ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Doribax 250 mg powder for solution for infusion
Each vial contains doripenem monohydrate equivalent to 250 mg doripenem
The medicinal product does not contain any excipients.
Powder for solution for infusion (Powder for infusion)
White to slightly yellowish off-white crystalline powder
Doribax is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1):
Nosocomial pneumonia (including ventilator–associated pneumonia)
Complicated intra-abdominal infections
Complicated urinary tract infections
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Posology
The recommended dose and administration by infection is shown in the following table:
Infection
Dose
Frequency Infusion time
Nosocomial pneumonia including
ventilator–associated pneumonia
500 mg every 8 hours 1 or 4 hours*
Complicated intra-abdominal infection 500 mg every 8 hours 1 hour
Complicated UTI, including pyelonephritis 500 mg every 8 hours 1 hour
*
Based mainly on PK/PD considerations, a 4-hour infusion time may be more suitable for infection with less
susceptible pathogens (see section 5.1). This dosing regimen should also be considered in particularly severe
infections.
For infusion solution shelf life see section 6.3.
The usual treatment duration of doripenem therapy is 5-14 days and should be guided by the severity,
site of the infection and the patient’s clinical response. Doripenem was given for up to 14 days in
clinical studies and the safety of longer durations of therapy has not been established. After
commencing treatment with intravenous doripenem, a switch to appropriate oral therapy to complete
the treatment course is possible once clinical improvement has been established.
Dose in paediatric patients
Doribax is not recommended for use in children below 18 years of age due to a lack of safety and
efficacy data.
Dose in patients with impaired renal function
In patients with mild renal impairment (i.e. creatinine clearance (CrCl) is 51-79 ml/min), no dose
adjustment is necessary. In patients with moderate renal impairment (CrCl 30-50 ml/min), the dose of
2
Doribax should be 250 mg every 8 hours (see section 6.6). In patients with severe renal impairment
(CrCl < 30 ml/min), the dose of Doribax should be 250 mg every 12 hours (see section 6.6). Due to
limited clinical data and an expected increased exposure of doripenem and its metabolite, Doribax
should be used with caution in patients with severe renal impairment (see section 5.2).
Dose in patients on dialysis
Doribax is haemodialysable; however, there is insufficient information to make dose adjustment
recommendationsin patients on dialysis. Therefore, Doribax is not recommended for patients on any
type of dialysis (see section 5.2).
Dose in elderly patients (
65 years of age)
No dose adjustment is necessary in elderly patients, except in cases of moderate to severe renal
impairment (see
Dose in patients with impaired renal function
above and section 5.2).
Dose in patients with impaired hepatic function
No dose adjustment is necessary.
Method for administration
Doribax is to be reconstituted and then further diluted (see section 6.6) prior to administration by
intravenous infusion over a period of one or four hours.
Hypersensitivity to the active substance
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 occurred in patients
receiving beta-lactam antibiotics. Before therapy with Doribax is started, careful inquiry should be
made concerning a previous history of hypersensitivity reactions to other active substances in this
class or to beta-lactam antibiotics. Doribax should be used with caution in patients with such a history.
Should a hypersensitivity reaction to Doribax occur, it should be discontinued immediately and
appropriate measures taken. Serious acute hypersensitivity (anaphylactic) reactions require immediate
emergency treatment.
Seizures have infrequently been reported during treatment with other carbapenems.
Pseudomembranous colitis due to
Clostridium difficile
has been reported with Doribax and may range
in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in
patients who present with diarrhoea during or subsequent to the administration of Doribax (see section
4.8).
Administration of doripenem, like other antibiotics, has been associated with emergence and selection
of strains with reduced susceptibility. Patients should be carefully monitored during therapy. If
superinfection occurs, appropriate measures should be taken. Prolonged use of Doribax should be
avoided.
The concomitant use of doripenem and valproic acid/sodium valproate is not recommended (see
section 4.5).
When Doribax was used investigationally
via
inhalation, pneumonitis occurred. Therefore, Doribax
should not be administered by this route.
Description of the patient population treated in clinical studies
3
In two clinical trials of patients with nosocomial pneumonia (N=979), 60% of the clinically-evaluable
Doribax-treated patients had ventilator-associated pneumonia (VAP). Of these, 50% had late-onset
VAP (defined as that occurring after five days of mechanical ventilation), 54% had an APACHE
(Acute Physiology And Chronic Health Evaluation) II score > 15 and 32% received concomitant
aminoglycosides (76% for more than 3 days).
In two clinical trials of patients with complicated intra-abdominal infections (N=962) the most
common anatomical site of infection in microbiologically-evaluable Doribax-treated patients was the
appendix (62%). Of these, 51% had generalised peritonitis at baseline. Other sources of infection
included colon perforation (20%), complicated cholecystitis (5%) and infections at other sites (14%).
Eleven percent had an APACHE II score of > 10, 9.5% had post-operative infections, 27% had single
or multiple intra-abdominal abscesses and 4% had concurrent bacteraemia at baseline.
In two clinical trials of patients with complicated urinary tract infections (N=1179), 52% of
microbiologically-evaluable Doribax-treated patients had complicated lower urinary tract infections
and 48% had pyelonephritis, of which 16% were complicated. Overall, 54% of patients had a
persistent complication, 9% had concurrent bacteraemia and 23% were infected with a levofloxacin
resistant uropathogen at baseline.
The experience in patients who are severely immunocompromised, receiving immunosuppressive
therapy, and patients with severe neutropenia is limited since this population was excluded from
phase III trials.
Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. Based on
in
vitro
studies it is not expected that doripenem will inhibit or induce the activities of CYP450.
Therefore, no CYP450-related drug interactions are to be expected (see section 5.2).
It has been shown that co-administration of doripenem and valproic acid significantly reduces serum
valproic acid levels below the therapeutic range. The lowered valproic acid levels can lead to
inadequate seizure control. In an interaction study, the serum concentrations of valproic acid were
markedly reduced (AUC was reduced by 63%) following co-administration of doripenem and valproic
acid. The interaction had a fast onset. Since patients were administered only four doses of doripenem,
a further decrease of valproic acid levels with longer concomitant administration cannot be excluded.
Decreases in valproic acid levels have also been reported when co-administered with other
carbapenem agents, achieving a 60-100% decrease in valproic acid levels in about two days. Therefore
alternative antibacterial or supplemental anticonvulsant therapies should be considered.
Probenecid competes with doripenem for renal tubular secretion and reduces the renal clearance of
doripenem. In an interaction study, the mean doripenem AUC increased by 75% following
co-administration with probenecid. Therefore, co-administration of probenecid with Doribax is not
recommended. An interaction with other medicinal products eliminated by renal tubular secretion
cannot be excluded.
For doripenem, limited clinical data on exposed pregnancies are available. Animal studies are
insufficient with respect to pregnancy, embryonal/foetal development, parturition or postnatal
development (see section 5.3). The potential risk for humans is unknown. Doribax should not be used
during pregnancy unless clearly necessary.
It is unknown whether doripenem is excreted in human breast milk. A study in rats has shown that
doripenem and its metabolite are transferred to milk. A decision on whether to continue/discontinue
breast-feeding or to continue/discontinue therapy with Doribax should be made taking into account the
benefit of breast-feeding to the child and the benefit of Doribax therapy to the woman.
4
No studies on the effects of Doribax on the ability to drive and use machines have been performed.
Based on reported adverse drug reactions, it is not anticipated that Doribax will affect the ability to
drive and use machines.
In 3,142 adult patients (1,817 of which received Doribax) evaluated for safety in phase II and phase III
clinical trials, adverse reactions due to Doribax 500 mg every 8 hours occurred at a rate of 32%.
Doribax was discontinued because of adverse drug reactions in 0.1% of patients overall. Adverse drug
reactions that led to Doribax discontinuation were nausea (0.1%), diarrhoea (0.1%), pruritus (0.1%),
vulvomycotic infection (0.1%), hepatic enzyme increased (0.2%) and rash (0.2%). The most common
adverse reactions were headache (10%), diarrhoea (9%) and nausea (8%).
Adverse drug reactions identified during clinical trials and post-marketing experience with Doribax
are listed below by frequency category. Frequency categories are defined as follows: Very common
(≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Not known (cannot be
estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse drug reactions identified during clinical trials and post-marketing experience with Doribax
Infections and infestation
Common: oral candidiasis, vulvomycotic infection
Blood and lymphatic system disorders
Uncommon: thrombocytopenia, neutropenia
Immune system disorders
Uncommon: hypersensitivity reactions (see section 4.4)
Not known: anaphylaxis (see section 4.4)
Nervous system disorders
Very common: headache
Vascular disorders
Common: phlebitis
Gastrointestinal disorders
Common: nausea, diarrhoea
Uncommon:
C. difficile
colitis (see section 4.4)
Hepato-biliary disorders
Common: hepatic enzyme increased
Skin and subcutaneous tissue disorders
Common: pruritus, rash
Not known: toxic epidermal necrolysis, Stevens-Johnson
syndrome
In a Phase 1 study in healthy subjects receiving doripenem 2 g infused over 1 hour every 8 hours for
10 to 14 days, the incidence of rash was very common (5 of 8 subjects). The rash resolved within
10 days after doripenem administration was discontinued.
In the event of overdose, Doribax should be discontinued and general supportive treatment given until
renal elimination takes place. Doribaxcan be removed by haemodialysis (see section 5.2); however, no
information is available on the use of haemodialysis to treat overdose.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Carbapenems, ATC code: J01DH04.
Mechanism of action
Doripenem is a synthetic carbapenem antibacterial agent.
5
Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem
inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall
synthesis with subsequent cell death.
In vitro
doripenem showed little potential to antagonise or be antagonised by other antibacterial
agents. Additive activity or weak synergy with amikacin and levofloxacin has been seen for
Pseudomonas aeruginosa
and for gram-positive bacteria with daptomycin, linezolid, levofloxacin, and
vancomycin.
Pharmacokinetic/pharmacodynamic relationship
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of doripenem
exceeds the minimum inhibitory concentration (%T>MIC) of the infecting organism has been shown
to best correlate with efficacy in pre-clinical pharmacokinetic/pharmacodynamic (PK/PD) studies.
Monte Carlo simulations using pathogen susceptibility results from completed phase III trials and
population PK data indicated that the %T>MIC target of 35% was achieved in greater than 90% of
patients with nosocomial pneumonia, complicated urinary tract infections and complicated
intra-abdominal infections, for all degrees of renal function.
Extending the infusion time of Doribax to 4 hours maximises the % T>MIC for a given dose and is the
basis for the option to administer 4-hour infusions in patients with nosocomial pneumonia including
ventilator-associated pneumonia. In seriously ill patients or those with an impaired immune response,
a 4-hour infusion time may be more suitable when the MIC of doripenem for the known or suspected
pathogen(s) has been shown or is expected to be > 0.5 mg/l, in order to reach a target attainment of
50% T>MIC in at least 95% of the patients (see section 4.2). Monte Carlo simulations supported the
use of 500 mg 4-hour infusions every 8 hours in subjects with normal renal function for target
pathogens with doripenem MICs 4 mg/l.
Mechanisms of resistance
Bacterial resistance mechanisms that effect doripenem include active substance inactivation by
carbapenem-hydrolysing enzymes, mutant or acquired PBP’s, decreased outer membrane permeability
and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases
and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of
relatively rare carbapenem hydrolysing beta-lactamases. Species resistant to other carbapenems do
generally express co-resistance to doripenem
.
Methicillin-resistant staphylococci should always be
considered as resistant to doripenem. As with other antimicrobial agents, including carbapenems,
doripenem has been shown to select for resistant bacterial strains.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) are as follows:
Non species related
S 1 mg/l and R > 4 mg/l
Staphylococci
inferred from the methicillin breakpoint
Enterobacteriaceae
S 1 mg/l and R > 4 mg/l
Acinetobacter
spp.
S 1 mg/l and R > 4 mg/l
Pseudomonas
spp.
S 1 mg/l and R > 4 mg/l
Streptococcus
spp. other than
S. pneumoniae
S 1 mg/l and R > 1 mg/l
S. pneumoniae
S 1 mg/l and R > 1 mg/l
Enterococci
“inappropriate target”
Haemophilus
spp.
S 1 mg/l and R > 1 mg/l
N. gonorrhoeae
IE (insufficient evidence)
Anaerobes
S 1 mg/l and R > 1 mg/l
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. As necessary,
6
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.
Localised 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 doripenem or not.
Commonly Susceptible Species:
Gram Positive Aerobes
Enterococcus faecalis
*
$
Staphylococcus aureus
(methicillin susceptible strains only)*^
Staphylococcus
spp
.
(methicillin susceptible strains only)^
Streptococcus pneumoniae
*
Streptococcus
spp.
Gram Negative Aerobes
Citrobacter diversus
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
*
Haemophilus influenzae
*
Escherichia coli
*
Klebsiella pneumoniae
*
Klebsiella oxytoca
Morganella morganii
Proteus mirabilis
*
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Salmonella species
Serratia marcescens
Shigella species
Anaerobes
Bacteroides fragilis
*
Bacteroides caccae
*
Bacteroides ovatus
Bacteroides uniformis
*
Bacteroides thetaiotaomicron
*
Bacteroides vulgatus
*
Bilophila wadsworthia
Peptostreptococcus magnus
Peptostreptococcus micros
*
Porphyromonas spp.
Prevotella spp.
Sutterella wadsworthenis
Species for which acquired resistance may be a problem:
Acinetobacter baumannii
*
Acinetobacter spp.
Burkholderia cepacia$+
Pseudomanas aeruginosa
*
Inherently resistant organisms:
Gram Positive Aerobes
Enterococcus faecium
7
Gram Negative Aerobes
Stenotrophomonas maltophilia
Legionella spp.
*
species against which activity has been demonstrated in clinical studies
$
species that show natural intermediate susceptibility
species with > 50% acquired resistance in one or more Member State
^ all methicillin-resistant staphylococci should be regarded as resistant to doripenem
5.2 Pharmacokinetic properties
The mean C
max
and AUC
0-∞
of doripenem in healthy subjects across studies following administration
of 500 mg over 1 hour are approximately 23 g/ml and 36 g.h/ml, respectively. The mean C
max
and
AUC
0
-∞
of doripenem in healthy subjects across studies following administration of 500 mg and 1 g
over 4 hours are approximately 8 g/ml and 17 g/ml, and 34 g.h/ml and 68 g.h/ml, respectively.
There is no accumulation of doripenem following multiple intravenous infusions of either 500 mg or
1 g administered every 8 hours for 7 to 10 days in subjects with normal renal function.
Distribution
The average binding of doripenem to plasma proteins was approximately 8.1% and is independent of
plasma concentrations. The volume of distribution at steady state is approximately 16.8 l, similar to
extracellular fluid volume in man. Doripenem penetrates well into several body fluids and tissues,
such as uterine tissue, retroperitoneal fluid, prostatic tissue, gallbladder tissue and urine.
Metabolism
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite occurs primarily via
dehydropeptidase-I. Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated
metabolism.
In vitro
studies have determined that doripenem does not inhibit or induce the activities of
CYP isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 or 3A4.
Elimination
Doripenem is primarily eliminated unchanged by the kidneys. Mean plasma terminal elimination half-
life of doripenem in healthy young adults is approximately 1 hour and plasma clearance is
approximately 15.9 l/hour. Mean renal clearance is 10.3 l/hour. The magnitude of this value, coupled
with the significant decrease in the elimination of doripenem seen with concomitant probenecid
administration, suggests that doripenem undergoes glomerular filtration, tubular secretion and re-
absorption. In healthy young adults given a single 500 mg dose of Doribax, 71% and 15% of the dose
was recovered in urine as unchanged active substance and ring-opened metabolite, respectively.
Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy young
adults, less than 1% of the total radioactivity was recovered in faeces. The pharmacokinetics of
doripenem are linear over a dose range of 500 mg to 2 g when intravenously infused over 1 hour and
500 mg to 1 g when intravenously infused over 4 hours.
Renal insufficiency
Following a single 500 mg dose of Doribax, doripenem AUC increased 1.6-fold, 2.8-fold, and 5.1-fold
in subjects with mild (CrCl 51-79 ml/min), moderate (CrCl 31-50 ml/min), and severe renal
impairment (CrCl 30 ml/min), respectively, compared to age-matched healthy subjects with normal
renal function (CrCl > 80 ml/min). AUC of the microbiologically inactive ring-opened metabolite is
expected to be considerably increased in patients with severe renal impairment compared with healthy
subjects. Dose adjustment is necessary in patients with moderate and severe renal impairment (see
section 4.2).
AUCs of doripenem and of the microbiologically inactive ring-opened metabolite are substantially
increased in patients who require haemodialysis compared with healthy subjects. In a study where six
subjects with end stage renal disease on haemodialysis received a single dose of 500 mg doripenem by
i.v. infusion, the amount of doripenem removed during the four-hour haemodialysis session was
231 mg (46% of the dose).
8
+
Hepatic impairment
The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As
doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of Doribax are not
expected to be affected by hepatic impairment.
Elderly
The impact of age on the pharmacokinetics of doripenem was evaluated in healthy elderly male and
female subjects (66-84 years of age). Doripenem AUC increased 49% in elderly adults relative to
young adults. These changes were mainly attributed to age-related changes in renal function. No dose
adjustment is necessary in elderly patients, except in cases of moderate to severe renal insufficiency
(see section 4.2).
Gender
The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female
subjects. Doripenem AUC was 15% higher in females compared to males. No dose adjustment is
recommended based on gender.
Race
The effect of race on doripenem pharmacokinetics was examined through a population
pharmacokinetic analysis. No significant difference in mean doripenem clearance was observed across
race groups and therefore, no dose adjustment is recommended for race.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology and genotoxicity. However, because of the design of the repeat dose toxicity studies
and differences in pharmacokinetics in animals and humans, continuous exposure of animals was not
assured in these studies.
No reproductive toxicity was observed in studies performed in rats and rabbits. However, these studies
are of limited relevance because studies were performed with single daily dosing resulting in less than
one tenth of daily doripenem exposure duration in animals.
6.1 List of excipients
None
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.3.
6.3 Shelf life
3 years.
Storage of reconstituted solutions: Upon reconstitution with sterile water for injections or sodium
chloride 9 mg/ml (0.9%) solution for injection, Doribax suspension in the vial may be held for up to
1 hour below 30C prior to transfer and dilution in the infusion bag.
Following dilution in the infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or
dextrose 50 mg/ml (5%) solution for injection, Doribax infusions stored at room temperature or under
refrigeration should be completed according to the times in the following table:
9
Time by which reconstitution, dilution and infusion must be completed for Doribax infusion solutions
Infusion solution
Solution stored at
room temperature
Solution stored in a
refrigerator
(2C-8C)
sodium chloride 9 mg/ml (0.9%) solution for injection 12 hours
72 hours*
dextrose 50 mg/ml (5%) solution for injection 4 hours 24 hours*
*
Once removed from the refrigerator, infusions should be completed within the room temperature stability time,
provided the total refrigeration time, time to reach room temperature and infusion time does not exceed refrigeration
stability time.
+
Dextrose 50 mg/ml (5%) solution for injection should not be used for infusion durations greater than 1 hour.
Chemical and physical in-use stability has been demonstrated for the times and solutions shown in the
above table.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2C-8C, unless reconstitution/dilution has taken place
in controlled and validated aseptic conditions.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted medicinal product, and infusion solutions see section 6.3.
6.5 Nature and contents of container
Clear 20 ml Type I glass vial.
The medicinal product is supplied in cartons containing 10 vials.
6.6 Special precautions for disposal and other handling
Each vial is for single use only.
Doribax is reconstituted and then further diluted prior to infusion.
Preparation of 250 mg dose of solution for infusion using the 250 mg vial
1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection to the 250 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct
infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing
50 ml or 100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose
50 mg/ml (5%) solution for injection and mix to complete dissolution. Infuse all of this solution
to administer a 250 mg dose of doripenem.
Doribax solutions for infusion range from clear, colourless solutions to solutions that are clear and
slightly yellow. Variations in colour within this range do not affect the potency of the product.
Any unused product or waste material should be disposed of in accordance with local requirements.
10
+
Janssen-Cilag International NV
Turnhoutseweg, 30
B-2340 Beerse
Belgium
EU/1/08/467/002
Date of first authorisation: 25 July 2008
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
11
Doribax 500 mg powder for solution for infusion
Each vial contains doripenem monohydrate equivalent to 500 mg doripenem.
The medicinal product does not contain any excipients.
Powder for solution for infusion (Powder for infusion)
White to slightly yellowish off-white crystalline powder
Doribax is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1):
Nosocomial pneumonia (including ventilator–associated pneumonia)
Complicated intra-abdominal infections
Complicated urinary tract infections
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Posology
The recommended dose and administration by infection is shown in the following table:
Infection
Dose
Frequency Infusion time
Nosocomial pneumonia including
ventilator–associated pneumonia
500 mg every 8 hours 1 or 4 hours*
Complicated intra-abdominal infection 500 mg every 8 hours 1 hour
Complicated UTI, including pyelonephritis 500 mg every 8 hours 1 hour
*
Based mainly on PK/PD considerations, a 4-hour infusion time may be more suitable for infection with less
susceptible pathogens (see section 5.1). This dosing regimen should also be considered in particularly severe
infections.
For infusion solution shelf life see section 6.3.
The usual treatment duration of doripenem therapy is 5-14 days and should be guided by the severity,
site of the infection and the patient’s clinical response. Doripenem was given for up to 14 days in
clinical studies and the safety of longer durations of therapy has not been established. After
commencing treatment with intravenous doripenem, a switch to appropriate oral therapy to complete
the treatment course is possible once clinical improvement has been established.
Dose in paediatric patients
Doribax is not recommended for use in children below 18 years of age due to a lack of safety and
efficacy data.
Dose in patients with impaired renal function
In patients with mild renal impairment (i.e. creatinine clearance (CrCl) is 51-79 ml/min), no dose
adjustment is necessary. In patients with moderate renal impairment (CrCl 30-50 ml/min), the dose of
12
Doribax should be 250 mg every 8 hours (see section 6.6). In patients with severe renal impairment
(CrCl < 30 ml/min), the dose of Doribax should be 250 mg every 12 hours (see section 6.6). Due to
limited clinical data and an expected increased exposure of doripenem and its metabolite, Doribax
should be used with caution in patients with severe renal impairment (see section 5.2).
Dose in patients on dialysis
Doribax is haemodialysable; however, there is insufficient information to make dose adjustment
recommendationsin patients on dialysis. Therefore, Doribax is not recommended for patients on any
type of dialysis (see section 5.2).
Dose in elderly patients (
65 years of age)
No dose adjustment is necessary in elderly patients, except in cases of moderate to severe renal
impairment (see
Dose in patients with impaired renal function
above and section 5.2).
Dose in patients with impaired hepatic function
No dose adjustment is necessary.
Method for administration
Doribax is to be reconstituted and then further diluted (see section 6.6) prior to administration by
intravenous infusion over a period of one or four hours.
Hypersensitivity to the active substance
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 occurred in patients
receiving beta-lactam antibiotics. Before therapy with Doribax is started, careful inquiry should be
made concerning a previous history of hypersensitivity reactions to other active substances in this
class or to beta-lactam antibiotics. Doribax should be used with caution in patients with such a history.
Should a hypersensitivity reaction to Doribax occur, it should be discontinued immediately and
appropriate measures taken. Serious acute hypersensitivity (anaphylactic) reactions require immediate
emergency treatment.
Seizures have infrequently been reported during treatment with other carbapenems.
Pseudomembranous colitis due to
Clostridium difficile
has been reported with Doribax and may range
in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in
patients who present with diarrhoea during or subsequent to the administration of Doribax (see section
4.8).
Administration of doripenem, like other antibiotics, has been associated with emergence and selection
of strains with reduced susceptibility. Patients should be carefully monitored during therapy. If
superinfection occurs, appropriate measures should be taken. Prolonged use of Doribax should be
avoided.
The concomitant use of doripenem and valproic acid/sodium valproate is not recommended (see
section 4.5).
When Doribax was used investigationally
via
inhalation, pneumonitis occurred. Therefore, Doribax
should not be administered by this route.
Description of the patient population treated in clinical studies
13
In two clinical trials of patients with nosocomial pneumonia (N=979), 60% of the clinically-evaluable
Doribax-treated patients had ventilator-associated pneumonia (VAP). Of these, 50% had late-onset
VAP (defined as that occurring after five days of mechanical ventilation), 54% had an APACHE
(Acute Physiology And Chronic Health Evaluation) II score > 15 and 32% received concomitant
aminoglycosides (76% for more than 3 days).
In two clinical trials of patients with complicated intra-abdominal infections (N=962) the most
common anatomical site of infection in microbiologically-evaluable Doribax-treated patients was the
appendix (62%). Of these, 51% had generalised peritonitis at baseline. Other sources of infection
included colon perforation (20%), complicated cholecystitis (5%) and infections at other sites (14%).
Eleven percent had an APACHE II score of > 10, 9.5% had post-operative infections, 27% had single
or multiple intra-abdominal abscesses and 4% had concurrent bacteraemia at baseline.
In two clinical trials of patients with complicated urinary tract infections (N=1179), 52% of
microbiologically-evaluable Doribax-treated patients had complicated lower urinary tract infections
and 48% had pyelonephritis, of which 16% were complicated. Overall, 54% of patients had a
persistent complication, 9% had concurrent bacteraemia and 23% were infected with a levofloxacin
resistant uropathogen at baseline.
The experience in patients who are severely immunocompromised, receiving immunosuppressive
therapy, and patients with severe neutropenia is limited since this population was excluded from
phase III trials.
Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. Based on
in
vitro
studies it is not expected that doripenem will inhibit or induce the activities of CYP450.
Therefore, no CYP450-related drug interactions are to be expected (see section 5.2).
It has been shown that co-administration of doripenem and valproic acid significantly reduces serum
valproic acid levels below the therapeutic range. The lowered valproic acid levels can lead to
inadequate seizure control. In an interaction study, the serum concentrations of valproic acid were
markedly reduced (AUC was reduced by 63%) following co-administration of doripenem and valproic
acid. The interaction had a fast onset. Since patients were administered only four doses of doripenem,
a further decrease of valproic acid levels with longer concomitant administration cannot be excluded.
Decreases in valproic acid levels have also been reported when co-administered with other
carbapenem agents, achieving a 60-100% decrease in valproic acid levels in about two days. Therefore
alternative antibacterial or supplemental anticonvulsant therapies should be considered.
Probenecid competes with doripenem for renal tubular secretion and reduces the renal clearance of
doripenem. In an interaction study, the mean doripenem AUC increased by 75% following
co-administration with probenecid. Therefore, co-administration of probenecid with Doribax is not
recommended. An interaction with other medicinal products eliminated by renal tubular secretion
cannot be excluded.
For doripenem, limited clinical data on exposed pregnancies are available. Animal studies are
insufficient with respect to pregnancy, embryonal/foetal development, parturition or postnatal
development (see section 5.3). The potential risk for humans is unknown. Doribax should not be used
during pregnancy unless clearly necessary.
It is unknown whether doripenem is excreted in human breast milk. A study in rats has shown that
doripenem and its metabolite are transferred to milk. A decision on whether to continue/discontinue
breast-feeding or to continue/discontinue therapy with Doribax should be made taking into account the
benefit of breast-feeding to the child and the benefit of Doribax therapy to the woman.
14
No studies on the effects of Doribax on the ability to drive and use machines have been performed.
Based on reported adverse drug reactions, it is not anticipated that Doribax will affect the ability to
drive and use machines.
In 3,142 adult patients (1,817 of which received Doribax) evaluated for safety in phase II and phase III
clinical trials, adverse reactions due to Doribax 500 mg every 8 hours occurred at a rate of 32%.
Doribax was discontinued because of adverse drug reactions in 0.1% of patients overall. Adverse drug
reactions that led to Doribax discontinuation were nausea (0.1%), diarrhoea (0.1%), pruritus (0.1%),
vulvomycotic infection (0.1%), hepatic enzyme increased (0.2%) and rash (0.2%). The most common
adverse reactions were headache (10%), diarrhoea (9%) and nausea (8%).
Adverse drug reactions identified during clinical trials and post-marketing experience with Doribax
are listed below by frequency category. Frequency categories are defined as follows: Very common
(≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Not known (cannot be
estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse drug reactions identified during clinical trials and post-marketing experience with Doribax
Infections and infestation
Common: oral candidiasis, vulvomycotic infection
Blood and lymphatic system disorders
Uncommon: thrombocytopenia, neutropenia
Immune system disorders
Uncommon: hypersensitivity reactions (see section 4.4)
Not known: anaphylaxis (see section 4.4)
Nervous system disorders
Very common: headache
Vascular disorders
Common: phlebitis
Gastrointestinal disorders
Common: nausea, diarrhoea
Uncommon:
C. difficile
colitis (see section 4.4)
Hepato-biliary disorders
Common: hepatic enzyme increased
Skin and subcutaneous tissue disorders
Common: pruritus, rash
Not known: toxic epidermal necrolysis, Stevens-Johnson
syndrome
In a Phase 1 study in healthy subjects receiving doripenem 2 g infused over 1 hour every 8 hours for
10 to 14 days, the incidence of rash was very common (5 of 8 subjects). The rash resolved within
10 days after doripenem administration was discontinued.
In the event of overdose, Doribax should be discontinued and general supportive treatment given until
renal elimination takes place. Doribaxcan be removed by haemodialysis (see section 5.2); however, no
information is available on the use of haemodialysis to treat overdose.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Carbapenems, ATC code: J01DH04.
Mechanism of action
Doripenem is a synthetic carbapenem antibacterial agent.
15
Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem
inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall
synthesis with subsequent cell death.
In vitro
doripenem showed little potential to antagonise or be antagonised by other antibacterial
agents. Additive activity or weak synergy with amikacin and levofloxacin has been seen for
Pseudomonas aeruginosa
and for gram-positive bacteria with daptomycin, linezolid, levofloxacin, and
vancomycin.
Pharmacokinetic/pharmacodynamic relationship
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of doripenem
exceeds the minimum inhibitory concentration (%T>MIC) of the infecting organism has been shown
to best correlate with efficacy in pre-clinical pharmacokinetic/pharmacodynamic (PK/PD) studies.
Monte Carlo simulations using pathogen susceptibility results from completed phase III trials and
population PK data indicated that the %T>MIC target of 35% was achieved in greater than 90% of
patients with nosocomial pneumonia, complicated urinary tract infections and complicated
intra-abdominal infections, for all degrees of renal function.
Extending the infusion time of Doribax to 4 hours maximises the % T>MIC for a given dose and is the
basis for the option to administer 4-hour infusions in patients with nosocomial pneumonia including
ventilator-associated pneumonia. In seriously ill patients or those with an impaired immune response,
a 4-hour infusion time may be more suitable when the MIC of doripenem for the known or suspected
pathogen(s) has been shown or is expected to be > 0.5 mg/l, in order to reach a target attainment of
50% T>MIC in at least 95% of the patients (see section 4.2). Monte Carlo simulations supported the
use of 500 mg 4-hour infusions every 8 hours in subjects with normal renal function for target
pathogens with doripenem MICs 4 mg/l.
Mechanisms of resistance
Bacterial resistance mechanisms that effect doripenem include active substance inactivation by
carbapenem-hydrolysing enzymes, mutant or acquired PBP’s, decreased outer membrane permeability
and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases
and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of
relatively rare carbapenem hydrolysing beta-lactamases. Species resistant to other carbapenems do
generally express co-resistance to doripenem
.
Methicillin-resistant staphylococci should always be
considered as resistant to doripenem. As with other antimicrobial agents, including carbapenems,
doripenem has been shown to select for resistant bacterial strains.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) are as follows:
Non species related
S 1 mg/l and R > 4 mg/l
Staphylococci
inferred from the methicillin breakpoint
Enterobacteriaceae
S 1 mg/l and R > 4 mg/l
Acinetobacter
spp.
S 1 mg/l and R > 4 mg/l
Pseudomonas
spp.
S 1 mg/l and R > 4 mg/l
Streptococcus
spp. other than
S. pneumoniae
S 1 mg/l and R > 1 mg/l
S. pneumoniae
S 1 mg/l and R > 1 mg/l
Enterococci
“inappropriate target”
Haemophilus
spp.
S 1 mg/l and R > 1 mg/l
N. gonorrhoeae
IE (insufficient evidence)
Anaerobes
S 1 mg/l and R > 1 mg/l
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. As necessary,
16
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.
Localised 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 doripenem or not.
Commonly Susceptible Species:
Gram Positive Aerobes
Enterococcus faecalis
*
$
Staphylococcus aureus
(methicillin susceptible strains only)*^
Staphylococcus
spp
.
(methicillin susceptible strains only)^
Streptococcus pneumoniae
*
Streptococcus
spp.
Gram Negative Aerobes
Citrobacter diversus
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
*
Haemophilus influenzae
*
Escherichia coli
*
Klebsiella pneumoniae
*
Klebsiella oxytoca
Morganella morganii
Proteus mirabilis
*
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Salmonella
species
Serratia marcescens
Shigella
species
Anaerobes
Bacteroides fragilis
*
Bacteroides caccae
*
Bacteroides ovatus
Bacteroides uniformis
*
Bacteroides thetaiotaomicron
*
Bacteroides vulgatus
*
Bilophila wadsworthia
Peptostreptococcus magnus
Peptostreptococcus micros
*
Porphyromonas
spp.
Prevotella
spp.
Sutterella wadsworthenis
Species for which acquired resistance may be a problem:
Acinetobacter baumannii
*
Acinetobacter
spp.
Burkholderia cepacia
$+
Pseudomanas aeruginosa
*
Inherently resistant organisms:
Gram Positive Aerobes
Enterococcus faecium
17
Gram Negative Aerobes
Stenotrophomonas maltophilia
Legionella
spp
.
*
species against which activity has been demonstrated in clinical studies
$
species that show natural intermediate susceptibility
species with > 50% acquired resistance in one or more Member State
^ all methicillin-resistant staphylococci should be regarded as resistant to doripenem
5.2 Pharmacokinetic properties
The mean C
max
and AUC
0-∞
of doripenem in healthy subjects across studies following administration
of 500 mg over 1 hour are approximately 23 g/ml and 36 g.h/ml, respectively. The mean C
max
and
AUC
0
-∞
of doripenem in healthy subjects across studies following administration of 500 mg and 1 g
over 4 hours are approximately 8 g/ml and 17 g/ml, and 34 g.h/ml and 68 g.h/ml, respectively.
There is no accumulation of doripenem following multiple intravenous infusions of either 500 mg or
1 g administered every 8 hours for 7 to 10 days in subjects with normal renal function.
Distribution
The average binding of doripenem to plasma proteins was approximately 8.1% and is independent of
plasma concentrations. The volume of distribution at steady state is approximately 16.8 l, similar to
extracellular fluid volume in man. Doripenem penetrates well into several body fluids and tissues,
such as uterine tissue, retroperitoneal fluid, prostatic tissue, gallbladder tissue and urine.
Metabolism
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite occurs primarily via
dehydropeptidase-I. Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated
metabolism.
In vitro
studies have determined that doripenem does not inhibit or induce the activities of
CYP isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 or 3A4.
Elimination
Doripenem is primarily eliminated unchanged by the kidneys. Mean plasma terminal elimination half-
life of doripenem in healthy young adults is approximately 1 hour and plasma clearance is
approximately 15.9 l/hour. Mean renal clearance is 10.3 l/hour. The magnitude of this value, coupled
with the significant decrease in the elimination of doripenem seen with concomitant probenecid
administration, suggests that doripenem undergoes glomerular filtration, tubular secretion and re-
absorption. In healthy young adults given a single 500 mg dose of Doribax, 71% and 15% of the dose
was recovered in urine as unchanged active substance and ring-opened metabolite, respectively.
Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy young
adults, less than 1% of the total radioactivity was recovered in faeces. The pharmacokinetics of
doripenem are linear over a dose range of 500 mg to 2 g when intravenously infused over 1 hour and
500 mg to 1 g when intravenously infused over 4 hours.
Renal insufficiency
Following a single 500 mg dose of Doribax, doripenem AUC increased 1.6-fold, 2.8-fold, and 5.1-fold
in subjects with mild (CrCl 51-79 ml/min), moderate (CrCl 31-50 ml/min), and severe renal
impairment (CrCl 30 ml/min), respectively, compared to age-matched healthy subjects with normal
renal function (CrCl > 80 ml/min). AUC of the microbiologically inactive ring-opened metabolite is
expected to be considerably increased in patients with severe renal impairment compared with healthy
subjects. Dose adjustment is necessary in patients with moderate and severe renal impairment (see
section 4.2).
AUCs of doripenem and of the microbiologically inactive ring-opened metabolite are substantially
increased in patients who require haemodialysis compared with healthy subjects. In a study where six
subjects with end stage renal disease on haemodialysis received a single dose of 500 mg doripenem by
i.v. infusion, the amount of doripenem removed during the four-hour haemodialysis session was
231 mg (46% of the dose).
18
+
Hepatic impairment
The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As
doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of Doribax are not
expected to be affected by hepatic impairment.
Elderly
The impact of age on the pharmacokinetics of doripenem was evaluated in healthy elderly male and
female subjects (66-84 years of age). Doripenem AUC increased 49% in elderly adults relative to
young adults. These changes were mainly attributed to age-related changes in renal function. No dose
adjustment is necessary in elderly patients, except in cases of moderate to severe renal insufficiency
(see section 4.2).
Gender
The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female
subjects. Doripenem AUC was 15% higher in females compared to males. No dose adjustment is
recommended based on gender.
Race
The effect of race on doripenem pharmacokinetics was examined through a population
pharmacokinetic analysis. No significant difference in mean doripenem clearance was observed across
race groups and therefore, no dose adjustment is recommended for race.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology and genotoxicity. However, because of the design of the repeat dose toxicity studies
and differences in pharmacokinetics in animals and humans, continuous exposure of animals was not
assured in these studies.
No reproductive toxicity was observed in studies performed in rats and rabbits. However, these studies
are of limited relevance because studies were performed with single daily dosing resulting in less than
one tenth of daily doripenem exposure duration in animals.
6.1 List of excipients
None
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.3.
6.3 Shelf life
3 years.
Storage of reconstituted solutions: Upon reconstitution with sterile water for injections or sodium
chloride 9 mg/ml (0.9%) solution for injection, Doribax suspension in the vial may be held for up to
1 hour below 30C prior to transfer and dilution in the infusion bag.
Following dilution in the infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or
dextrose 50 mg/ml (5%) solution for injection, Doribax infusions stored at room temperature or under
refrigeration should be completed according to the times in the following table:
19
Time by which reconstitution, dilution and infusion must be completed for Doribax infusion solutions
Infusion solution
Solution stored at
room temperature
Solution stored in a
refrigerator
(2C-8C)
sodium chloride 9 mg/ml (0.9%) solution for injection 12 hours
72 hours*
dextrose 50 mg/ml (5%) solution for injection 4 hours 24 hours*
*
Once removed from the refrigerator, infusions should be completed within the room temperature stability time,
provided the total refrigeration time, time to reach room temperature and infusion time does not exceed refrigeration
stability time.
+
Dextrose 50 mg/ml (5%) solution for injection should not be used for infusion durations greater than 1 hour.
Chemical and physical in-use stability has been demonstrated for the times and solutions shown in the
above table.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2C-8C, unless reconstitution/dilution has taken place
in controlled and validated aseptic conditions.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted medicinal product, and infusion solutions see section 6.3.
6.5 Nature and contents of container
Clear 20 ml Type I glass vial.
The medicinal product is supplied in cartons containing 10 vials.
6.6 Special precautions for disposal and other handling
Each vial is for single use only.
Doribax is reconstituted and then further diluted prior to infusion.
Preparation of 500 mg dose of solution for infusion using the 500 mg vial
1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection to the 500 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct
infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing
100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml
(5%) solution for injection and mix to complete dissolution. Infuse all of this solution to
administer a 500 mg dose of doripenem.
Preparation of 250 mg dose of solution for infusion using the 500 mg vial
1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection to the 500 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct
infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing
100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml
(5%) solution for injection and mix to complete dissolution.
20
+
4. Remove 55 ml of this solution from the infusion bag and discard. Infuse all of the remaining
solution to administer a 250 mg dose of doripenem.
Doribax solutions for infusion range from clear, colourless solutions to solutions that are clear and
slightly yellow. Variations in colour within this range do not affect the potency of the product.
Any unused product or waste material should be disposed of in accordance with local requirements.
Janssen-Cilag International NV
Turnhoutseweg, 30
B-2340 Beerse
Belgium
EU/1/08/467/001
Date of first authorisation: 25 July 2008
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
21
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
22
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Janssen Pharmaceutica N.V.
Turnhoutseweg 30
B-2340 Beerse
Belgium
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 6.0 (dated
28 May 2010) presented in Module 1.8.1. of the Marketing Authorisation, 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 3 (dated 30 November 2009) of the Risk
Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation 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, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
23
ANNEX III
LABELLING AND PACKAGE LEAFLET
24
A. LABELLING
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
Doribax 250 mg powder for solution for infusion
doripenem
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains doripenem monohydrate equivalent to 250 mg doripenem
3. LIST OF EXCIPIENTS
10 vials
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Intravenous use
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7. OTHER SPECIAL WARNING(S), IF NECESSARY
For single use only
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
26
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Janssen Cilag International N.V.
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/08/467/002
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not using Braille accepted
27
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL
Doribax 250 mg powder for infusion
doripenem
2. STATEMENT OF ACTIVE SUBSTANCE
Each vial contains doripenem monohydrate equivalent to 250 mg doripenem
3. LIST OF EXCIPIENTS
250 mg
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7. OTHER SPECIAL WARNING (S) IF NECESSARY
For single use only
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
28
Janssen Cilag International N.V.
Turnhoutseweg 30
B-2340 Beerse
Belgium
12. MARKETING AUTHORISATION NUMBER (S)
EU/1/08/467/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION ON BRAILLE
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
Doribax 500 mg powder for solution for infusion
doripenem
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains doripenem monohydrate equivalent to 500 mg doripenem
3. LIST OF EXCIPIENTS
10 vials
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Intravenous use
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7. OTHER SPECIAL WARNING(S), IF NECESSARY
For single use only
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
30
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Janssen Cilag International N.V.
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/08/467/001
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not using Braille accepted
31
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL
Doribax 500 mg powder for infusion
doripenem
2. STATEMENT OF ACTIVE SUBSTANCE
Each vial contains doripenem monohydrate equivalent to 500 mg doripenem
3. LIST OF EXCIPIENTS
500 mg
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7. OTHER SPECIAL WARNING (S) IF NECESSARY
For single use only
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
32
Janssen Cilag International N.V.
Turnhoutseweg 30
B-2340 Beerse
Belgium
12. MARKETING AUTHORISATION NUMBER (S)
EU/1/08/467/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION ON BRAILLE
33
B. PACKAGE LEAFLET
34
PACKAGE LEAFLET: INFORMATION FOR THE USER
Doribax 250 mg powder for solution for infusion
doripenem
Read all of this leaflet carefully before you start taking this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Doribax is and what it is used for
2. Before you use Doribax
3. How to use Doribax
4. Possible side effects
5. How to store Doribax
6. Further information
1. WHAT DORIBAX IS AND WHAT IT IS USED FOR
Doribax is an antibiotic. Doribax works by killing different types of bacteria (germs) that cause
infections in various parts of the body.
Doribax is used for the following infections:
- Pneumonia (a serious type of chest or lung infection) that you catch in a hospital or similar
setting. This includes pneumonia that you catch when on a machine that helps you breathe.
- Complicated infections of the area around your stomach (abdominal infections).
- Complicated urinary tract infections, including kidney infections and cases that have spread to
the bloodstream.
2. BEFORE YOU USE DORIBAX
Do not use Doribax
- If you are allergic (hypersensitive) to doripenem.
- If you are allergic to other antibiotics such as penicillins, cephalosporins or carbapenems (which
are used to treat various infections) as you may also be allergic to Doribax.
Do not use Doribax if any of the above applies to you. If you are not sure, talk to your doctor or
pharmacist before being given Doribax.
Take special care with Doribax
If you have:
- Kidney problems. Your doctor may need to lower your dose of Doribax.
- Diarrhoea. It is important that you tell your doctor if you have bloody diarrhoea before, during
or after your treatment with Doribax. This is because you may have a condition known as colitis
(an inflammation of the bowel).
Do not take any medicine to treat diarrhoea without first
checking with your doctor.
Convulsions have infrequently been reported during treatment with closely related antibiotics.
While antibiotics including Doribax kill certain bacteria, other bacteria and fungi may continue to
grow more than normal. This is called overgrowth. Your doctor will monitor you for overgrowth and
treat you if necessary.
35
Tell your doctor if you are taking medicines called valproic acid or sodium valproate (see
Taking other
medicines
below).
Doribax should not be inhaled as it may cause inflammation of the lung (pneumonitis).
Doribax should not be given to children or adolescents (under 18 years of age) as there is not enough
information to be sure that Doribax can be used safely in children or adolescents.
Taking other medicines
Always tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
This includes medicines you get without a prescription or herbal medicines. Tell your doctor if you are
taking medicines called valproic acid or sodium valproate (used to treat epilepsy, bipolar disorder,
migraines or schizophrenia) or probenecid (used to treat gout or high levels of uric acid in the blood).
Your doctor will decide whether you should use Doribax in combination with these other medicines.
Pregnancy and breast-feeding
Tell your doctor or pharmacist before using Doribax if:
- You are pregnant or think you may be pregnant. Your doctor will decide whether you should
use Doribax.
- You are breast-feeding or if you plan to breast-feed. Small amounts of this medicine may pass
into breast milk and it may affect the baby. Therefore, your doctor will decide whether you
should use Doribax while breast-feeding.
Driving and using machines
Doribax is not likely to affect your ability to drive or operate machinery.
3. HOW TO USE DORIBAX
How Doribax is given
- Doribax will be prepared and given to you by a doctor or nurse over one or four hours as an
intravenous infusion into one of your veins (this is sometimes known as a “drip”).
How much Doribax is given
- Your doctor will decide how much Doribax you need and for how long.
Adults (including people over 65 years of age)
- The usual dose is 500 mg every eight hours. Each dose is given over a period of one or four
hours.
- The course usually lasts 5 to 14 days.
- If you have kidney problems, your doctor may lower your dose of Doribax to 250 mg given over
one or four hours every eight or 12 hours.
If you use more Doribax than you should
If you are concerned that you may have been given too much Doribax, talk to your doctor or
pharmacist straight away.
If a Doribax dose has been missed
If you are concerned that you may have missed a dose of Doribax, talk to your doctor or pharmacist
straight away. It is important that you receive treatment with Doribax as long as your doctor feels it is
necessary.
If you have any further questions on the use of Doribax, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
36
Like all medicines, Doribax 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).
Very common
- Headache
Common
- Rash, itching or hives
- Diarrhoea. Tell your doctor straight away if you get bloody diarrhoea before, during or after
your treatment with Doribax.
- Feeling sick (nausea)
- Vein wall inflammation where the intravenous infusion (or “drip”) goes into your vein
(phlebitis)
- Fungal infections (thrush) in your mouth or vagina
- Increase in the level of some liver enzymes in your blood.
Uncommon
- Inflammation of the bowel with diarrhoea (
Clostridium difficile
colitis)
- Decrease of blood platelet count
- Decrease of white blood cells which may increase your risk of infections
- Sudden swelling of your lips, face, throat or tongue, a rash, swallowing or breathing problems.
These may be signs of a severe allergic reaction (anaphylaxis) and may be life-threatening.
Tell
your doctor straight away if you get these as you may need urgent medical treatment.
The following side effects were also seen in a small number of patients
- Serious skin reactions, with a widespread rash with peeling skin and blisters in the mouth, eyes
and genitals (toxic epidermal necrolysis or Stevens-Johnson syndrome).
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 DORIBAX
Keep out of the reach and sight of children.
Do not use this medicine after the expiry date stated on the container. The first two numbers indicate
the month. The next four numbers indicate the year. The expiry date refers to the last day of that
month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of
via
wastewater or household waste. These measures will help to
protect the environment.
6. FURTHER INFORMATION
What Doribax contains
37
- The active substance is doripenem. Each vial contains doripenem monohydrate equivalent to
250 mg doripenem.
What Doribax looks like and contents of the pack
Doribax is a white to slightly yellowish off-white crystalline powder in a glass vial. Doribax is
supplied in packs of 10 vials.
Marketing Authorisation Holder
Janssen Pharmaceutica
Turnhoutseweg 30
Turnhoutseweg 30
B-2340 Beerse
B-2340 Beerse
Belgium
Belgium
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
JANSSEN-CILAG N.V./S.A.
Tél/Tel: + 32 3 280 54 11
Luxembourg/Luxemburg
JANSSEN-CILAG N.V./S.A.
België/Belgique/Belgien
Tél/Tel: +32 3 280 54 11
България
Johnson & Johnson D. O. O.
Teл.: +359 2 489 94 00
Magyarország
JANSSEN-CILAG Kft.
Tel.: +36 23 513-800
Česká republika
JANSSEN-CILAG s.r.o.
Tel: +420 227 012 222
Malta
AM MANGION LTD
Tel: +356 2397 6000
Danmark
JANSSEN-CILAG A/S
Tlf: +45 45 94 82 82
Nederland
JANSSEN-CILAG B.V.
Tel: +31 13 583 73 73
Deutschland
JANSSEN-CILAG GmbH
Tel: +49 2137-955-955
Norge
JANSSEN-CILAG AS
Tlf: + 47 24 12 65 00
Eesti
Janssen-Cilag Polska Sp. z o.o. Eesti filiaal
Tel: + 372 617 7410
Österreich
JANSSEN-CILAG
Tel: +43 1 610 300
Ελλάδα
JANSSEN-CILAG Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 809 0000
Polska
JANSSEN–CILAG Polska Sp. z o.o.
Tel.: + 48 22 237 60 00
España
JANSSEN-CILAG, S.A.
Tel: +34 91 722 81 00
Portugal
JANSSEN-CILAG FARMACEUTICA, LDA
Tel: +351 21-4368835
France
JANSSEN-CILAG
Tel: 0800 25 50 75/+ 33 1 55 00 44 44
România
Johnson&Johnson d.o.o.
Rep.Office Janssen-Cilag
.
Tel: +4 021 2071800
38
Janssen-Cilag International NV
Manufacturer
Ireland
JANSSEN-CILAG Ltd.
Tel: +44 (0)1494 567567
Slovenija
Johnson & Johnson d.o.o.
Tel: + 386 1 401 18 30
Ísland
JANSSEN-CILAG, c/o Vistor Hf
Sími: +354 535 7000
Slovenská republika
JANSSEN-CILAG, a Johnson&Johnson
company
Tel: +421 233 552 600
Italia
JANSSEN-CILAG SpA
Tel: +39 02/2510.1
Suomi/Finland
JANSSEN-CILAG OY
Puh/Tel: +358 207 531 300
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Tηλ: +357 22 755 214
Sverige
JANSSEN-CILAG AB
Tel: +46 8 626 50 00
Latvija
Janssen-Cilag Polska Sp. z o.o. filiāle Latvijā
Tel: +371 678 93561
United Kingdom
JANSSEN-CILAG Ltd.
Tel: +44 (0)1494 567567
Lietuva
UAB „Johnson & Johnson“
Tel: +370 5 278 68 88
This leaflet was last approved in MM/YYYY
Detailed information on this medicine is available on the European Medicines Agency website:
---------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only
Each vial is for single use only.
Doribax is reconstituted and then further diluted prior to infusion.
Preparation of 250 mg dose of solution for infusion using the 250 mg vial
1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection to the 250 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct
infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing
50 ml or 100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose
50 mg/ml (5%) solution for injection and mix to complete dissolution. Infuse all of this solution
to administer a 250 mg dose of doripenem.
Doribax solutions for infusion range from clear, colourless solutions to solutions that are clear and
slightly yellow. Variations in colour within this range do not affect the potency of the product.
Storage of reconstituted solutions
Upon reconstitution with sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection, Doribax suspension in the vial may be held for up to 1 hour below 30C prior to transfer and
dilution in the infusion bag.
39
Following dilution in the infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or
dextrose 50 mg/ml (5%) solution for injection, Doribax infusions stored at room temperature or under
refrigeration should be completed according to the times in the following table:
Time by which reconstitution, dilution and infusion must be completed for Doribax infusions
solutions
Infusion solution
Solution stored at
room temperature
Solution stored in a
refrigerator
(2C-8C)
sodium chloride 9 mg/ml (0.9%) solution for injection 12 hours
72 hours*
dextrose 50 mg/ml (5%) solution for injection 4 hours 24 hours*
*
Once removed from the refrigerator, infusions should be completed within the room temperature stability time,
provided the total refrigeration time, time to reach room temperature and infusion time does not exceed refrigeration
stability time.
+
Dextrose 50 mg/ml (5%) solution for injection should not be used for infusion durations greater than 1 hour.
Chemical and physical in-use stability has been demonstrated for the times and solutions shown in the
above table.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2C-8C, unless reconstitution/dilution has taken place
in controlled and validated aseptic conditions.
Any unused product or waste material should be disposed of in accordance with local requirements.
40
+
PACKAGE LEAFLET: INFORMATION FOR THE USER
Doribax 500 mg powder for solution for infusion
doripenem
Read all of this leaflet carefully before you start taking this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Doribax is and what it is used for
2. Before you use Doribax
3. How to use Doribax
4. Possible side effects
5. How to store Doribax
6. Further information
1. WHAT DORIBAX IS AND WHAT IT IS USED FOR
Doribax is an antibiotic. Doribax works by killing different types of bacteria (germs) that cause
infections in various parts of the body.
Doribax is used for the following infections:
- Pneumonia (a serious type of chest or lung infection) that you catch in a hospital or similar
setting. This includes pneumonia that you catch when on a machine that helps you breathe.
- Complicated infections of the area around your stomach (abdominal infections).
- Complicated urinary tract infections, including kidney infections and cases that have spread to
the bloodstream.
2. BEFORE YOU USE DORIBAX
Do not use Doribax
- If you are allergic (hypersensitive) to doripenem.
- If you are allergic to other antibiotics such as penicillins, cephalosporins or carbapenems (which
are used to treat various infections) as you may also be allergic to Doribax.
Do not use Doribax if any of the above applies to you. If you are not sure, talk to your doctor or
pharmacist before being given Doribax.
Take special care with Doribax
If you have:
- Kidney problems. Your doctor may need to lower your dose of Doribax.
- Diarrhoea. It is important that you tell your doctor if you have bloody diarrhoea before, during
or after your treatment with Doribax. This is because you may have a condition known as colitis
(an inflammation of the bowel).
Do not take any medicine to treat diarrhoea without first
checking with your doctor.
Convulsions have infrequently been reported during treatment with closely related antibiotics.
While antibiotics including Doribax kill certain bacteria, other bacteria and fungi may continue to
grow more than normal. This is called overgrowth. Your doctor will monitor you for overgrowth and
treat you if necessary.
41
Tell your doctor if you are taking medicines called valproic acid or sodium valproate (see
Taking other
medicines
below).
Doribax should not be inhaled as it may cause inflammation of the lung (pneumonitis).
Doribax should not be given to children or adolescents (under 18 years of age) as there is not enough
information to be sure that Doribax can be used safely in children or adolescents.
Taking other medicines
Always tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
This includes medicines you get without a prescription or herbal medicines. Tell your doctor if you are
taking medicines called valproic acid or sodium valproate (used to treat epilepsy, bipolar disorder,
migraines or schizophrenia) or probenecid (used to treat gout or high levels of uric acid in the blood).
Your doctor will decide whether you should use Doribax in combination with these other medicines.
Pregnancy and breast-feeding
Tell your doctor or pharmacist before using Doribax if:
- You are pregnant or think you may be pregnant. Your doctor will decide whether you should
use Doribax.
- You are breast-feeding or if you plan to breast-feed. Small amounts of this medicine may pass
into breast milk and it may affect the baby. Therefore, your doctor will decide whether you
should use Doribax while breast-feeding.
Driving and using machines
Doribax is not likely to affect your ability to drive or operate machinery.
3. HOW TO USE DORIBAX
How Doribax is given
- Doribax will be prepared and given to you by a doctor or nurse over one or four hours as an
intravenous infusion into one of your veins (this is sometimes known as a “drip”).
How much Doribax is given
- Your doctor will decide how much Doribax you need and for how long.
Adults (including people over 65 years of age)
- The usual dose is 500 mg every eight hours. Each dose is given over a period of one or four
hours.
- The course usually lasts 5 to 14 days.
- If you have kidney problems, your doctor may lower your dose of Doribax to 250 mg given over
one or four hours every eight or 12 hours.
If you use more Doribax than you should
If you are concerned that you may have been given too much Doribax, talk to your doctor or
pharmacist straight away.
If a Doribax dose has been missed
If you are concerned that you may have missed a dose of Doribax, talk to your doctor or pharmacist
straight away. It is important that you receive treatment with Doribax as long as your doctor feels it is
necessary.
If you have any further questions on the use of Doribax, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
42
Like all medicines, Doribax 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).
Very common
- Headache
Common
- Rash, itching or hives
- Diarrhoea. Tell your doctor straight away if you get bloody diarrhoea before, during or after
your treatment with Doribax.
- Feeling sick (nausea)
- Vein wall inflammation where the intravenous infusion (or “drip”) goes into your vein
(phlebitis)
- Fungal infections (thrush) in your mouth or vagina
- Increase in the level of some liver enzymes in your blood.
Uncommon
- Inflammation of the bowel with diarrhoea (
Clostridium difficile
colitis)
- Decrease of blood platelet count
- Decrease of white blood cells which may increase your risk of infections
- Sudden swelling of your lips, face, throat or tongue, a rash, swallowing or breathing problems.
These may be signs of a severe allergic reaction (anaphylaxis) and may be life-threatening.
Tell
your doctor straight away if you get these as you may need urgent medical treatment.
The following side effects were also seen in a small number of patients
- Serious skin reactions, with a widespread rash with peeling skin and blisters in the mouth, eyes
and genitals (toxic epidermal necrolysis or Stevens-Johnson syndrome).
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 DORIBAX
Keep out of the reach and sight of children.
Do not use this medicine after the expiry date stated on the container. The first two numbers indicate
the month. The next four numbers indicate the year. The expiry date refers to the last day of that
month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of
via
wastewater or household waste. These measures will help to
protect the environment.
6. FURTHER INFORMATION
What Doribax contains
43
- The active substance is doripenem. Each vial contains doripenem monohydrate equivalent to
500 mg doripenem.
What Doribax looks like and contents of the pack
Doribax is a white to slightly yellowish off-white crystalline powder in a glass vial. Doribax is
supplied in packs of 10 vials.
Marketing Authorisation Holder
Janssen Pharmaceutica
Turnhoutseweg 30
Turnhoutseweg 30
B-2340 Beerse
B-2340 Beerse
Belgium
Belgium
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
JANSSEN-CILAG N.V./S.A.
Tél/Tel: + 32 3 280 54 11
Luxembourg/Luxemburg
JANSSEN-CILAG N.V./S.A.
België/Belgique/Belgien
Tél/Tel: +32 3 280 54 11
България
Johnson & Johnson D. O. O.
Teл.: +359 2 489 94 00
Magyarország
JANSSEN-CILAG Kft.
Tel.: +36 23 513-800
Česká republika
JANSSEN-CILAG s.r.o.
Tel: +420 227 012 222
Malta
AM MANGION LTD
Tel: +356 2397 6000
Danmark
JANSSEN-CILAG A/S
Tlf: +45 45 94 82 82
Nederland
JANSSEN-CILAG B.V.
Tel: +31 13 583 73 73
Deutschland
JANSSEN-CILAG GmbH
Tel: +49 2137-955-955
Norge
JANSSEN-CILAG AS
Tlf: + 47 24 12 65 00
Eesti
Janssen-Cilag Polska Sp. z o.o. Eesti filiaal
Tel: + 372 617 7410
Österreich
JANSSEN-CILAG
Tel: +43 1 610 300
Ελλάδα
JANSSEN-CILAG Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 809 0000
Polska
JANSSEN–CILAG Polska Sp. z o.o.
Tel.: + 48 22 237 60 00
España
JANSSEN-CILAG, S.A.
Tel: +34 91 722 81 00
Portugal
JANSSEN-CILAG FARMACEUTICA, LDA
Tel: +351 21-4368835
France
JANSSEN-CILAG
Tel: 0800 25 50 75/+ 33 1 55 00 44 44
România
Johnson&Johnson d.o.o.
Rep.Office Janssen-Cilag
.
Tel: +4 021 2071800
44
Janssen-Cilag International NV
Manufacturer
Ireland
JANSSEN-CILAG Ltd.
Tel: +44 (0)1494 567567
Slovenija
Johnson & Johnson d.o.o.
Tel: + 386 1 401 18 30
Ísland
JANSSEN-CILAG, c/o Vistor Hf
Sími: +354 535 7000
Slovenská republika
JANSSEN-CILAG, a Johnson&Johnson
company
Tel: +421 233 552 600
Italia
JANSSEN-CILAG SpA
Tel: +39 02/2510.1
Suomi/Finland
JANSSEN-CILAG OY
Puh/Tel: +358 207 531 300
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Tηλ: +357 22 755 214
Sverige
JANSSEN-CILAG AB
Tel: +46 8 626 50 00
Latvija
Janssen-Cilag Polska Sp. z o.o. filiāle Latvijā
Tel: +371 678 93561
United Kingdom
JANSSEN-CILAG Ltd.
Tel: +44 (0)1494 567567
Lietuva
UAB „Johnson & Johnson“
Tel: +370 5 278 68 88
This leaflet was last approved in MM/YYYY
Detailed information on this medicine is available on the European Medicines Agency website:
---------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only
Each vial is for single use only.
Doribax is reconstituted and then further diluted prior to infusion.
Preparation of 500 mg dose of solution for infusion using the 500 mg vial
1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection to the 500 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct
infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing
100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml
(5%) solution for injection and mix to complete dissolution. Infuse all of this solution to
administer a 500 mg dose of doripenem.
Preparation of 250 mg dose of solution for infusion using the 500 mg vial
1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection to the 500 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct
infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing
100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml
(5%) solution for injection and mix to complete dissolution.
45
4. Remove 55 ml of this solution from the infusion bag and discard. Infuse all of the remaining
solution to administer a 250 mg dose of doripenem.
Doribax solutions for infusion range from clear, colourless solutions to solutions that are clear and
slightly yellow. Variations in colour within this range do not affect the potency of the product.
Storage of reconstituted solutions
Upon reconstitution with sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for
injection, Doribax suspension in the vial may be held for up to 1 hour below 30C prior to transfer and
dilution in the infusion bag.
Following dilution in the infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or
dextrose 50 mg/ml (5%) solution for injection, Doribax infusions stored at room temperature or under
refrigeration should be completed according to the times in the following table:
Time by which reconstitution, dilution and infusion must be completed for Doribax infusions
solutions
Infusion solution
Solution stored at
room temperature
Solution stored in a
refrigerator
(2C-8C)
sodium chloride 9 mg/ml (0.9%) solution for injection 12 hours
72 hours*
dextrose 50 mg/ml (5%) solution for injection 4 hours 24 hours*
*
Once removed from the refrigerator, infusions should be completed within the room temperature stability time,
provided the total refrigeration time, time to reach room temperature and infusion time does not exceed refrigeration
stability time.
+
Dextrose 50 mg/ml (5%) solution for injection should not be used for infusion durations greater than 1 hour.
Chemical and physical in-use stability has been demonstrated for the times and solutions shown in the
above table.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2C-8C, unless reconstitution/dilution has taken place
in controlled and validated aseptic conditions.
Any unused product or waste material should be disposed of in accordance with local requirements.
46
+
Source: European Medicines Agency
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