/001
EU/1/05/328/003
9.
19 January 2006
16
1.
Cubicin 500 mg powder for solution for injection or infusion
2.
Each vial contains 500 mg daptomycin.
One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml
(0.9%) solution.
For a full list of excipients, see section 6.1.
3.
Powder for solution for injection or infusion
A pale yellow to light brown lyophilised powder.
4.
Cubicin is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1).
-
Complicated skin and soft-tissue infections (cSSTI).
-
Right-sided infective endocarditis (RIE) due to
Staphylococcus aureus.
It is recommended that
the decision to use daptomycin should take into account the antibacterial susceptibility of the
organism and should be based on expert advice. See sections 4.4 and 5.1.
-
Staphylococcus aureus
bacteraemia (SAB) when associated with RIE or with cSSTI.
Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where
Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-
administered with appropriate antibacterial agent(s).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical
experience in patients with the administration of daptomycin as an injection over 2 minutes. This
mode of administration was only studied in healthy subjects. However, when compared with the same
doses given as intravenous infusions over 30 minutes there were no clinically important differences in
the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).
Posology
-
cSSTI without concurrent
Staphylococcus aureus
bacteraemia: Cubicin 4 mg/kg is administered
once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).
-
cSSTI with concurrent
Staphylococcus aureus
bacteraemia: Cubicin 6 mg/kg is administered
once every 24 hours. See below for dose adjustments in patients with renal insufficiency. The
duration of therapy may need to be longer than 14 days in accordance with the perceived risk of
complications in the individual patient.
17
-
Known or suspected right-sided infective endocarditis due to
Staphylococcus aureus
: Cubicin
6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with
renal insufficiency. The duration of therapy should be in accordance with available official
recommendations.
Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not
be used more frequently than once a day.
Renal insufficiency
Daptomycin is eliminated primarily by the kidney
.
Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in
patients with any degree of renal insufficiency (CrCl < 80 ml/min) when it is considered that the
expected clinical benefit outweighs the potential risk. The response to treatment, renal function and
creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of
renal insufficiency (see also sections 4.4 and 5.2)
.
Dose adjustments in patients with renal insufficiency by indication and creatinine clearance
Indication for use
Creatinine clearance
Dose recommendation
Comments
cSSTI without
S.
aureus
bacteraemia
30 ml/min
4 mg/kg once daily
See section 5.1
< 30 ml/min
4 mg/kg every 48 hours
(1, 2)
RIE or cSSTI
associated with
S.
aureus
bacteraemia
30 ml/min
6 mg/kg once daily
See section 5.1
< 30 ml/min
6 mg/kg every 48 hours
(1, 2)
(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled
clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see
sections 4.4 and 5.2).
(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK
modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory
peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the
completion of dialysis on dialysis days (see section 5.2).
Hepatic insufficiency
No dose adjustment is necessary when administering Cubicin to patients with mild or moderate
hepatic insufficiency (Child-Pugh Class B) (see section 5.2). No data are available in patients with
severe hepatic insufficiency (Child-Pugh Class C). Therefore caution should be exercised if Cubicin
is given to such patients.
Elderly patients
The recommended doses should be used in elderly patients except those with severe renal
insufficiency (see above and section 4.4). However, there are limited data on the safety and efficacy
of daptomycin in patients aged > 65 years and caution should be exercised if Cubicin is given to such
patients.
18
Children and adolescents
Cubicin is not recommended for use in children and adolescents below the age of 18 years due to a
lack of data on safety and efficacy (see section 5.2).
Method of administration
Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period
or by intravenous injection (see section 6.6) and administered over a 2-minute period.
Hypersensitivity to the active substance or to any of the excipients.
If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy
consideration should be given to instituting alternative antibacterial therapy that has been
demonstrated to be efficacious in the treatment of the specific type of infection(s) present.
Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to
Cubicin occurs, discontinue use and institute appropriate therapy.
It has been demonstrated in clinical studies that
Cubicin is not effective in the treatment of
pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.
Clinical data on the use of Cubicin to treat RIE due to
Staphylococcus aureus
are limited to
19 patients (see “Information from clinical trials” in section 5.1).
The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective
endocarditis due to
Staphylococcus aureus
has not been demonstrated.
Patients with deep-seated infections should receive any required surgical interventions (e.g.
debridement, removal of prosthetic devices, valve replacement surgery) without delay.
There is insufficient evidence to be able to draw any conclusions regarding the possible clinical
efficacy of Cubicin against infections due to enterococci, including
Enterococcus faecalis
and
Enterococcus faecium
. In addition, dose regimens of daptomycin that might be appropriate for the
treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures
with daptomycin in the treatment of enterococcal infections that were mostly accompanied by
bacteraemia have been reported. In some instances treatment failure has been associated with the
selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).
The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If
superinfection occurs during therapy, appropriate measures should be taken.
Clostridium difficile
-associated diarrhoea (CDAD) has been reported with Cubicin. If CDAD is
suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as
clinically indicated.
False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR)
have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see
also section 4.5).
19
Creatine phosphokinase and myopathy
Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular
pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been
reported during therapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked
increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred
more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%).
Therefore, it is recommended that:
Plasma CPK should be measured at baseline and at regular intervals (at least once weekly)
during therapy in all patients.
CPK should be measured more frequently (e.g. every 2-3 days at least during the first two
weeks of treatment) in patients who are at higher risk of developing myopathy. For example,
patients with any degree of renal insufficiency (creatinine clearance < 80 ml/min; see also
section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal
products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates
and ciclosporin).
It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at
baseline may be at increased risk of further increases during daptomycin therapy. This should
be taken into account when initiating daptomycin therapy and, if daptomycin is given, these
patients should be monitored more frequently than once weekly.
Cubicin should not be administered to patients who are taking other medicinal products
associated with myopathy unless it is considered that the benefit to the patient outweighs the
risk.
Patients should be reviewed regularly while on therapy for any signs or symptoms that might
represent myopathy.
Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should
have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of
unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of
normal.
Peripheral neuropathy
Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy
with Cubicin should be investigated and consideration should be given to discontinuation of
daptomycin (see sections 4.8 and 5.3).
Renal insufficiency
Renal insufficiency has been reported during treatment with Cubicin. Severe renal insufficiency may
in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of
development of myopathy (see above).
Dose adjustment is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2
and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled
clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin
should only be used in such patients when it is considered that the expected clinical benefit outweighs
the potential risk.
Caution is advised when administering Cubicin to patients who already have some degree of renal
insufficiency (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular
monitoring of renal function is advised (see also section 5.2).
In addition, regular monitoring of renal function is advised during concomitant administration of
potentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see also section
4.5).
20
Obesity
In obese subjects with Body Mass Index (BMI) > 40 kg/m
2
but with creatinine clearance > 70 ml/min,
the AUC
0-∞
daptomycin was significantly increased (mean 42% higher) compared with non-obese
matched controls. There is limited information on the safety and efficacy of daptomycin in the very
obese and so caution is recommended. However, there is currently no evidence that a dose reduction
is required (see section 5.2).
Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely
that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450
system.
Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid.
Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal
products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not
significantly altered by aztreonam.
Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during
coadministration using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The
interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown.
Caution is warranted when Cubicin is co-administered with tobramycin.
Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of
Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in
patients receiving Cubicin and warfarin should be monitored for the first several days after therapy
with Cubicin is initiated.
There is limited experience regarding concomitant administration of daptomycin with other medicinal
products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of
marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these
medicinal products at the same time as Cubicin. It is recommended that other medicinal products
associated with myopathy should if possible be temporarily discontinued during treatment with
Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration
cannot be avoided, CPK levels should be measured more frequently than once weekly and patients
should be closely monitored for any signs or symptoms that might represent myopathy. See sections
4.4, 4.8 and 5.3.
Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-
administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2
inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-
administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-
administered with any other medicinal product known to reduce renal filtration.
During post–marketing surveillance, cases of interference between daptomycin and particular reagents
used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported.
This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities
of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in
vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by
drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin.
21
No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or
indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition
or postnatal development (see section 5.3).
Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the potential benefit
outweighs the possible risk.
In a single case study, Cubicin was administered daily for 28 days to a nursing mother at a dose of
500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27.
The highest measured concentration of daptomycin in the breast milk was 0.045 µg/ml, which is a low
concentration. Therefore, until more experience is gained, breast-feeding should be discontinued
when Cubicin is administered to nursing women.
No studies on the effects on the ability to drive and use machines have been performed.
On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an
effect on the ability to drive or use machinery.
In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a
daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects
received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers.
Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to
the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.
The following adverse reactions were reported during therapy and during follow-up with frequencies
corresponding to common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to
< 1/1,000); very rare (< 1/10,000):
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1
Adverse reactions from clinical studies and post-marketing reports
System organ class
Frequency
Adverse reactions
Infections and infestations
Common:
Fungal infections, urinary tract infection, candida
infection
Uncommon:
Fungaemia
Not known*:
Clostridium difficile
-associated diarrhoea
Blood and lymphatic system
disorders
Common:
Anaemia
Uncommon:
Thrombocythaemia, eosinophilia, international
normalised ratio (INR) increased
Rare:
Prothrombin time (PT) prolonged
22
Immune system disorders
Not known*:
Hypersensitivity, manifested by isolated spontaneous
reports including, but not limited to pulmonary
eosinophilia, vesicobullous rash with mucous
membrane involvement and sensation of
oropharyngeal swelling
Not known*:
Anaphylaxis
Not known*:
Infusion reactions including the following symptoms:
tachycardia, wheezing, pyrexia, rigors, systemic
flushing, vertigo, syncope and metallic taste
Metabolism and nutrition
disorders
Uncommon:
Decreased appetite, hyperglycaemia, electrolyte
imbalance
Psychiatric disorders
Common:
Anxiety, insomnia
Nervous system disorders
Common:
Dizziness, headache
Uncommon:
Paraesthesia, taste disorder, tremor
Not known*:
Peripheral neuropathy
Ear and labyrinth disorders
Uncommon:
Vertigo
Cardiac disorders
Uncommon:
Supraventricular tachycardia, extrasystole
Vascular disorders
Common:
Hypertension, hypotension
Uncommon:
Flushes
Gastrointestinal disorders
Common:
Gastrointestinal and abdominal pain, nausea,
vomiting, constipation, diarrhoea, flatulence,
bloating and distension
Uncommon:
Dyspepsia, glossitis
Hepatobiliary disorders
Common:
Liver function tests abnormal
1
(increased alanine
aminotransferase (ALT), aspartate aminotransferase
(AST) or alkaline phosphatase (ALP))
Rare:
Jaundice
Skin and subcutaneous tissue
disorders
Common:
Rash, pruritus
Uncommon:
Urticaria
Musculoskeletal and
connective tissue disorders
Common:
Limb pain, serum creatine phosphokinase (CPK)
1
increased
Uncommon:
Myositis, increased myoglobin, muscular weakness,
muscle pain, arthralgia, serum lactate dehydrogenase
(LDH) increased
Not known*:
Rhabdomyolysis
2
Renal and urinary disorders
Uncommon:
Renal insufficiency, including renal impairment and
renal failure, serum creatinine increased
Reproductive system and
breast disorders
Uncommon:
Vaginitis
Common:
Infusion site reactions, pyrexia, asthenia
Uncommon:
Fatigue, pain
* Based on post-marketing reports. Since these reports are from a population of uncertain size and
are subject to confounding factors, it is not possible to reliably estimate their frequency or
establish a causal relationship to exposure to the medicinal product.
1
In some cases of myopathy involving raised CPK and muscle symptoms, the patients also
presented with elevated transaminases. These transaminase increases were likely to be related to
the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicity
and resolved upon discontinuation of treatment.
2
When clinical information on the patients was available to make a judgement, approximately
50% of the cases occurred in patients with pre-existing renal insufficiency, or in those receiving
concomitant medicinal products known to cause rhabdomyolysis.
23
General disorders and
administration site conditions
The safety data for the administration of daptomycin via 2-minute intravenous injection are derived
from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods
of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous
infusion, had a similar safety and tolerability profile. There was no relevant difference in local
tolerability or in the nature and frequency of adverse reactions.
In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by
haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal
dialysis (approximately 11% of the administered dose is removed over 48 hours).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code:
J01XX09
Mode of action
Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.
The mechanism of action involves binding
(in the presence of calcium ions) to bacterial membranes
of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of
protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.
PK/PD relationship
Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive
organisms
in vitro
and in
in vivo
animal models. In animal models AUC/MIC and C
max
/MIC correlate
with efficacy and predicted bacterial kill
in vivo
at single doses equivalent to human doses of 4 mg/kg
and 6 mg/kg once daily.
Mechanisms of resistance
Strains with decreased susceptibility to daptomycin have been reported especially during the
treatment of patients with difficult-to-treat infections and/or following administration for prolonged
periods. In particular, there have been reports of treatment failures in patients infected with
Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium,
including bacteraemic
patients, that have been associated with the selection of organisms with reduced susceptibility or frank
resistance to daptomycin during therapy.
The mechanism of resistance to daptomycin has not yet been identified.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except
S.
pneumoniae
) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.
Susceptibility
The prevalence of resistance may vary geographically and over time for selected species and local
information on resistance is desirable, particularly when treating severe infections. As necessary,
expert advice should be sought when the local prevalence of resistance is such that the utility of the
agent in at least some types of infections is questionable.
24
Commonly Susceptible Species
Staphylococcus aureus
*
Staphylococcus haemolyticus
Coagulase negative staphylococci
Streptococcus agalactiae
*
Streptococcus dysgalactiae
subsp
equisimilis
*
Streptococcus pyogenes
*
Group G streptococci
Clostridium perfringens
Peptostreptococcus spp
Inherently resistant organisms
Gram negative organisms
*
denotes species against which it is considered that activity has been satisfactorily demonstrated in
clinical studies.
Information from clinical trials
In two clinical trials in complicated skin and soft tissues infections, 36% of patients treated with
Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common
type of infection treated was wound infection (38% of patients), while 21% had major abscesses.
These limitations of the patients population treated should be taken into account when deciding to use
Cubicin.
In a randomised controlled open-label study in 235 patients with
Staphylococcus aureus
bacteraemia
(i.e, at least one positive blood culture of
Staphylococcus aureus
prior to receiving the first dose) 19
of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11 were infected
with methicillin-susceptible and 8 with methicillin-resistant
Staphylococcus aureus
. The success rates
in RIE patients are shown in the table below.
Population
Daptomycin
Comparator
Differences in
Success
n/N (%)
n/N (%)
Rates (95% CI)
ITT (intention to treat) Population
RIE
8/19 (42.1%)
7/16 (43.8%)
-1.6% (-34.6, 31.3)
PP (per protocol) Population
RIE
6/12 (50.0%)
4/8 (50.0%)
0.0% (-44.7, 44.7)
Failure of treatment due to persisting or relapsing
Staphylococcus aureus
infections was observed in
19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and
2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these
failures six patients treated with Cubicin and one patient treated with vancomycin were infected with
Staphylococcus aureus
that developed increasing MICs of daptomycin on or following therapy (see
“Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing
Staphylococcus aureus
infection had deep-seated infection and did not receive necessary surgical
intervention.
5.2 Pharmacokinetic properties
Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg
administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy
volunteers. Steady-state concentrations are achieved by the third daily dose.
Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional
pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure
25
(AUC and C
max
) was demonstrated in healthy subjects following administration of daptomycin as a
30-minute intravenous infusion or as a 2-minute intravenous injection.
Animal studies showed that daptomycin is not absorbed to any significant extent after oral
administration.
Distribution
The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately
0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin
appears to only minimally penetrate the blood-brain barrier and the placental barrier following single
and multiple doses.
Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In
healthy volunteers and patients treated with daptomycin, protein binding averaged about 90%
including subjects with renal insufficiency.
Metabolism
In
in vitro
studies, daptomycin was not metabolised by human liver microsomes.
In vitro
studies with
human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following
human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that
daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450
system.
After infusion of 14C-daptomycin, the plasma radioactivity was similar to the concentration
determined by microbiological assay. Inactive metabolites were detected in urine, as determined by
the difference in total radioactive concentrations and microbiologically active concentrations. In a
separate study, no metabolites were observed in plasma, and minor amounts of three oxidative
metabolites and one unidentified compound were detected in urine. The site of metabolism has not
been identified.
Elimination
Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and
daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active
tubular secretion of daptomycin.
Following intravenous administration, plasma clearance of daptomycin is approximately 7 to
9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.
In a mass balance study using radiolabelled material, 78% of the administered dose was recovered
from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was
approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.
Special populations
Elderly
Following administration of a single 4 mg/kg intravenous dose of Cubicin, the mean total clearance of
daptomycin decreased approximately 35% and the mean AUC
0-∞
increased approximately 58% in
elderly subjects (≥ 75 years of age) compared with those in young healthy subjects (18 to 30 years of
age). There were no differences in C
max
. The differences noted are most likely due to the normal
reduction in renal function observed in the geriatric population.
No dose adjustment is necessary based on age alone. However, renal function should be assessed and
the dose should be reduced if there is evidence of severe renal insufficiency.
26
Children and adolescents (< 18 years of age)
The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three
groups of paediatric patients with proven or suspected Gram-positive infection (2-6 years, 7-11 years
and 12-17 years). The pharmacokinetics of daptomycin following a single 4 mg/kg dose in
adolescents aged 12-17 years are generally similar to those of healthy adult subjects with normal renal
function with trends towards lower AUC and C
max
in adolescents. In the younger age groups
(2-6 years and 7-11 years), exposure (C
max
and AUC) and elimination half-life for the same mg/kg
dose were reduced compared with adolescents. Efficacy was not assessed in this study.
A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single
8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to
6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard
antibiotic therapy.
The mean exposure (AUC
0-∞
) was approximately 429 and 550 μg*hr/ml after the administration of 8
and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at
steady state (495 μg*hr/ml). The pharmacokinetics of daptomycin appears to be linear in the dose
range studied. The half life, clearance and volume of distribution were similar at both dose levels.
Obesity
Relative to non-obese subjects daptomycin systemic exposure measured by AUC is increased by
about 28% in moderately obese subjects (Body Mass Index of 25-40 kg/m
2
) and by 42% in extremely
obese subjects (Body Mass Index of > 40 kg/m
2
). However, no dose adjustment is considered to be
necessary based on obesity alone.
Gender
No clinically significant gender-related differences in daptomycin pharmacokinetics have been
observed.
Renal insufficiency
Following administration of a single 4 mg/kg or 6 mg/kg dose of daptomycin to subjects with various
degrees of renal insufficiency, daptomycin clearance (CL) decreased and systemic exposure (AUC)
increased as renal function (creatinine clearance) decreased.
Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after
administration of a 6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in
patients with normal renal function who received the same dose. On the second day after
administration of a 6 mg/kg dose to HD and CAPD patients the daptomcyin AUC was approximately
1.3-fold higher than that observed after a second 6 mg/kg dose in patients with normal renal function.
On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every
48 hours at the dose recommended for the type of infection being treated (see section 4.2).
Hepatic insufficiency
The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic insufficiency
(Child-Pugh B classification of hepatic insufficiency) compared with healthy volunteers matched for
gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when
administering daptomycin in patients with moderate hepatic insufficiency. The pharmacokinetics of
daptomycin in patients with severe hepatic insufficiency (Child-Pugh C classification) have not been
evaluated.
5.3 Preclinical safety data
In studies of clinically-relevant duration (14-28 days), daptomycin administration was associated with
minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic
changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the
higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed.
27
Depending on the study duration, all muscle effects, including microscopic changes, were fully
reversible within 1-3 months following cessation of dosing. No functional or pathological changes in
smooth or cardiac muscle were observed.
The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels
of 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) for
patients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, the
safety margins for both methods of administration are very similar.
A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as
compared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animals
were primarily related to time between doses.
Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle
effects in adult rats and dogs, and were primarily related to plasma C
max
. Peripheral nerve changes
were characterised by minimal to slight axonal degeneration and were frequently accompanied by
functional changes. Reversal of both the microscopic and functional effects was complete within
6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold,
respectively, based on comparison of C
max
values at the No Observed Effect Level (NOEL) with the
C
max
achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients with
normal renal function.
The findings of
in vitro
and some
in vivo
studies designed to investigate the mechanism of
daptomycin myotoxicity indicate that the plasma membrane of differentiated spontaneously
contracting muscle cells is the target of toxicity. The specific cell surface component directly targeted
has not been identified. Mitochondrial loss/damage was also observed; however the role and
significance of this finding in the overall pathology are unknown. This finding was not associated
with an effect on muscle contraction.
In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as
compared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses
lower than those associated with skeletal muscle toxicity.
Reproductive toxicity testing showed no evidence of effects on fertility, embryofetal, or postnatal
development. However, daptomycin can cross the placenta in pregnant rats (see section 5.2).
Excretion of daptomycin into milk of lactating animals has not been studied.
Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or
clastogenic in a battery of
in vivo
and
in vitro
genotoxicity tests.
6.
6.1 List of excipients
Sodium hydroxide
6.2 Incompatibilities
Cubicin is not physically or chemically compatible with glucose-containing solutions. This medicinal
product must not be mixed with other medicinal products except those mentioned in section 6.6.
28
6.3 Shelf life
3 years
After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has
been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical
stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C –
8°C.
For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and
diluted solution in infusion bag; see section 6.6) at 25°C must not exceed 12 hours (or 24 at 2°C –
8°C).
For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see
section 6.6) at 25°C must not exceed 12 hours (or 48 at 2°C – 8°C).
However, from a microbiological point of view the product should be used immediately. No
preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage
times are the responsibility of the user and would not normally be longer than 24 hours at 2C – 8°C,
unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2C – 8C).
For storage conditions of the reconstituted or reconstituted and diluted medicinal product see section
6.3.
6.5 Nature and contents of container
Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with blue
plastic flip off caps.
Available in packs containing 1 vial or 5 vials.
6.6 Special precautions for disposal and other handling
Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over
2 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional
dilution step as detailed below.
Cubicin given as 30-minute intravenous infusion
A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised
product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous infusion, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
29
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical
volume 50 ml).
6.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
7.
Replace needle with a new needle for the intravenous infusion.
8.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9.
The reconstituted and diluted solution should then be infused intravenously over 30 minutes as
directed in section 4.2.
The following have been shown to be compatible when added to Cubicin containing infusion
solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine,
heparin and lidocaine.
Cubicin given as 2-minute intravenous injection
Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only
be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised
product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous injection, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
6.
Replace needle with a new needle for the intravenous injection.
7.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8.
The reconstituted solution should then be injected intravenously slowly over 2 minutes as
directed in section 4.2.
30
Cubicin vials are for single-use only.
From a microbiological point of view, the product should be used immediately after reconstitution
(see section 6.3).
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/05/328/002
EU/1/05/328/004
9.
19 January 2006
31
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
32
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Novartis Pharmaceuticals UK Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder shall ensure that all physicians who are expected to
prescribe/use Cubicin are provided with:
-
Summary of Product Characteristics
-
Dosage card
The dosage card should contain the following key messages:
-
That there is a risk of severe skeletal muscle toxicity and so measuring the CPK at treatment
initiation and at regular intervals is important. Patients at higher risk of developing myopathy
should have more frequent CPK measurements.
-
That Cubicin can interfere with coagulation tests (PT/INR) and this might lead to false results.
To minimise this risk, physicians should be advised that for coagulation levels testing it is
recommended to draw blood samples near the time of Cubicin trough plasma concentration.
-
The dosage card should contain the appropriate algorithms for calculating the Cubicin dose for
reconstitution, to help minimise the risk of medication errors (high osmolarity, overdose).
The Marketing Authorisation Holder shall ensure that all laboratories expected to perform Cubicin
susceptibility testing are provided with:
-
Summary of Product Characteristics
-
Laboratory susceptibility testing leaflet
The laboratory susceptibility testing leaflet should contain the following key messages:
-
That susceptibility testing minimises the risk of treatment failure by identifying strains with
potential resistance to daptomycin
-
That daptomycin susceptibility testing needs Ca in the testing medium and testing methods with
mediums providing consistent Ca concentrations are recommended.
33
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 8.0 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 dated 27
th
October 2009 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 EMEA
34
ANNEX III
LABELLING AND PACKAGE LEAFLET
35
A. LABELLING
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR 1 VIAL
CARTON FOR 5 VIALS
1.
Cubicin 350 mg powder for solution for injection or infusion
daptomycin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 350 mg daptomycin.
One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml
(0.9%) solution.
3.
LIST OF EXCIPIENTS
Sodium hydroxide
4.
1 vial
5 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use for directions on reconstitution.
When administration is by injection reconstitute with 0.9% sodium chloride only.
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
Read the leaflet for the shelf life of the reconstituted product
37
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C).
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Dispose of in accordance with local requirements
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/05/328/001
1 vial
EU/1/05/328/003
5 vials
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
38
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Cubicin 350 mg powder for solution for injection or infusion
daptomycin
For intravenous use
2.
METHOD OF ADMINISTRATION
When administration is by injection reconstitute with 0.9% sodium chloride only.
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
350 mg
6.
OTHER
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR 1 VIAL
CARTON FOR 5 VIALS
1.
Cubicin 500 mg powder for solution for injection or infusion
daptomycin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 500 mg daptomycin.
One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml
(0.9%) solution.
3.
LIST OF EXCIPIENTS
Sodium hydroxide
4.
1 vial
5 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use for directions on reconstitution.
When administration is by injection reconstitute with 0.9% sodium chloride only.
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
Read the leaflet for the shelf life of the reconstituted product
40
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C).
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Dispose of in accordance with local requirements
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/05/328/002
1 vial
EU/1/05/328/004
5 vials
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
41
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Cubicin 500 mg powder for solution for injection or infusion
daptomycin
For intravenous use
2.
METHOD OF ADMINISTRATION
When administration is by injection reconstitute with 0.9% sodium chloride only.
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
500 mg
6.
OTHER
42
B. PACKAGE LEAFLET
43
PACKAGE LEAFLET: INFORMATION FOR THE USER
Cubicin 350 mg powder for solution for injection or infusion
daptomycin
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, nurse 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, nurse or pharmacist.
In this leaflet
:
1.
What Cubicin is and what it is used for
2.
Before you are given Cubicin
3.
How Cubicin is given
4.
Possible side effects
5.
How to store Cubicin
1.
WHAT CUBICIN IS AND WHAT IT IS USED FOR
The active substance in Cubicin powder for solution for injection or infusion is daptomycin.
Daptomycin is an antibiotic that can stop the growth of certain bacteria. Cubicin is used in adults to
treat infections of the skin and the tissues below the skin. It is also used in adults to treat infections in
the tissues that line the inside of the heart (including heart valves) which are caused by a bacterium
called
Staphyloccocus aureus
and to treat infections in the blood caused by the same bacterium when
associated with skin or heart infection.
Depending on the type of infection(s) that you have, your doctor may also prescribe other antibiotics
while you are receiving treatment with Cubicin.
2.
BEFORE YOU ARE GIVEN CUBICIN
You should not be given Cubicin
If you are allergic (hypersensitive) to daptomycin or to sodium hydroxide.
If this applies to you, tell your doctor or nurse. If you think you may be allergic, ask your doctor or
nurse for advice.
Take special care with Cubicin
-
If you have, or have previously had kidney problems. Your doctor may need to change the dose
of Cubicin (see section 3 of this leaflet).
-
Occasionally, patients receiving Cubicin may develop tender or aching muscles or muscle
weakness (see section 4 of this leaflet for more information). If this happens tell your doctor.
Your doctor will make sure you have a blood test and will advise whether or not to continue
with Cubicin. The symptoms generally go away within a few days of stopping Cubicin.
-
If you are very overweight. There is a possibility that your blood levels of Cubicin could be
higher than those found in persons of average weight and you may need careful monitoring in
case of side effects.
If any of these applies to you, tell your doctor or nurse before you are given Cubicin.
44
6.
Further information
Tell your doctor straight away if you develop any of the following symptoms:
-
Serious, acute allergic reactions have been observed in patients treated with nearly all
antibacterial agents, including Cubicin. Tell a doctor or a nurse straight away if you experience
symptoms suggestive of allergic reaction, such as wheezing, difficulty breathing, rashes and
hives, fever (see section 4 of this leaflet for more information).
-
Any unusual tingling or numbness of the hands or feet, loss of feeling or difficulties with
movements. If this happens, tell your doctor who will decide whether you should continue the
treatment.
-
Diarrhoea, especially if you notice blood or
mucus, or if diarrhoea becomes severe or
persistent.
Cubicin may interfere with laboratory tests that measure how well your blood is clotting. The results
can suggest poor blood clotting when, in fact, there is no problem. Therefore it is important that your
doctor takes into account that you are receiving Cubicin. Please inform your doctor that you are on
treatment with Cubicin.
Your doctor will perform blood tests to monitor the health of your muscles both before you start
treatment and frequently during treatment with Cubicin.
Use in children
The use of Cubicin in children has not been studied and is therefore not recommended.
Use in elderly
People over the age of 65 can be given the same dose as other adults, provided their kidneys are
working well.
Taking other medicines
Please tell your doctor, nurse or pharmacist if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription.
It is particularly important that you mention the following:
-
Medicines called statins or fibrates (to lower cholesterol) or ciclosporin (a medicinal product
used in transplantation to prevent organ rejection or for other conditions, e.g. rheumathoid
arthritis or atopic dermatitis). It is possible that the risk of side effects affecting the muscles
may be higher when any of these medicines (and some others that can affect muscles) is taken
during treatment with Cubicin. Your doctor may decide not to give you Cubicin or to stop the
other medicine for a while.
-
Pain killing medicines called non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2
inhibitors (e.g. celecoxib). These could interfere with the effects of Cubicin in the kidney.
-
Oral anti-coagulants (e.g. warfarin), which are medicines that prevent blood from clotting. It
may be necessary for your doctor to monitor your blood clotting times.
Pregnancy and breast-feeding
Cubicin is not usually given to pregnant women. Tell your doctor if you are pregnant, think you may
be pregnant, or are planning to become pregnant.
Do not breast-feed if you are receiving Cubicin, because it may pass into your breast milk and could
affect the baby.
Driving and using machines
Cubicin has no known effects on the ability to drive or use machines.
45
3.
HOW CUBICIN IS GIVEN
Cubicin will usually be given to you by a doctor or a nurse.
The dose will depend on how much you weigh and the type of infection being treated. The usual dose
for adults is 4 mg for every kilogram (kg) of body weight once daily for skin infections or 6 mg for
every kg of body weight once daily for a heart infection or a blood infection associated with skin or
heart infection. This dose is given directly into your blood stream (into a vein), either as an infusion
lasting about 30 minutes or as an injection lasting about 2 minutes. The same dose is recommended in
people aged over 65 years provided their kidneys are working well.
If your kidneys do not work well, you may receive Cubicin less often, e.g. once every other day. If
you are receiving dialysis, and your next dose of Cubicin is due on a dialysis day, you will be usually
given Cubicin after the dialysis session.
A course of treatment usually lasts for 1 to 2 weeks for skin infections. For blood or heart infections
and skin infections your doctor will decide how long you should be treated.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Cubicin can cause side effects, although not everybody gets them.
The frequency of possible side effects 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)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data).
Some side effects are very rare
A hypersensitivity reaction (serious allergic reaction including anaphylaxis) has been reported, in
some cases during administration of Cubicin. This serious allergic reaction needs immediate medical
attention. Tell your doctor or nurse straight away if you experience any of the following symptoms:
-
Chest pain or tightness
-
Rash with blistering, sometimes affecting the mouth and genitals
-
Swelling around throat
-
Rapid or weak pulse
-
Wheezing
-
Fever
-
Shivering or trembling
-
Hot flushes
-
Dizziness
-
Fainting
-
Metallic taste
Tell your doctor straight away if you experience unexplained muscle pain, tenderness, or weakness. In
very rare cases (reported in less than 1 in every 10,000 patients), muscle problems can be serious,
including muscle breakdown (rhabdomyolysis), which can result in kidney damage.
46
Cubicin may also cause other side effects:
Some side effects are common
-
Fungal infections such as thrush,
-
Urinary tract infection,
-
Decreased number of red blood cells (anaemia),
-
Dizziness, anxiety, difficulty in sleeping,
-
Headache,
-
Fever, weakness (asthenia),
-
High or low blood pressure,
-
Constipation, abdominal pain,
-
Diarrhoea, felling sick (nausea) or being sick (vomiting),
-
Flatulence,
-
Abdominal swelling or bloating,
-
Skin rash or itching,
-
Pain, itchiness or redness at the site of infusion,
-
Pain in arms or legs,
-
Blood testing showing higher levels of liver enzymes or creatine phosphokinase (CPK).
Some side effects are uncommon
-
Blood disorders (e.g increased number of small blood particles called platelets, which may
increase the tendency for blood clotting, or higher levels of certain types of white blood cells),
-
Decreased appetite,
-
Tingling or numbness of the hands or feet, taste disturbance,
-
Trembling,
-
Changes in heart rhythm, flushes,
-
Indigestion (dyspepsia), inflammation of the tongue,
-
Itchy rash of skin,
-
Muscle pain or weakness, inflammation of the muscles (myositis), joint pain,
-
kidney problems,
-
Inflammation and irritation of the vagina,
-
General pain or weakness, tiredness (fatigue),
-
Blood test showing increased levels of blood sugar, serum creatinine, myoglobin, or lactate
dehydrogenase (LDH), prolonged blood clotting time or imbalance of salts.
Some side effects are rare
-
Yellowing of the skin and eyes,
-
Prothrombin time prolonged.
Frequency not known
Antibiotic-associated colitis, including pseudomembranous colitis (severe or persistent diarrhoea
containing blood and/or mucus, associated with abdominal pain or fever).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor, nurse or pharmacist.
5.
HOW TO STORE CUBICIN
-
Keep out of the reach and sight of children.
-
Do not use after the expiry date which is stated on the carton and label. The expiry date refers
to the last day of that month.
-
Store in a refrigerator (2°C – 8°C).
-
Dispose of in accordance with local requirements.
47
6.
FURTHER INFORMATION
What Cubicin contains
-
The active substance is daptomycin.
-
The other ingredient is sodium hydroxide.
What Cubicin looks like and contents of the pack
Cubicin powder for solution for injection or infusion is supplied as a pale yellow to light brown
powder in a glass vial. It is mixed with a solvent to form a liquid before it is administered.
Cubicin is available in packs containing 1 vial or 5 vials.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharmaceuticals UK Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
48
Ελλά
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200
Κύπρς
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
49
The following information is intended for medical or healthcare professionals only
Important: Please refer to the Summary of Product Characteristics before prescribing.
Instructions for use and handling
350 mg presentation:
Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over
2 minutes. Preparation of the solution for infusion requires an additional dilution step as detailed
below.
Cubicin given as 30-minute intravenous infusion
A 50 mg/ml concentration of Cubicin for infusion can be achieved by reconstituting the lyophilised
product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous infusion, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical
volume 50 ml).
6.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
7.
Replace needle with a new needle for the intravenous infusion.
8.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9.
The reconstituted and diluted solution should then be infused intravenously over 30 minutes.
Cubicin is not physically or chemically compatible with glucose-containing solutions. The following
have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam,
ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) at 25°C
must not exceed 12 hours (24 hours if refrigerated).
Stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours if
stored under refrigeration at 2°C – 8°C.
50
Cubicin given as 2-minute intravenous injection
Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only
be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised
product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous injection, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
6.
Replace needle with a new needle for the intravenous injection.
7.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8.
The reconstituted solution should then be injected intravenously slowly over 2 minutes.
Chemical and physical in-use stability on the reconstituted solution in the vial has been demonstrated
for 12 hours at 25°C and up to 48 hours if stored under refrigeration (2°C – 8°C).
However, from a microbiological point of view the product should be used immediately. If not used
immediately, in-use storage times are the responsibility of the user and would normally not be longer
than 24 hours at 2°C – 8°C unless reconstitution /dilution has taken place in controlled and validated
aseptic conditions.
This medicinal product must not be mixed with other medicinal products except those mentioned
above.
Cubicin vials are for single-use only. Any unused portion remaining in the vial should be discarded.
51
PACKAGE LEAFLET: INFORMATION FOR THE USER
Cubicin 500 mg powder for solution for injection or infusion
daptomycin
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, nurse 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, nurse or pharmacist.
In this leaflet
:
1.
What Cubicin is and what it is used for
2.
Before you are given Cubicin
3.
How Cubicin is given
4.
Possible side effects
5.
How to store Cubicin
1.
WHAT CUBICIN IS AND WHAT IT IS USED FOR
The active substance in Cubicin powder for solution for injection or infusion is daptomycin.
Daptomycin is an antibiotic that can stop the growth of certain bacteria. Cubicin is used in adults to
treat infections of the skin and the tissues below the skin. It is also used in adults to treat infections in
the tissues that line the inside of the heart (including heart valves) which are caused by a bacterium
called
Staphyloccocus aureus
and to treat infections in the blood caused by the same bacterium when
associated with skin or heart infection.
Depending on the type of infection(s) that you have, your doctor may also prescribe other antibiotics
while you are receiving treatment with Cubicin.
2.
BEFORE YOU ARE GIVEN CUBICIN
You should not be given Cubicin
If you are allergic (hypersensitive) to daptomycin or to sodium hydroxide.
If this applies to you, tell your doctor or nurse. If you think you may be allergic, ask your doctor or
nurse for advice.
Take special care with Cubicin
-
If you have, or have previously had kidney problems. Your doctor may need to change the dose
of Cubicin (see section 3 of this leaflet).
-
Occasionally, patients receiving Cubicin may develop tender or aching muscles or muscle
weakness (see section 4 of this leaflet for more information). If this happens tell your doctor.
Your doctor will make sure you have a blood test and will advise whether or not to continue
with Cubicin. The symptoms generally go away within a few days of stopping Cubicin.
-
If you are very overweight. There is a possibility that your blood levels of Cubicin could be
higher than those found in persons of average weight and you may need careful monitoring in
case of side effects.
If any of these applies to you, tell your doctor or nurse before you are given Cubicin.
52
6.
Further information
Tell your doctor straight away if you develop any of the following symptoms:
-
Serious, acute allergic reactions have been observed in patients treated with nearly all
antibacterial agents, including Cubicin. Tell a doctor or a nurse straight away if you experience
symptoms suggestive of allergic reaction, such as wheezing, difficulty breathing, rashes and
hives, fever (see section 4 of this leaflet for more information).
-
Any unusual tingling or numbness of the hands or feet, loss of feeling or difficulties with
movements. If this happens, tell your doctor who will decide whether you should continue the
treatment.
-
Diarrhoea, especially if you notice blood or
mucus, or if diarrhoea becomes severe or
persistent.
Cubicin may interfere with laboratory tests that measure how well your blood is clotting. The results
can suggest poor blood clotting when, in fact, there is no problem. Therefore it is important that your
doctor takes into account that you are receiving Cubicin. Please inform your doctor that you are on
treatment with Cubicin.
Your doctor will perform blood tests to monitor the health of your muscles both before you start
treatment and frequently during treatment with Cubicin.
Use in children
The use of Cubicin in children has not been studied and is therefore not recommended.
Use in elderly
People over the age of 65 can be given the same dose as other adults, provided their kidneys are
working well.
Taking other medicines
Please tell your doctor, nurse or pharmacist if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription.
It is particularly important that you mention the following:
-
Medicines called statins or fibrates (to lower cholesterol) or ciclosporin (a medicinal product
used in transplantation to prevent organ rejection or for other conditions, e.g. rheumathoid
arthritis or atopic dermatitis). It is possible that the risk of side effects affecting the muscles
may be higher when any of these medicines (and some others that can affect muscles) is taken
during treatment with Cubicin. Your doctor may decide not to give you Cubicin or to stop the
other medicine for a while.
-
Pain killing medicines called non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2
inhibitors (e.g. celecoxib). These could interfere with the effects of Cubicin in the kidney.
-
Oral anti-coagulants (e.g. warfarin), which are medicines that prevent blood from clotting. It
may be necessary for your doctor to monitor your blood clotting times.
Pregnancy and breast-feeding
Cubicin is not usually given to pregnant women. Tell your doctor if you are pregnant, think you may
be pregnant, or are planning to become pregnant.
Do not breast-feed if you are receiving Cubicin, because it may pass into your breast milk and could
affect the baby.
Driving and using machines
Cubicin has no known effects on the ability to drive or use machines.
53
3.
HOW CUBICIN IS GIVEN
Cubicin will usually be given to you by a doctor or a nurse.
The dose will depend on how much you weigh and the type of infection being treated. The usual dose
for adults is 4 mg for every kilogram (kg) of body weight once daily for skin infections or 6 mg for
every kg of body weight once daily for a heart infection or a blood infection associated with skin or
heart infection. This dose is given directly into your blood stream (into a vein), either as an infusion
lasting about 30 minutes or as an injection lasting about 2 minutes. The same dose is recommended in
people aged over 65 years provided their kidneys are working well.
If your kidneys do not work well, you may receive Cubicin less often, e.g. once every other day. If
you are receiving dialysis, and your next dose of Cubicin is due on a dialysis day, you will be usually
given Cubicin after the dialysis session.
A course of treatment usually lasts for 1 to 2 weeks for skin infections. For blood or heart infections
and skin infections your doctor will decide how long you should be treated.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Cubicin can cause side effects, although not everybody gets them.
The frequency of possible side effects 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)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data).
Some side effects are very rare
A hypersensitivity reaction (serious allergic reaction including anaphylaxis) has been reported, in
some cases during administration of Cubicin. This serious allergic reaction needs immediate medical
attention. Tell your doctor or nurse straight away if you experience any of the following symptoms:
-
Chest pain or tightness
-
Rash with blistering, sometimes affecting the mouth and genitals
-
Swelling around throat
-
Rapid or weak pulse
-
Wheezing
-
Fever
-
Shivering or trembling
-
Hot flushes
-
Dizziness
-
Fainting
-
Metallic taste
Tell your doctor straight away if you experience unexplained muscle pain, tenderness, or weakness. In
very rare cases (reported in less than 1 in every 10,000 patients), muscle problems can be serious,
including muscle breakdown (rhabdomyolysis), which can result in kidney damage.
54
Cubicin may also cause other side effects:
Some side effects are common
-
Fungal infections such as thrush,
-
Urinary tract infection,
-
Decreased number of red blood cells (anaemia),
-
Dizziness, anxiety, difficulty in sleeping,
-
Headache,
-
Fever, weakness (asthenia),
-
High or low blood pressure,
-
Constipation, abdominal pain,
-
Diarrhoea, felling sick (nausea) or being sick (vomiting),
-
Flatulence,
-
Abdominal swelling or bloating,
-
Skin rash or itching,
-
Pain, itchiness or redness at the site of infusion,
-
Pain in arms or legs,
-
Blood testing showing higher levels of liver enzymes or creatine phosphokinase (CPK).
Some side effects are uncommon
-
Blood disorders (e.g increased number of small blood particles called platelets, which may
increase the tendency for blood clotting, or higher levels of certain types of white blood cells),
-
Decreased appetite,
-
Tingling or numbness of the hands or feet, taste disturbance,
-
Trembling,
-
Changes in heart rhythm, flushes,
-
Indigestion (dyspepsia), inflammation of the tongue,
-
Itchy rash of skin,
-
Muscle pain or weakness, inflammation of the muscles (myositis), joint pain,
-
kidney problems,
-
Inflammation and irritation of the vagina,
-
General pain or weakness, tiredness (fatigue),
-
Blood test showing increased levels of blood sugar, serum creatinine, myoglobin, or lactate
dehydrogenase (LDH), prolonged blood clotting time or imbalance of salts.
Some side effects are rare
-
Yellowing of the skin and eyes,
-
Prothrombin time prolonged.
Frequency not known
Antibiotic-associated colitis, including pseudomembranous colitis (severe or persistent diarrhoea
containing blood and/or mucus, associated with abdominal pain or fever).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor, nurse or pharmacist.
5.
HOW TO STORE CUBICIN
-
Keep out of the reach and sight of children.
-
Do not use after the expiry date which is stated on the carton and label. The expiry date refers
to the last day of that month.
-
Store in a refrigerator (2°C – 8°C).
-
Dispose of in accordance with local requirements.
55
6.
FURTHER INFORMATION
What Cubicin contains
-
The active substance is daptomycin.
-
The other ingredient is sodium hydroxide.
What Cubicin looks like and contents of the pack
Cubicin powder for solution for injection or infusion is supplied as a pale yellow to light brown
powder in a glass vial. It is mixed with a solvent to form a liquid before it is administered.
Cubicin is available in packs containing 1 vial or 5 vials.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharmaceuticals UK Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
56
Ελλά
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200
Κύπρς
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
57
The following information is intended for medical or healthcare professionals only
Important: Please refer to the Summary of Product Characteristics before prescribing.
Instructions for use and handling
500 mg presentation:
Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over
2 minutes. Preparation of the solution for infusion requires an additional dilution step as detailed
below.
Cubicin given as 30-minute intravenous infusion
A 50 mg/ml concentration of Cubicin for infusion can be achieved by reconstituting the lyophilised
product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous infusion, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical
volume 50 ml).
6.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
7.
Replace needle with a new needle for the intravenous infusion.
8.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9.
The reconstituted and diluted solution should then be infused intravenously over 30 minutes.
Cubicin is not physically or chemically compatible with glucose-containing solutions. The following
have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam,
ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) at 25°C
must not exceed 12 hours (24 hours if refrigerated).
Stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours if
stored under refrigeration at 2°C – 8°C.
58
Cubicin given as 2-minute intravenous injection
Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only
be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised
product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product
will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous injection, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1.
The polypropylene flip off cap should be removed to expose the central portions of the rubber
stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe,
then slowly inject through the centre of the rubber stopper into the vial pointing the needle
towards the wall of the vial.
2.
The vial should be gently rotated to ensure complete wetting of the product and then allowed to
stand for 10 minutes.
3.
Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear
reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the
product.
4.
The reconstituted solution should be checked carefully to ensure that the product is in solution
and visually inspected for the absence of particulates prior to use. Reconstituted solutions of
Cubicin range in colour from pale yellow to light brown.
5.
Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe,
insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the
very bottom of the solution in the vial when drawing the solution into the syringe. Before
removing the needle from the vial, pull the plunger all the way back to the end of the syringe
barrel in order to remove all of the solution from the inverted vial.
6.
Replace needle with a new needle for the intravenous injection.
7.
Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8.
The reconstituted solution should then be injected intravenously slowly over 2 minutes.
Chemical and physical in-use stability on the reconstituted solution in the vial has been demonstrated
for 12 hours at 25°C and up to 48 hours if stored under refrigeration (2°C – 8°C).
However, from a microbiological point of view the product should be used immediately. If not used
immediately, in-use storage times are the responsibility of the user and would normally not be longer
than 24 hours at 2°C – 8°C unless reconstitution /dilution has taken place in controlled and validated
aseptic conditions.
This medicinal product must not be mixed with other medicinal products except those mentioned
above.
Cubicin vials are for single-use only. Any unused portion remaining in the vial should be discarded.
59
Source: European Medicines Agency
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