ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
INVANZ 1 g powder for concentrate for solution for infusion.
2.
Each vial contains 1.0 g ertapenem equivalent to 1.046 g ertapenem sodium.
Excipients: each 1.0 g dose contains approximately 6.0 mEq of sodium (approximately 137 mg).
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion. White to off-white powder.
4.
Treatment
Treatment of the following infections when caused by bacteria known or very likely to be susceptible
to ertapenem and when parenteral therapy is required (see section 4.4 and section 5.1):
•
Intra-abdominal infections
•
Community acquired pneumonia
•
Acute gynaecological infections
•
Diabetic foot infections of the skin and soft tissue (see section 4.4)
Prevention
INVANZ is indicated in adults for the prophylaxis of surgical site infection following elective
colorectal surgery.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Adults and adolescents (13 to 17 years of age)
: The dose of INVANZ is 1 gram (g) given once a day
by the intravenous route (see section 6.6).
Prophylaxis of surgical site infection following elective colorectal surgery in adults
: To prevent
surgical site infections, the recommended dosage is 1 g administered as a single intravenous dose to be
completed within 1 hour prior to the surgical incision.
For Infants and children (3 months to 12 years of age)
: The dose of INVANZ is 15 mg/kg given twice
daily (not to exceed 1 g/day) by the intravenous route (see section 6.6). INVANZ is not recommended
for use in children below 3 months of age due to a lack of data on safety and efficacy (see sections 4.4;
5.1 and section 5.2).
Intravenous administration
: INVANZ should be infused over a period of 30 minutes.
2
The usual duration of therapy with INVANZ is 3 to 14 days but may vary depending on the type and
severity of infection and causative pathogen(s). When clinically indicated, a switch to an appropriate
oral antibacterial agent may be implemented if clinical improvement has been observed.
Renal insufficiency
:
INVANZ may be used for the treatment of infections in adult patients with renal insufficiency. In
patients whose creatinine clearance is > 30 ml/min/1.73 m
2
, no dosage adjustment is necessary. There
are inadequate data on the safety and efficacy of ertapenem in patients with advanced renal
insufficiency to support a dose recommendation. Therefore, ertapenem should not be used in these
patients (see section 5.2.). There are no data in children and adolescents with renal insufficiency.
Patients on haemodialysis
:
There are inadequate data on the safety and efficacy of ertapenem in patients on haemodialysis to
support a dose recommendation. Therefore, ertapenem should not be used in these patients.
Hepatic insufficiency
:
No dosage adjustment is recommended in patients with impaired hepatic function (see section 5.2).
Elderly
:
The recommended dose of INVANZ should be administered, except in cases of advanced renal
insufficiency (see
Renal insufficiency
).
•
Hypersensitivity to the active substance or to any of the excipients
•
Hypersensitivity to any other carbapenem antibacterial agent
•
Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any other type of
beta-lactam antibacterial agent (e.g., penicillins or cephalosporins).
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients
receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a
history of sensitivity to multiple allergens. Before initiating therapy with ertapenem, careful inquiry
should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other
beta-lactams and other allergens (see section 4.3). If an allergic reaction to ertapenem occurs (see
section 4.8), discontinue the therapy immediately.
Serious anaphylactic reactions require
immediate emergency treatment.
As with other antibiotics, prolonged use of ertapenem may result in overgrowth of non-susceptible
organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during
therapy, appropriate measures should be taken.
Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all
antibacterial agents, including ertapenem, and may range in severity from mild to life-threatening.
Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent
to the administration of antibacterial agents. Discontinuation of therapy with INVANZ and the
administration of specific treatment for
Clostridium difficile
should be considered. Medicinal products
that inhibit peristalsis should not be given.
Seizures have been reported during clinical investigation in adult patients treated with ertapenem
sodium (1 g once a day) during therapy or in the 14-day follow-up period. Seizures occurred most
commonly in elderly patients and those with pre-existing CNS disorders (e.g., brain lesions or history
of seizures) and/or compromised renal function. Similar observations have been made in the post-
marketing environment.
3
The concomitant use of ertapenem and valproic acid/sodium valproate is not recommended (see
section 4.5).
The efficacy of INVANZ in the treatment of community acquired pneumonia due to penicillin-
resistant
Streptococcus pneumoniae
has not been established.
There is relatively little experience with ertapenem in children less than two years of age. In this age
group, particular care should be taken to establish the susceptibility of the infecting organism(s) to
ertapenem. No data are available in children under 3 months of age.
Experience in the use of ertapenem in the treatment of severe infections is limited. In clinical studies
for the treatment of community-acquired pneumonia, in adults, 25 % of evaluable patients treated with
ertapenem had severe disease (defined as pneumonia severity index > III). In a clinical study for the
treatment of acute gynaecologic infections, in adults, 26 % of evaluable patients treated with
ertapenem had severe disease (defined as temperature ≥ 39°C and/or bacteraemia); ten patients had
bacteraemia. Of evaluable patients treated with ertapenem in a clinical study for the treatment of intra-
abdominal infections, in adults, 30 % had generalized peritonitis and 39 % had infections involving
sites other than the appendix including the stomach, duodenum, small bowel, colon, and gallbladder;
there were limited numbers of evaluable patients who were enrolled with APACHE II scores ≥ 15 and
efficacy in these patients has not been established.
Efficacy of ertapenem in the treatment of diabetic foot infections with concurrent osteomyelitis has not
been established.
Based on the data available it cannot be excluded that in the few cases of surgical interventions
exceeding 4 hours, patients could be exposed to sub-optimal Ertapenem concentrations and
consequently to a risk of potential treatment failure. Therefore, caution should be exercised in such
unusual cases.
This medicinal product contains approximately 6.0 mEq (approximately 137 mg) of sodium per 1.0 g
dose which should be taken into consideration by patients on a controlled sodium diet.
Interactions caused by inhibition of P-glycoprotein-mediated clearance or CYP-mediated clearance of
medicinal products are unlikely (see section 5.2).
Decreases in valproic acid levels that may fall below the therapeutic range have been reported when
valproic acid was co-administered with carbapenem agents. The lowered valproic acid levels can lead
to inadequate seizure control; therefore, concomitant use of ertapenem and valproic acid/sodium
valproate is not recommended and alternative antibacterial or anti-convulsant therapies should be
considered.
Adequate and well-controlled studies have not been performed in pregnant women. Animal studies do
not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development,
parturition or post-natal development. However, ertapenem should not be used during pregnancy
unless the potential benefit outweighs the possible risk to the foetus.
Ertapenem is excreted in human milk. Because of the potential for adverse reactions on the infant,
mothers should not breast-feed their infants while receiving ertapenem.
No studies on the effects on the ability to drive and use machines have been performed.
4
INVANZ may influence patients' ability to drive and use machines. Patients should be informed that
dizziness and somnolence have been reported with INVANZ (see section 4.8).
Adults 18 years of age and older
:
The total number of patients treated with ertapenem in clinical studies was over 2,200 of which over
2,150 received a 1 g dose of ertapenem. Adverse reactions (i.e., considered by the investigator to be
possibly, probably, or definitely related to the medicinal product) were reported in approximately
20 % of patients treated with ertapenem. Treatment was discontinued due to adverse reactions in 1.3 %
of patients. An additional 476 patients received ertapenem as a single 1 g dose prior to surgery in a
clinical study for the prophylaxis of surgical site infections following colorectal surgery.
For patients who received only INVANZ, the most common adverse reactions reported during therapy
plus follow-up for 14 days after treatment was stopped were: diarrhoea (4.8 %), infused vein
complication (4.5 %) and nausea (2.8 %).
For patients who received only INVANZ, the most frequently reported laboratory abnormalities and
their respective incidence rates during therapy plus follow-up for 14 days after treatment was stopped
were: elevations in ALT (4.6 %), AST (4.6 %), alkaline phosphatase (3.8 %) and platelet count
(3.0 %).
Children and adolescents (3 months to 17 years of age):
The total number of patients treated with ertapenem in clinical studies was 384. The overall safety
profile is comparable to that in adult patients. Adverse reactions (i.e., considered by the investigator to
be possibly, probably, or definitely related to the medicinal product) were reported in approximately
20.8 % of patients treated with ertapenem. Treatment was discontinued due to adverse reactions in
0.5 % of patients.
For patients who received only INVANZ, the most common adverse reactions reported during therapy
plus follow-up for 14 days after treatment was stopped were: diarrhoea (5.2 %) and infusion site pain
(6.1 %).
For patients who received only INVANZ, the most frequently reported laboratory abnormalities and
their respective incidence rates during therapy plus follow-up for 14 days after treatment was stopped
were: decreases in neutrophil count (3.0 %), and elevations in ALT (2.9 %) and AST (2.8 %).
For patients who received only INVANZ, the following adverse reactions were reported during
therapy plus follow-up for 14 days after treatment was stopped:
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)
Adults 18 years of age and older
Children and adolescents
(3 months to 17 years of age)
Infections and infestations:
Uncommon
: Oral candidiasis
Blood and lymphatic
disorders:
Rare
: Neutropenia,
thrombocytopenia
Metabolism and nutrition
disorders:
Uncommon
: Anorexia
Rare
: Hypoglycaemia
Nervous system disorders:
Common
: Headache
Uncommon
: Dizziness,
somnolence, insomnia, confusion,
seizure (see section 4.4)
Rare
: Agitation, anxiety,
depression, tremor
Uncommon
: Headache
5
Adults 18 years of age and older
Children and adolescents
(3 months to 17 years of age)
Cardiac Disorders
:
Uncommon
: Sinus bradycardia
Rare
: Arrhythmia, tachycardia
Vascular Disorders:
Common
:
Phlebitis/thrombophlebitis
Uncommon
: Hypotension
Rare
: Haemorrhage, increased
blood pressure
Uncommon
: Hot flush,
hypertension, petechiae
Respiratory, thoracic and
mediastinal disorders:
Uncommon
: Dyspnoea,
pharyngeal discomfort
Rare
: Nasal congestion, cough,
epistaxis, pneumonia,
rales/rhonchi, wheezing
Gastrointestinal disorders:
Common
: Diarrhoea, nausea,
vomiting
Uncommon
: Constipation,
pseudomembranous enterocolitis,
acid regurgitation,
dry mouth, dyspepsia
Rare
: Dysphagia, faecal
incontinence
Common
: Diarrhoea
Uncommon
: Faeces
discoloured, melaena
Hepato-biliary disorders:
Rare
: Cholecystitis, jaundice, liver
disorder
Skin and subcutaneous tissue
disorders:
Common
: Rash, pruritus
Uncommon
: Erythema, urticaria
Rare
: Dermatitis,
dermatomycosis, desquamation,
postoperative wound infection
Common
: Diaper dermatitis
Uncommon
: Erythema, rash
Musculoskeletaland
connective tissue disorders:
Rare
: Muscle cramp, shoulder
pain
Renal and urinary disorders:
Rare
: Urinary tract infection, renal
insufficiency, acute renal
insufficiency
Reproductive system and
breast disorders:
Uncommon
: Vaginitis
Rare
: Abortion, genital bleeding
General disorders and
administration site conditions:
Common
: Infused vein
complication
Uncommon
: Extravasation,
abdominal pain, candidiasis,
asthenia/fatigue, fungal infection,
fever, oedema/swelling, chest
pain, taste perversion
Rare
: Allergy, injection-site
induration, malaise, pelvic
peritonitis, scleral disorder,
syncope
Common
: Infusion site pain
Uncommon
: Infusion site
burning, infusion site pruritus,
infusion site erythema,
injection site erythema,
infusion site warmth
6
Adults 18 years of age and older
Children and adolescents
(3 months to 17 years of age)
Laboratory test findings
:
Chemistry:
Common
: Elevations in ALT,
AST, alkaline phosphatase
Uncommon
: Increases in total
serum bilirubin, direct serum
bilirubin, indirect serum bilirubin,
serum creatinine, serum urea,
serum glucose
Rare
: Decreases in serum
bicarbonate, serum creatinine, and
serum potassium; increases in
serum LDH, serum phosphorus,
serum potassium
Common
: Elevations in ALT
and AST
Haematology:
Common
: Elevation in platelet
count
Uncommon
: Decreases in white
blood cells, platelet count,
segmented neutrophils,
haemoglobin and haematocrit;
increases in eosinophils, activated
partial thromboplastin time,
prothrombin time, segmented
neutrophils, and white blood cells
Rare
: Decrease in lymphocytes;
increases in band neutrophils,
lymphocytes, metamyelocytes,
monocytes, myelocytes; atypical
lymphocytes
Common
: Decreases in
neutrophil count
Uncommon
: Increases in
platelet count, activated
partial thromboplastin time,
prothrombin time, decreases
in haemoglobin
Urinalysis:
Uncommon
: Increases in urine
bacteria, urine white blood cells,
urine epithelial cells, and urine red
blood cells; urine yeast present
Rare
: Increase in urobilinogen
Miscellaneous:
Uncommon
: Positive
Clostridium
difficile
toxin
Post Marketing Experience
:
Immune system disorder:
Anaphylaxis including
anaphylactoid reactions
Psychiatric disorders:
Altered mental status (including
aggression, delirium,
disorientation, mental status
changes)
Nervous system disorders:
Hallucinations, dyskinesia,
myoclonus
Skin and subcutaneous tissue
disorders:
Drug Rash with Eosinophilia and
Systemic Symptoms (DRESS
syndrome)
No specific information is available on the treatment of overdose with ertapenem. Overdosing of
ertapenem is unlikely. Intravenous administration of ertapenem at a 3 g daily dose for 8 days to
healthy adult volunteers did not result in significant toxicity. In clinical studies in adults inadvertent
administration of up to 3 g in a day did not result in clinically important adverse reactions. In
7
paediatric clinical studies, a single IV dose of 40 mg/kg up to a maximum of 2 g did not result in
toxicity.
However, in the event of an overdose, treatment with INVANZ should be discontinued and general
supportive treatment given until renal elimination takes place.
Ertapenem can be removed to some extent by haemodialysis (see section 5.2); however, no
information is available on the use of haemodialysis to treat overdose.
5.
5.1 Pharmacodynamic properties
General properties
Pharmacotherapeutic group: carbapenems, ATC code: J01D H03
Mode of action
Ertapenem inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins
(PBPs). In
Escherichia coli
, affinity is strongest to PBPs 2 and 3.
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of ertapenem
exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in pre-
clinical PK/PD studies.
Mechanism of Resistance
For species considered susceptible to ertapenem, resistance was uncommon in surveillance studies in
Europe. In resistant isolates, resistance to other antibacterial agents of the carbapenem class was seen
in some but not all isolates. Ertapenem is effectively stable to hydrolysis by most classes of beta-
lactamases, including penicillinases, cephalosporinases and extended spectrum beta-lactamases, but
not metallo-beta-lactamases.
Methicillin-resistant staphylococci and enterococci are resistant to ertapenem, owing to PBP target
insensitivity;
P. aeruginosa
and other non-fermentative bacteria are generally resistant, probably
owing to limited penetration and to active efflux.
Resistance is uncommon in Enterobacteriaceae and the drug is generally active against those with
extended-spectrum beta-lactamases (ESBLs). Resistance can however be observed when ESBLs or
other potent beta-lactamases (e.g. AmpC types) are present in conjunction with reduced permeability,
arising by the loss of one or more outer membrane porins, or with up-regulated efflux. Resistance can
also arise via the acquisition of betalactamases with significant carbapenem-hydrolysing activity (e.g.
IMP and VIM metallo-beta-lactamases or KPC types), though these are rare.
The mechanism of action of ertapenem differs from that of other classes of antibiotics, such as
quinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based cross-resistance
between ertapenem and these substances. However, micro-organisms may exhibit resistance to more
than one class of antibacterial agents when the mechanism is, or includes, impermeability to some
compounds and/or an efflux pump.
Breakpoints
The EUCAST MIC breakpoints are as follows:
•
Enterobacteriaceae: S ≤ 0.5 mg/l and R > 1 mg/l
•
Streptococcus A,B,C,G: S ≤ 0.5 mg/l and R > 0.5 mg/l
•
Streptococcus pneumoniae: S ≤ 0.5 mg/l and R > 0.5 mg/l
•
Haemophilus influenzae: S ≤ 0.5 mg/l and R > 0.5 mg/l
8
•
M. catarrhalis: S ≤ 0.5 mg/l and R > 0.5 mg/l
•
Gram negative anaerobes: S ≤ 1mg/l and R > 1 mg/l
•
Non species related breakpoints: S ≤ 0.5 mg/l and R > 1 mg/l
(NB: Susceptibility of staphylococci to ertapenem is inferred from the methicillin susceptibility)
The prescribers are informed that local MIC breakpoints, if available, should be consulted.
Microbiological Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and
local information on resistance is desirable, particularly when treating severe infections. Localized
clusters of infections due to carbapenem-resistant organisms have been reported in the European
Union. The information below gives only approximate guidance on the probability as to whether the
micro-organism will be susceptible to ertapenem or not.
Commonly susceptible species:
Gram-positive aerobes:
Methicillin-susceptible-staphylococci (including
Staphylococcus aureus)
*
Streptococcus agalactiae
*
Streptococcus pneumoniae
*†
Streptococcus pyogenes
Gram-negative aerobes:
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
*
Haemophilus influenzae
*
Haemophilus parainfluenzae
Klebsiella oxytoca
Klebsiella pneumoniae
*
Moraxella catarrhalis
*
Morganella morganii
Proteus mirabilis*
Proteus vulgaris
Serratia marcescens
Anaerobes:
Bacteroides fragilis
and species in the
B. fragilis
Group*
Clostridium
species (excluding
C. difficile
)*
Eubacterium
species*
Fusobacterium
species*
Peptostreptococcus
species*
Porphyromonas asaccharolytica
*
Prevotella
species*
Species for which acquired resistance may be a problem:
Methicillin-resistant staphylococci +#
Inherently resistant organisms:
Gram-positive aerobes:
Corynebacterium jeikeium
Enterococci
including
Enterococcus faecalis
and
Enterococcus faecium
Gram-negative aerobes:
Aeromonas
species
Acinetobacter
species
Burkholderia cepacia
Pseudomonas aeruginosa
Stenotrophomonas maltophilia
9
Anaerobes:
Lactobacillus
species
Others:
Chlamydia
species
Mycoplasma
species
Rickettsia
species
Legionella
species
* Activity has been satisfactorily demonstrated in clinical studies.
† The efficacy of INVANZ in the treatment of community acquired pneumonia due to penicillin-resistant
Streptococcus pneumoniae
has not been established.
+ frequency of acquired resistance > 50 % in some Member States
# Methicillin-resistant staphylococci (including MRSA) are always resistant to betalactams.
Information from clinical studies
Efficacy in Pediatric Studies
Ertapenem was evaluated primarily for pediatric safety and secondarily for efficacy in randomized
comparative, multicenter studies in patients 3 months to 17 years of age.
The proportion of patients with a favorable clinical response assessment at posttreatment visit in the
clinical MITT population is shown below:
Ertapenem
Ceftriaxone
Disease Stratum
†
Age Stratum
n/m
%
n/m
%
Community Acquired
Pneumonia (CAP)
3 to 23 months
31/35
88.6
13/13
100.0
2 to 12 years
55/57
96.5
16/17
94.1
13 to 17 years
3/3
100.0
3/3
100.0
Ertapenem Ticarcillin/clavulanate
Disease Stratum Age Stratum n/m % n/m %
Intraabdominal Infections (IAI) 2 to 12 years 28/34 82.4 7/9 77.8
13 to 17 years 15/16 93.8 4/6 66.7
Acute Pelvic Infections (API) 13 to 17 years 25/25 100.0 8/8 100.0
†
. This includes 9 patients in the ertapenem group (7 CAP and 2 IAI), 2 patients in the ceftriaxone group
(2 CAP), and 1 patient with IAI in the ticarcillin/clavulanate group with secondary bacteremia at entry into the
study.
5.2 Pharmacokinetic properties
Plasma concentrations
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a
1 g dose in healthy young adults (25 to 45 years of age) were 155 micrograms/ml (C
max
) at 0.5 hour
postdose (end of infusion), 9 micrograms/ml at 12 hour postdose, and 1 microgram/ml at 24 hour
postdose.
Area under the plasma concentration curve (AUC) of ertapenem in adults increases nearly dose-
proportionally over the 0.5 to 2 g dose range.
There is no accumulation of ertapenem in adults following multiple intravenous doses ranging from
0.5 to 2 g daily.
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a
15 mg/kg (up to a maximum dose of 1 g) dose in patients 3 to 23 months of age were
103.8 micrograms/ml (C
max
) at 0.5 hour postdose (end of infusion), 13.5 micrograms/ml at 6 hour
postdose, and 2.5 micrograms/ml at 12 hour postdose.
10
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a
15 mg/kg (up to a maximum dose of 1 g) dose in patients 2 to 12 years of age were
113.2 micrograms/ml (C
max
) at 0.5 hour postdose (end of infusion), 12.8 micrograms/ml at 6 hour
postdose, and 3.0 micrograms/ml at 12 hour postdose.
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a
20 mg/kg (up to a maximum dose of 1 g) dose in patients 13 to 17 years of age were
170.4 micrograms/ml (C
max
) at 0.5 hour postdose (end of infusion), 7.0 micrograms/ml at 12 hour
postdose, and 1.1 microgram/ml at 24 hour postdose.
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a
1 g dose in three patients 13 to 17 years of age were 155.9 micrograms/ml (C
max
) at 0.5 hour postdose
(end of infusion), and 6.2 micrograms/ml at 12 hour postdose.
Distribution
Ertapenem is highly bound to human plasma proteins. In healthy young adults (25 to 45 years of age),
the protein binding of ertapenem decreases, as plasma concentrations increase, from approximately
95 % bound at an approximate plasma concentration of < 50 micrograms/ml to approximately 92 %
bound at an approximate plasma concentration of 155 micrograms/ml (average concentration achieved
at the end of infusion following 1 g intravenously).
The volume of distribution (V
dss
) of ertapenem in adults is approximately 8 litres (0.11 liter/kg) and
approximately 0.2 liter/kg in paediatric patients 3 months to 12 years of age and approximately
0.16 liter/kg in paediatric patients 13 to 17 years of age.
Concentrations of ertapenem achieved in adult skin blister fluid at each sampling point on the third
day of 1 g once daily intravenous doses showed a ratio of AUC in skin blister fluid: AUC in plasma
of 0.61.
In-vitro
studies indicate that the effect of ertapenem on the plasma protein binding of highly protein
bound medicinal products (warfarin, ethinyl estradiol, and norethindrone) was small. The change in
binding was < 12 % at peak plasma ertapenem concentration following a 1 g dose.
In vivo
, probenecid
(500 mg every 6 hours) decreased the bound fraction of ertapenem in plasma at the end of infusion in
subjects administered a single 1 g intravenous dose from approximately 91 % to approximately 87 %.
The effects of this change are anticipated to be transient. A clinically significant interaction due to
ertapenem displacing another medicinal product or another medicinal product displacing ertapenem is
unlikely.
In-vitro
studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin
or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
Metabolism
In healthy young adults (23 to 49 years of age), after intravenous infusion of radiolabelled 1 g
ertapenem, the plasma radioactivity consists predominantly (94 %) of ertapenem. The major
metabolite of ertapenem is the ring-opened derivative formed by dehydropeptidase-I-mediated
hydrolysis of the beta-lactam ring.
In-vitro
studies in human liver microsomes indicate that ertapenem does not inhibit metabolism
mediated by any of the six major CYP isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.
Elimination
Following administration of a 1 g radiolabelled intravenous dose of ertapenem to healthy young adults
(23 to 49 years of age), approximately 80 % is recovered in urine and 10 % in faeces. Of the 80 %
recovered in urine, approximately 38 % is excreted as unchanged ertapenem and approximately 37 %
as the ring-opened metabolite.
11
In healthy young adults (18 to 49 years of age) and patients 13 to 17 years of age given a 1 g
intravenous dose, the mean plasma half-life is approximately 4 hours. The mean plasma half-life in
children 3 months to 12 years of age is approximately 2.5 hours. Average concentrations of ertapenem
in urine exceed 984 micrograms/ml during the period 0 to 2 hours postdose and exceed
52 micrograms/ml during the period 12 to 24 hours post-administration.
Special Populations
Gender
The plasma concentrations of ertapenem are comparable in men and women.
Elderly
Plasma concentrations following a 1 g and 2 g intravenous dose of ertapenem are slightly higher
(approximately 39 % and 22 %, respectively) in healthy elderly adults (≥ 65 years) relative to young
adults (< 65 years). In the absence of advanced renal insufficiency, no dosage adjustment is necessary
in elderly patients.
Paediatric Patients
Plasma concentrations of ertapenem are comparable in paediatric patients 13 to 17 years of age and
adults following a 1 g once daily intravenous dose.
Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in
patients 13 to 17 years of age were generally comparable to those in healthy young adults. To provide
an estimate of the pharmacokinetic data if all patients in this age group were to receive a 1 g dose, the
pharmacokinetic data were calculated adjusting for a 1 g dose, assuming linearity. A comparison of
results show that a 1 g once daily dose of ertapenem achieves a pharmacokinetic profile in patients
13 to 17 years of age comparable to that of adults. The ratios (13 to 17 years/Adults) for AUC, the end
of infusion concentration and the concentration at the midpoint of the dosing interval were 0.99, 1.20,
and 0.84, respectively.
Plasma concentrations at the midpoint of the dosing interval following a single 15 mg/kg intravenous
dose of ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations at
the midpoint of the dosing interval following a 1 g once daily intravenous dose in adults (see Plasma
concentrations). The plasma clearance (ml/min/kg) of ertapenem in patients 3 months to 12 years of
age is approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC value
and plasma concentrations at the midpoint of the dosing interval in patients 3 months to 12 years of
age were comparable to those in young healthy adults receiving a 1 g intravenous dose of ertapenem.
Hepatic Insufficiency
The pharmacokinetics of ertapenem in patients with hepatic insufficiency have not been established.
Due to the limited extent of hepatic metabolism of ertapenem, its pharmacokinetics are not expected to
be affected by hepatic impairment. Therefore, no dosage adjustment is recommended in patients with
hepatic impairment.
Renal Insufficiency
Following a single 1 g intravenous dose of ertapenem in adults, AUCs of total ertapenem (bound and
unbound) and of unbound ertapenem are similar in patients with mild renal insufficiency (Cl
cr
60 to
90 ml/min/1.73 m
2
) compared with healthy subjects (ages 25 to 82 years). AUCs of total ertapenem
and of unbound ertapenem are increased in patients with moderate renal insufficiency (Cl
cr
31 to
59 ml/min/1.73 m
2
) approximately 1.5-fold and 1.8-fold, respectively, compared with healthy subjects.
AUCs of total ertapenem and of unbound ertapenem are increased in patients with advanced renal
insufficiency (Cl
cr
5 to 30 ml/min/1.73 m
2
) approximately 2.6-fold and 3.4-fold, respectively,
compared with healthy subjects. AUCs of total ertapenem and of unbound ertapenem are increased in
patients who require haemodialysis approximately 2.9-fold and 6.0-fold, respectively, between dialysis
sessions, compared with healthy subjects. Following a single 1 g intravenous dose given immediately
prior to a haemodialysis session, approximately 30 % of the dose is recovered in the dialysate. There
are no data in paediatric patients with renal insufficiency.
12
There are inadequate data on the safety and efficacy of ertapenem in patients with advanced renal
insufficiency and patients who require haemodialysis to support a dose recommendation. Therefore,
ertapenem should not be used in these patients.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety,
pharmacology, repeated-dose toxicity, genotoxicity and toxicity in reproduction. Decreased neutrophil
counts, however, occurred in rats that received high doses of ertapenem, which was not considered a
significant safety issue.
Long-term studies in animals to evaluate the carcinogenic potential of ertapenem have not been
performed.
6.
6.1 List of excipients
Sodium bicarbonate (E500).
Sodium hydroxide (E524) to adjust pH to 7.5.
6.2 Incompatibilities
Do not use solvents or infusion fluids containing dextrose for reconstitution or administration of
ertapenem sodium.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
2 years.
After reconstitution:
Diluted solutions should be used immediately. If not used immediately, in use storage times are the
responsibility of the user. Diluted solutions (approximately 20 mg/ml ertapenem) are physically and
chemically stable for 6 hours at room temperature (25°C) or for 24 hours at 2 to 8°C (in a refrigerator).
Solutions should be used within 4 hours of their removal from the refrigerator.
6.4 Special precautions for storage
Do not store above 25°C.
For storage instructions after reconstitution, see section 6.3.
Do not freeze solutions of INVANZ.
6.5 Nature and contents of container
20 ml Type I glass vials with a grey butyl stopper and a white plastic cap on a coloured aluminium
band seal.
Supplied in packs of 1 vial or 10 vials.
Not all pack sizes may be marketed.
13
6.6 Special precautions for disposal and other handling
Instructions for use:
For single use only.
Reconstituted solutions should be diluted in sodium chloride 9 mg/ml (0.9 %) solution immediately
after preparation.
Preparation for intravenous administration
:
INVANZ must be reconstituted and then diluted prior to administration.
Adults and adolescents (13 to 17 years of age):
1. Reconstitution
:
Reconstitute the contents of a 1 g vial of INVANZ with 10 ml of water for injection or sodium
chloride 9 mg/ml (0.9 %) solution to yield a reconstituted solution of approximately 100 mg/ml. Shake
well to dissolve. (see section 6.4.)
2. Dilution
:
For a 50 ml bag of diluent: For a 1 g dose, immediately transfer contents of the reconstituted vial to a
50 ml bag of sodium chloride 9 mg/ml (0.9 %) solution; or
For a 50 ml vial of diluent: For a 1 g dose, withdraw 10 ml from a 50 ml vial of sodium chloride
9 mg/ml (0.9 %) solution and discard. Transfer the contents of the reconstituted 1 g vial of INVANZ
to the 50 ml vial of sodium chloride 9 mg/ml (0.9 %) solution.
3. Infusion
:
Infuse over a period of 30 minutes.
Children (3 months to 12 years of age):
1. Reconstitution
:
Reconstitute the contents of a 1 g vial of INVANZ with 10 ml of water for injection or sodium
chloride 9 mg/ml (0.9 %) solution to yield a reconstituted solution of approximately 100 mg/ml. Shake
well to dissolve. (see section 6.4.)
2. Dilution
:
For a bag of diluent: Transfer a volume equal to 15 mg/kg of body weight (not to exceed 1 g/day) to a
bag of sodium chloride 9 mg/ml (0.9 %) solution for a final concentration of 20 mg/ml or less; or
For a vial of diluent: Transfer a volume equal to 15 mg/kg of body weight (not to exceed 1 g/day) to a
vial of sodium chloride 9 mg/ml (0.9 %) solution for a final concentration of 20 mg/ml or less.
3. Infusion
:
Infuse over a period of 30 minutes.
Compatibility of INVANZ with intravenous solutions containing heparin sodium and potassium
chloride has been demonstrated.
The reconstituted solutions should be inspected visually for particulate matter and discolouration prior
to administration, whenever the container permits. Solutions of INVANZ range from colourless to
pale yellow. Variations of colour within this range do not affect potency.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
14
8.
EU/1/02/216/001
EU/1/02/216/002
9.
Date of first authorisation: 18 April 2002
Date of latest renewal: 18 April 2007
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/.
15
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
16
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Merck & Co. Inc.
Merck Manufacturing Division:
Cherokee (Danville) Plant
100 Avenue C
Riverside, Pennsylvania, USA 17868
Name and address of the manufacturer responsible for batch release
Laboratoire Merck Sharp & Dohme – Chibret (Mirabel), Route de Marsat.
F-63963 Clermont-Ferrand Cedex 9, France.
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
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 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.
The Marketing Authorisation Holder will continue to submit yearly PSURs, unless otherwise specified
by the CHMP.
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A. LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
INVANZ 1 g Powder for concentrate for solution for infusion
Ertapenem
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains: 1.0 g ertapenem equivalent to 1.046 g ertapenem sodium.
3.
LIST OF EXCIPIENTS
Sodium bicarbonate (E500); sodium hydroxide (E524) to adjust pH to 7.5.
4.
1 vial
10 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use after reconstitution and dilution.
For single use 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
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C
20
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/02/216/001 1 vial
EU/1/02/216/002 10 vials
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
21
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
INVANZ 1 g Powder for concentrate for solution for infusion
Ertapenem
Intravenous use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
For single use only.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
22
B. PACKAGE LEAFLET
23
PACKAGE LEAFLET: INFORMATION FOR THE USER
INVANZ 1 g powder for concentrate for solution for infusion
(ertapenem)
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or your pharmacist.
In this leaflet
:
1.
What INVANZ is and what it is used for
2.
Before you take INVANZ
4.
Possible side effects
5.
How to store INVANZ
6.
Further information
1.
WHAT INVANZ IS AND WHAT IT IS USED FOR
INVANZ is an injectable antibiotic which will always be prepared and given to you by a doctor or
another healthcare professional.
INVANZ contains ertapenem which is an antibiotic of the beta-lactam group. It has the ability to kill a
wide range of bacteria (germs) that cause infections in various parts of the body.
Treatment:
Your doctor has prescribed INVANZ because you have one (or more) of the following types of
infection:
•
Infection in the abdomen
•
Infection affecting the lungs (pneumonia)
•
Gynaecological infections
•
Skin infections of the foot in diabetic patients.
Prevention:
•
Prevention of surgical site infections following surgery of the colon or rectum.
2.
BEFORE YOU TAKE INVANZ
Do not take INVANZ
-
if you are allergic to the active substance (ertapenem) or any of the other ingredients of
INVANZ
-
if you are allergic to antibiotics such as penicillins, cephalosporins or carbapenems.
Take special care with INVANZ
Tell your doctor about any medical condition you have or have had including:
-
Kidney disease (see Patients with kidney disease)
-
Colitis or any other gastrointestinal disease.
-
Central nervous system disorders, such as localized tremors, or seizures.
24
-
Keep this leaflet. You may need to read it again.
3.
How to take INVANZ
-
Allergies to any medicines, including antibiotics
During treatment, if you experience an allergic reaction (such as swelling of the face, tongue or throat,
difficulty in breathing or swallowing, skin rash), you must stop taking INVANZ immediately and seek
medical advice.
Tell your doctor if you are taking medicines called valproic acid or sodium valproate. (see
Taking
other medicines
below)
Patients with kidney disease
It is particularly important that your doctor knows if you have kidney disease and whether you
undergo dialysis treatment.
Children and adolescents (3 months to 17 years of age)
INVANZ can be given to children 3 months of age and older. Experience with INVANZ is limited in
children less than two years of age. In this age group your doctor will decide on the potential benefit of
its use. There is no experience in children under 3 months of age.
Elderly
INVANZ works well and is well tolerated by most older and younger adult patients. The
recommended dosage of INVANZ can be administered without regard to age.
Taking other medicines
Always tell your doctor about all medicines that you are taking or plan to take, including those
obtained without a prescription.
Tell your doctor if you are taking medicines called valproic acid or sodium valproate (used to treat
epilepsy, bipolar disorder, migraines, or schizophrenia). Your doctor will decide whether you should
use INVANZ in combination with these other medicines.
Pregnancy and breast-feeding
It is important that you tell your doctor if you are pregnant or are planning to become pregnant before
receiving INVANZ.
INVANZ has not been studied in pregnant women. INVANZ should not be used during pregnancy
unless your doctor decides the potential benefit justifies the potential risk to the foetus.
It is important that you tell your doctor if you are breast-feeding or if you intend to breast-feed before
receiving INVANZ.
Women who are receiving INVANZ should not breast-feed, because it has been found in human milk
and the breast-fed baby may therefore be affected.
Driving and using machines
Do not drive or use any tools or machines until you know how you react to the medicine.
Certain side effects, such as dizziness and sleepiness, have been reported with INVANZ, which may
affect some patients’ ability to drive or operate machinery.
Important information about some of the ingredients of INVANZ :
This medicinal product
contains approximately 6.0
mEq (approximately 137 mg) of sodium per 1.0 g dose which should be
taken into consideration by patients on a controlled sodium diet.
3.
HOW TO TAKE INVANZ
INVANZ will always be prepared and given to you by a doctor or another healthcare professional.
INVANZ is given intravenously (into a vein).
25
The normal dose of INVANZ for adults and adolescents 13 years of age and older is 1 gram (g) given
once a day. The normal dose for children 3 months to 12 years of age is 15 mg/kg given twice daily
(not to exceed 1 g/day). INVANZ is not recommended in children under 3 months of age, as no data
are available. Your doctor will decide how many days’ treatment you need.
For prevention of surgical site infections following surgery of the colon or rectum, the recommended
dose of INVANZ is 1 g administered as a single intravenous dose 1 hour before surgery.
It is very important that you continue to receive INVANZ for as long as your doctor prescribes it.
If you take more INVANZ than you should
If you are concerned that you may have been given too much INVANZ, contact your doctor or another
healthcare professional immediately.
If you forget to take INVANZ
If you are concerned that you may have missed a dose, contact your doctor or another healthcare
professional immediately.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, INVANZ can cause side effects, although not everybody gets them.
Adults 18 years of age and older:
The most common (more than 1 in 100 patients and less than 1 in 10 patients) side effects are:
•
Headache
•
Diarrhoea, nausea, vomiting
•
Rash, itching
•
Problems with the vein into which the medicine is given (including inflammation, formation of
a lump, swelling at the injection site, or leaking of fluid into the tissue and skin around the
injection site).
Less common (more than 1 in 1,000 patients and less than 1 in 100 patients) side effects are:
•
Dizziness, sleepiness, sleeplessness, confusion, seizure
•
Low blood pressure, slow heart rate
•
Shortness of breath, sore throat
•
Constipation, yeast infection of the mouth, antibiotic-associated diarrhoea, acid regurgitation,
dry mouth, indigestion, loss of appetite
•
Skin redness
•
Vaginal discharge and irritation
•
Abdominal pain, fatigue, fungal infection, fever, oedema/swelling, chest pain, abnormal taste.
Side effects reported rarely (more than 1 in 10,000 patients and less than 1 in 1,000 patients) are:
•
Decrease in white blood cells, decrease in blood platelet count
•
Low blood sugar
•
Agitation, anxiety, depression, tremor
•
Irregular heart rate, increased blood pressure, bleeding, fast heart rate
•
Nasal congestion, cough, bleeding from the nose, pneumonia, abnormal breathing sounds,
wheezing
•
Inflammation of the gall bladder, difficulty in swallowing, faecal incontinence, jaundice, liver
disorder
•
Inflammation of the skin, fungal infection of the skin, skin peeling, infection of the wound after
an operation
26
•
Muscle cramp, shoulder pain
•
Urinary tract infection, kidney impairment
•
Miscarriage, genital bleeding
•
Allergy, feeling unwell, pelvic peritonitis, changes to the white part of the eye, fainting.
There have also been reports of changes in some laboratory blood tests.
Children and adolescents (3 months to 17 years of age):
The most common (more than 1 in 100 patients and less than 1 in 10 patients) side effects are:
•
Diarrhoea
•
Diaper rash
•
Pain at the infusion site
Less common (more than 1 in 1,000 patients and less than 1 in 100 patients) side effects are:
•
Headache
•
Hot flush, high blood pressure, red or purple, flat, pinhead spots under the skin
•
Discoloured faeces, black tar-like faeces
•
Skin redness, skin rash
•
Burning, itching, redness and warmth at infusion site, redness at injection site
•
Increase in platelet count,
There have also been reports of changes in some laboratory blood tests
Since the drug has been marketed, severe allergic reactions (anaphylaxis), hypersensitivity syndromes
(allergic reactions including rash, fever, abnormal blood tests), hallucinations, altered mental status
(including aggression, delirium, disorientation, mental status changes), and abnormal movements have
been reported. The first signs of a severe allergic reaction may include swelling of the face and/or
throat. If these symptoms occur you must stop taking INVANZ immediately and inform your doctor or
nurse immediately.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE INVANZ
Keep out of the reach and sight of children.
Do not use INVANZ after the expiry date which is stated on the container.
The first 2 numbers indicate the month; the next 4 numbers indicate the year.
Do not store above 25°C
6.
FURTHER INFORMATION
What INVANZ contains
The active ingredient of INVANZ is ertapenem 1 g.
The other ingredients are: sodium bicarbonate (E500) and sodium hydroxide (E524).
What INVANZ looks like and contents of the pack
INVANZ is a sterile, white to off-white, freeze-dried powder.
Solutions of INVANZ range from colourless to pale yellow. Variations of colour within this range do
not affect potency.
INVANZ 1 g powder for concentrate for solution for infusion is supplied in packs of 1 vial or 10 vials.
27
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Manufacturer
Merck Sharp & Dohme Limited
Laboratoires Merck Sharp & Dohme – Chibret
Hertfordshire EN11 9BU
F-63963 Clermont-Ferrand Cedex 9
United Kingdom
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme (Middle East) Limited
Tel: +357 22866700
info_cyprus@merck.com
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme B.V.
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
Invanz@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
28
Hertford Road, Hoddesdon
Route de Marsat - Riom
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme (Middle East) Limited
Τηλ: +357 22866700
info_cyprus@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.emea.europa.eu
/
.
---------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Instructions of how to reconstitute and dilute INVANZ:
For single use only.
Preparation for intravenous administration
:
INVANZ must be reconstituted and then diluted prior to administration.
Adult and adolescents (13 to 17 years of age)
:
1. Reconstitution
:
Reconstitute the contents of a 1 g vial of INVANZ with 10 ml of water for injection or sodium
chloride 9 mg/ml (0.9 %) solution to yield a reconstituted solution of approximately 100 mg/ml. Shake
well to dissolve.
29
2. Dilution
:
For a 50 ml bag of diluent
: For a 1 g dose, immediately transfer contents of the reconstituted vial to a
50 ml bag of sodium chloride 9 mg/ml (0.9 %) solution; or
For a 50 ml vial of diluent
: For a 1 g dose, withdraw 10 ml from a 50 ml vial of sodium chloride
9 mg/ml (0.9 %) solution and discard. Transfer the contents of the reconstituted 1 g vial of INVANZ
to the 50 ml vial of sodium chloride 9 mg/ml (0.9 %) solution.
3. Infusion
:
Infuse over a period of 30 minutes.
Children (3 months to 12 years of age)
:
1. Reconstitution
:
Reconstitute the contents of a 1 g vial of INVANZ with 10 ml of water for injection or sodium
chloride 9 mg/ml (0.9 %) solution to yield a reconstituted solution of approximately 100 mg/ml. Shake
well to dissolve.
2. Dilution
:
For a bag of diluent: Transfer a volume equal to 15 mg/kg of body weight (not to exceed 1 g/day) to a
bag of sodium chloride 9 mg/ml (0.9 %) solution for a final concentration of 20 mg/ml or less; or
For a vial of diluent: Transfer a volume equal to 15 mg/kg of body weight (not to exceed 1 g/day) to a
vial of sodium chloride 9 mg/ml (0.9 %) solution for a final concentration of 20 mg/ml or less.
3. Infusion
:
Infuse over a period of 30 minutes
The reconstituted solution should be diluted in sodium chloride 9 mg/ml (0.9 %) solution immediately
after preparation. Diluted solutions should be used immediately. If not used immediately, in use
storage times are the responsibility of the user. Diluted solutions (approximately 20 mg/ml ertapenem)
are physically and chemically stable for 6 hours at room temperature (25°C) or for 24 hours at 2 to
8°C (in a refrigerator). Solutions should be used within 4 hours of their removal from the refrigerator.
Do not freeze the reconstituted solutions.
The reconstituted solutions should be inspected visually for particulate matter and discolouration prior
to administration, whenever the container permits. Solutions of INVANZ range from colourless to
pale yellow. Variations of colour within this range do not affect potency.
Any unused product or waste material should be disposed of in accordance with local requirements.
30
Source: European Medicines Agency
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