INVANZ 1g powder for concentrate infusion solution medication leaflet

INVANZ 1 g powder for concentrate for solution for infusion

Each vial contains 1.0 g ertapenem.

Each 1.0 g dose contains approximately 6.0 mEq of sodium (approximately 137 mg).

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white powder.

INVANZ is indicated in paediatric patients (3 months to 17 years of age) and in adults for thetreatment of the following infections when caused by bacteria known or very likely to be susceptibleto ertapenem and when parenteral therapy is required (see sections 4.4 and 5.1):

- Intra-abdominal infections

- Community acquired pneumonia

- Acute gynaecological infections

- Diabetic foot infections of the skin and soft tissue (see section 4.4)

INVANZ is indicated in adults for the prophylaxis of surgical site infection following electivecolorectal surgery (see section 4.4).

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 dayby the intravenous route (see section 6.6).

Infants and children (3 months to 12 years of age): The dose of INVANZ is 15 mg/kg given twicedaily (not to exceed 1 g/day) by the intravenous route (see section 6.6).

Adults: To prevent surgical site infections following elective colorectal surgery, the recommendeddosage is 1 g administered as a single intravenous dose to be completed within 1 hour prior to thesurgical incision.

The safety and efficacy of INVANZ in children below 3 months of age have not yet been established.

No data are available.

INVANZ may be used for the treatment of infections in adult patients with mild to moderate renalimpairment. In patients whose creatinine clearance is  30 mL/min/1.73 m2, no dosage adjustment isnecessary. There are inadequate data on the safety and efficacy of ertapenem in patients with severerenal impairment to support a dose recommendation. Therefore, ertapenem should not be used in thesepatients (see section 5.2.). There are no data in children and adolescents with renal impairment.

There are inadequate data on the safety and efficacy of ertapenem in patients on haemodialysis tosupport a dose recommendation. Therefore, ertapenem should not be used in these patients.

No dosage adjustment is recommended in patients with impaired hepatic function (see section 5.2).

The recommended dose of INVANZ should be administered, except in cases of severe renalimpairment (see Renal impairment).

Intravenous administration: INVANZ should be infused over a period of 30 minutes.

The usual duration of therapy with INVANZ is 3 to 14 days but may vary depending on the type andseverity of infection and causative pathogen(s). When clinically indicated, a switch to an appropriateoral antibacterial agent may be implemented if clinical improvement has been observed.

For instructions on preparation of the medicinal product before administration, see section 6.6.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Hypersensitivity to any other carbapenem antibacterial agent

- Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any other type ofbeta-lactam antibacterial agent (e.g., penicillins or cephalosporins).

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patientsreceiving therapy with beta-lactams. These reactions are more likely to occur in individuals with ahistory of sensitivity to multiple allergens. Before initiating therapy with ertapenem, careful inquiryshould be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, otherbeta-lactams and other allergens (see section 4.3). If an allergic reaction to ertapenem occurs (seesection 4.8), discontinue the therapy immediately. Serious anaphylactic reactions requireimmediate emergency treatment.

Prolonged use of ertapenem may result in overgrowth of non-susceptible organisms. Repeatedevaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriatemeasures should be taken.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with ertapenem andmay range in severity from mild to life-threatening. Therefore, it is important to consider thisdiagnosis in patients who present with diarrhoea subsequent to the administration of antibacterialagents. Discontinuation of therapy with INVANZ and the administration of specific treatment for

Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not begiven.

Seizures have been reported during clinical investigation in adult patients treated with ertapenem (1 gonce a day) during therapy or in the 14-day follow-up period. Seizures occurred most commonly inelderly patients and those with pre-existing central nervous system (CNS) disorders (e.g. brain lesionsor history of seizures) and/or compromised renal function. Similar observations have been made in thepost-marketing environment.

Encephalopathy has been reported with the use of ertapenem (see section 4.8). If ertapenem-inducedencephalopathy is suspected (e.g. myoclonus, seizures, altered mental status, depressed level ofconsciousness), discontinuation of ertapenem should be considered. Patients with renal impairment areat higher risk of ertapenem-induced encephalopathy and the resolution may be prolonged.

The concomitant use of ertapenem and valproic acid/sodium valproate is not recommended (seesection 4.5).

Based on the data available it cannot be excluded that in the few cases of surgical interventionsexceeding 4 hours, patients could be exposed to sub-optimal ertapenem concentrations andconsequently to a risk of potential treatment failure. Therefore, caution should be exercised in suchunusual cases.

Experience in the use of ertapenem in the treatment of severe infections is limited. In clinical studiesfor the treatment of community-acquired pneumonia, in adults, 25 % of evaluable patients treated withertapenem had severe disease (defined as pneumonia severity index > III). In a clinical study for thetreatment of acute gynaecologic infections, in adults, 26 % of evaluable patients treated withertapenem had severe disease (defined as temperature ≥ 39°C and/or bacteraemia); ten patients hadbacteraemia. Of evaluable patients treated with ertapenem in a clinical study for the treatment ofintra-abdominal infections, in adults, 30 % had generalised peritonitis and 39 % had infectionsinvolving sites other than the appendix including the stomach, duodenum, small bowel, colon, andgallbladder; there were limited numbers of evaluable patients who were enrolled with APACHE IIscores ≥ 15 and efficacy in these patients has not been established.

The efficacy of INVANZ in the treatment of community acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae has not been established.

Efficacy of ertapenem in the treatment of diabetic foot infections with concurrent osteomyelitis has notbeen established.

There is relatively little experience with ertapenem in children less than two years of age. In this agegroup, particular care should be taken to establish the susceptibility of the infecting organism(s) toertapenem. No data are available in children under 3 months of age.

This medicinal product contains approximately 137 mg sodium per 1.0 g dose, equivalent to 6.85 % ofthe WHO recommended maximum daily intake of 2 g sodium for an adult.

Interactions caused by inhibition of P-glycoprotein-mediated clearance or CYP-mediated clearance ofmedicinal products are unlikely (see section 5.2).

Decreases in valproic acid levels that may fall below the therapeutic range have been reported whenvalproic acid was co-administered with carbapenem agents. The lowered valproic acid levels can leadto inadequate seizure control; therefore, concomitant use of ertapenem and valproic acid/sodiumvalproate is not recommended and alternative antibacterial or anti-convulsant therapies should beconsidered.

Adequate and well-controlled studies have not been performed in pregnant women. Animal studies donot 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 pregnancyunless 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.

There are no adequate and well-controlled studies regarding the effect of ertapenem use on fertility inmen and women. Preclinical studies do not indicate direct or indirect harmful effects with respect tofertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed.

INVANZ may influence patients' ability to drive and use machines. Patients should be informed thatdizziness and somnolence have been reported with INVANZ (see section 4.8).

The total number of patients treated with ertapenem in clinical studies was over 2,200 of which over2,150 received a 1 g dose of ertapenem. Adverse reactions (i.e., considered by the investigator to bepossibly, probably, or definitely related to the medicinal product) were reported in approximately20 % 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 aclinical study for the prophylaxis of surgical site infections following colorectal surgery.

For patients who received only INVANZ, the most common adverse reactions reported during therapyplus follow-up for 14 days after treatment was stopped were: diarrhoea (4.8 %), infused veincomplication (4.5 %) and nausea (2.8 %).

For patients who received only INVANZ, the most frequently reported laboratory abnormalities andtheir respective incidence rates during therapy plus follow-up for 14 days after treatment was stoppedwere: elevations in ALT (4.6 %), AST (4.6 %), alkaline phosphatase (3.8 %) and platelet count(3.0 %).

The total number of patients treated with ertapenem in clinical studies was 384. The overall safetyprofile is comparable to that in adult patients. Adverse reactions (i.e., considered by the investigator tobe possibly, probably, or definitely related to the medicinal product) were reported in approximately20.8 % of patients treated with ertapenem. Treatment was discontinued due to adverse reactions in0.5 % of patients.

For patients who received only INVANZ, the most common adverse reactions reported during therapyplus 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 andtheir respective incidence rates during therapy plus follow-up for 14 days after treatment was stoppedwere: 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 duringtherapy 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); Not known (cannot be estimated from the available data)

Adults 18 years of age and older Children and adolescents(3 months to 17 years of age)

Infections and infestations Uncommon: Oral candidiasis,candidiasis, fungal infection,pseudomembranous enterocolitis,vaginitis

Rare: Pneumonia,dermatomycosis, postoperativewound infection, urinary tractinfection

Blood and lymphatic system Rare: Neutropenia,disorders thrombocytopenia

Immune system disorders Rare: Allergy

Not known: Anaphylaxisincluding anaphylactoid reactions

Metabolism and nutrition Uncommon: Anorexiadisorders Rare: Hypoglycaemia

Psychiatric disorders Uncommon: Insomnia, confusion Not known: Altered mental

Rare: Agitation, anxiety, status (including aggression)depression

Not known: Altered mental status(including aggression, delirium,disorientation, mental statuschanges)

Adults 18 years of age and older Children and adolescents(3 months to 17 years of age)

Nervous system disorders Common: Headache Uncommon: Headache

Uncommon: Dizziness, Not known: Hallucinationssomnolence, taste perversion,seizure (see section 4.4)

Rare: Tremor, syncope

Not known: Hallucinations,depressed level of consciousness,dyskinesia, myoclonus, gaitdisturbance, encephalopathy (seesection 4.4)

Eye disorders Rare: Scleral disorder

Cardiac disorders Uncommon: Sinus bradycardia

Rare: Arrhythmia, tachycardia

Vascular disorders Common: Infused vein Uncommon: Hot flush,complication, hypertensionphlebitis/thrombophlebitis

Uncommon: Hypotension

Rare: Haemorrhage, increasedblood pressure

Respiratory, thoracic and Uncommon: Dyspnoea,mediastinal disorders pharyngeal discomfort

Rare: Nasal congestion, cough,epistaxis, rales/rhonchi, wheezing

Gastrointestinal disorders Common: Diarrhoea, nausea, Common: Diarrhoeavomiting Uncommon: Faeces

Uncommon: Constipation, acid discoloured, melaenaregurgitation, dry mouth,dyspepsia, abdominal pain

Rare: Dysphagia, faecalincontinence, pelvic peritonitis

Not known: teeth staining

Hepatobiliary disorders Rare: Cholecystitis, jaundice, liverdisorder

Skin and subcutaneous tissue Common: Rash, pruritus Common: Diaper dermatitisdisorders Uncommon: Erythema, urticaria Uncommon: Erythema, rash,

Rare: Dermatitis, desquamation, petechiaehypersensitivity vasculitis

Not known: Acute Generalised

Exanthematous Pustulosis(AGEP), Drug Rash with

Eosinophilia and Systemic

Symptoms (DRESS syndrome)

Musculoskeletal and Rare: Muscle cramp, shoulderconnective tissue disorders pain

Not known: Muscular weakness

Renal and urinary disorders Rare: Renal insufficiency, acuterenal insufficiency

Pregnancy, puerperium and Rare: Abortionperinatal conditions

Reproductive system and Rare: Genital bleedingbreast disorders

Adults 18 years of age and older Children and adolescents(3 months to 17 years of age)

General disorders and Uncommon: Extravasation, Common: Infusion site painadministration site conditions asthenia/fatigue, fever, Uncommon: Infusion siteoedema/swelling, chest pain burning, infusion site pruritus,

Rare: Injection-site induration, infusion site erythema,malaise injection site erythema,infusion site warmth

Chemistry Common: Elevations in ALT, Common: Elevations in ALT

AST, alkaline phosphatase and AST

Uncommon: Increases in totalserum bilirubin, direct serumbilirubin, indirect serum bilirubin,serum creatinine, serum urea,serum glucose

Rare: Decreases in serumbicarbonate, serum creatinine, andserum potassium; increases inserum LDH, serum phosphorus,serum potassium

Haematology Common: Elevation in platelet Common: Decreases incount neutrophil count

Uncommon: Decreases in white Uncommon: Increases inblood cells, platelet count, platelet count, activatedsegmented neutrophils, partial thromboplastin time,haemoglobin and haematocrit; prothrombin time, decreasesincreases in eosinophils, activated in haemoglobinpartial thromboplastin time,prothrombin time, segmentedneutrophils, and white blood cells

Rare: Decrease in lymphocytes;increases in band neutrophils,lymphocytes, metamyelocytes,monocytes, myelocytes; atypicallymphocytes

Urinalysis Uncommon: Increases in urinebacteria, urine white blood cells,urine epithelial cells, and urine redblood cells; urine yeast present

Rare: Increase in urobilinogen

Miscellaneous Uncommon: Positive

Clostridioides difficile toxin

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific information is available on the treatment of overdose with ertapenem. Overdosing ofertapenem is unlikely. Intravenous administration of ertapenem at a 3 g daily dose for 8 days tohealthy adult volunteers did not result in significant toxicity. In clinical studies in adults inadvertentadministration of up to 3 g in a day did not result in clinically important adverse reactions. Inpaediatric clinical studies, a single intravenous (IV) dose of 40 mg/kg up to a maximum of 2 g did notresult in toxicity.

However, in the event of an overdose, treatment with INVANZ should be discontinued and generalsupportive treatment given until renal elimination takes place.

Ertapenem can be removed to some extent by haemodialysis (see section 5.2); however, noinformation is available on the use of haemodialysis to treat overdose.

General properties

Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems, ATC code: J01DH03

Ertapenem inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins(PBPs). In Escherichia coli, affinity is strongest to PBPs 2 and 3.

Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of ertapenemexceeds the MIC of the infecting organism has been shown to best correlate with efficacy inpre-clinical PK/PD studies.

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 seenin 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, butnot metallo-beta-lactamases.

Methicillin-resistant staphylococci and enterococci are resistant to ertapenem, owing to PBP targetinsensitivity; P. aeruginosa and other non-fermentative bacteria are generally resistant, probablyowing to limited penetration and to active efflux.

Resistance is uncommon in Enterobacteriaceae and ertapenem is generally active against those withextended-spectrum beta-lactamases (ESBLs). Resistance can however be observed when ESBLs orother 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 canalso arise via the acquisition of beta-lactamases 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 asquinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based cross-resistancebetween ertapenem and these substances. However, micro-organisms may exhibit resistance to morethan one class of antibacterial agents when the mechanism is, or includes, impermeability to somecompounds and/or an efflux pump.

The EUCAST MIC breakpoints are as follows:

- Enterobacterales: 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

- M. catarrhalis: S ≤ 0.5 mg/L and R > 0.5 mg/L

- Gram negative anaerobes: S ≤ 0.5 mg/L and R > 0.5 mg/L

- Gram positive anaerobes: S ≤ 0.5 mg/L and R > 0.5 mg/L

- Viridans group streptococci: S ≤ 0.5 mg/L and R > 0.5 mg/L

- Non species related breakpoints: S ≤ 0.5 mg/L and R > 0.5 mg/L(NB: Susceptibility of staphylococci to ertapenem is inferred from methicillin susceptibility andsusceptibility of group A, B, C,& G streptococci is inferred from benzylpenicillin susceptibility)

The prescribers are informed that local MIC breakpoints, if available, should be consulted.

The prevalence of acquired resistance may vary geographically and with time for selected species andlocal information on resistance is desirable, particularly when treating severe infections. Localisedclusters 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 themicro-organism will be susceptible to ertapenem or not.

Methicillin-susceptible-staphylococci (including Staphylococcus aureus)*

Streptococcus agalactiae*

Streptococcus pneumoniae*†

Streptococcus pyogenes

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

Clostridium species (excluding C. difficile)*

Eubacterium species*

Fusobacterium species*

Peptostreptococcus species*

Porphyromonas asaccharolytica*

Prevotella species*

Methicillin-resistant staphylococci +#

Bacteroides fragilis and species in the B. fragilis Group*

Corynebacterium jeikeium

Enterococci including Enterococcus faecalis and Enterococcus faecium

Aeromonas species

Acinetobacter species

Burkholderia cepacia

Pseudomonas aeruginosa

Stenotrophomonas maltophilia

Lactobacillus species

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 beta-lactams.

Efficacy in Paediatric Studies

Ertapenem was evaluated primarily for paediatric safety and secondarily for efficacy in randomisedcomparative, multicentre studies in patients 3 months to 17 years of age.

The proportion of patients with a favourable clinical response assessment at posttreatment visit in theclinical MITT population is shown below:

Ertapenem Ceftriaxone

Disease Stratum† Age Stratum n/m % n/m %

Community Acquired 3 to 23 months 31/35 88.6 13/13 100.0

Pneumonia (CAP)2 to 12 years 55/57 96.5 16/17 94.113 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 77.813 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 bacteraemia at entry intothe study.

Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a1 g dose in healthy young adults (25 to 45 years of age) were 155 micrograms/mL (Cmax) at 0.5 hourpostdose (end of infusion), 9 micrograms/mL at 12 hour postdose, and 1 microgram/mL at 24 hourpostdose.

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 from0.5 to 2 g daily.

Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a15 mg/kg (up to a maximum dose of 1 g) dose in patients 3 to 23 months of age were103.8 micrograms/mL (Cmax) at 0.5 hour postdose (end of infusion), 13.5 micrograms/mL at 6 hourpostdose, and 2.5 micrograms/mL at 12 hour postdose.

Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a15 mg/kg (up to a maximum dose of 1 g) dose in patients 2 to 12 years of age were113.2 micrograms/mL (Cmax) at 0.5 hour postdose (end of infusion), 12.8 micrograms/mL at 6 hourpostdose, and 3.0 micrograms/mL at 12 hour postdose.

Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a20 mg/kg (up to a maximum dose of 1 g) dose in patients 13 to 17 years of age were170.4 micrograms/mL (Cmax) at 0.5 hour postdose (end of infusion), 7.0 micrograms/mL at 12 hourpostdose, and 1.1 microgram/mL at 24 hour postdose.

Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a1 g dose in three patients 13 to 17 years of age were 155.9 micrograms/mL (Cmax) at 0.5 hour postdose(end of infusion), and 6.2 micrograms/mL at 12 hour postdose.

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 approximately95 % bound at an approximate plasma concentration of < 50 micrograms/mL to approximately 92 %bound at an approximate plasma concentration of 155 micrograms/mL (average concentrationachieved at the end of infusion following 1 g intravenously).

The volume of distribution (Vdss) of ertapenem in adults is approximately 8 litres (0.11 litre/kg) andapproximately 0.2 litre/kg in paediatric patients 3 months to 12 years of age and approximately0.16 litre/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 thirdday of 1 g once daily intravenous doses showed a ratio of AUC in skin blister fluid: AUC in plasmaof 0.61.

In vitro studies indicate that the effect of ertapenem on the plasma protein binding of highly proteinbound medicinal products (warfarin, ethinyl estradiol, and norethindrone) was small. The change inbinding 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 insubjects 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 toertapenem displacing another medicinal product or another medicinal product displacing ertapenem isunlikely.

In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxinor vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.

In healthy young adults (23 to 49 years of age), after intravenous infusion of radiolabelled 1 gertapenem, the plasma radioactivity consists predominantly (94 %) of ertapenem. The majormetabolite of ertapenem is the ring-opened derivative formed by dehydropeptidase-I-mediatedhydrolysis of the beta-lactam ring.

In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolismmediated by any of the six major CYP isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.

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.

In healthy young adults (18 to 49 years of age) and patients 13 to 17 years of age given a 1 gintravenous dose, the mean plasma half-life is approximately 4 hours. The mean plasma half-life inchildren 3 months to 12 years of age is approximately 2.5 hours. Average concentrations of ertapenemin urine exceed 984 micrograms/mL during the period 0 to 2 hours postdose and exceed52 micrograms/mL during the period 12 to 24 hours post-administration.

The plasma concentrations of ertapenem are comparable in men and women.

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 youngadults ( 65 years). In the absence of severe renal impairment, no dosage adjustment is necessary inelderly patients.

Plasma concentrations of ertapenem are comparable in paediatric patients 13 to 17 years of age andadults 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 inpatients 13 to 17 years of age were generally comparable to those in healthy young adults. To providean estimate of the pharmacokinetic data if all patients in this age group were to receive a 1 g dose, thepharmacokinetic data were calculated adjusting for a 1 g dose, assuming linearity. A comparison ofresults show that a 1 g once daily dose of ertapenem achieves a pharmacokinetic profile in patients13 to 17 years of age comparable to that of adults. The ratios (13 to 17 years/adults) for AUC, the endof 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 intravenousdose of ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations atthe midpoint of the dosing interval following a 1 g once daily intravenous dose in adults (see Plasmaconcentrations). The plasma clearance (mL/min/kg) of ertapenem in patients 3 months to 12 years ofage is approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC valueand plasma concentrations at the midpoint of the dosing interval in patients 3 months to 12 years ofage were comparable to those in young healthy adults receiving a 1 g intravenous dose of ertapenem.

The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established.

Due to the limited extent of hepatic metabolism of ertapenem, its pharmacokinetics are not expected tobe affected by hepatic impairment. Therefore, no dosage adjustment is recommended in patients withhepatic impairment.

Following a single 1 g intravenous dose of ertapenem in adults, AUCs of total ertapenem (bound andunbound) and of unbound ertapenem are similar in patients with mild renal impairment (Clcr 60 to90 mL/min/1.73 m2) compared with healthy subjects (ages 25 to 82 years). AUCs of total ertapenemand of unbound ertapenem are increased in patients with moderate renal impairment (Clcr 31 to59 mL/min/1.73 m2) approximately 1.5-fold and 1.8-fold, respectively, compared with healthysubjects. AUCs of total ertapenem and of unbound ertapenem are increased in patients with severerenal impairment (Clcr 5 to 30 mL/min/1.73 m2) approximately 2.6-fold and 3.4-fold, respectively,compared with healthy subjects. AUCs of total ertapenem and of unbound ertapenem are increased inpatients who require haemodialysis approximately 2.9-fold and 6.0-fold, respectively, between dialysissessions, compared with healthy subjects. Following a single 1 g intravenous dose given immediatelyprior to a haemodialysis session, approximately 30 % of the dose is recovered in the dialysate. Thereare no data in paediatric patients with renal impairment.

There are inadequate data on the safety and efficacy of ertapenem in patients with advanced renalimpairment and patients who require haemodialysis to support a dose recommendation. Therefore,ertapenem should not be used in these patients.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety,pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Decreased neutrophil counts, however, occurred in rats that received high doses of ertapenem, whichwas not considered a significant safety issue.

Long-term studies in animals to evaluate the carcinogenic potential of ertapenem have not beenperformed.

Sodium bicarbonate (E500)

Sodium hydroxide (E524) to adjust pH to 7.5

Do not use solvents or infusion fluids containing dextrose for reconstitution or administration ofertapenem.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

2 years.

After reconstitution: Diluted solutions should be used immediately. If not used immediately, in usestorage times are the responsibility of the user. Diluted solutions (approximately 20 mg/mLertapenem) are physically and chemically stable for 6 hours at room temperature (25°C) or for24 hours at 2 to 8°C (in a refrigerator). Solutions should be used within 4 hours of their removal fromthe refrigerator. Do not freeze solutions of INVANZ.

Do not store above 25°C.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

15 mL Type I glass vials with a grey butyl stopper and a white plastic cap on a coloured aluminiumband seal.

Supplied in packs of 1 vial or 10 vials.

Not all pack sizes may be marketed.

For single use only.

Reconstituted solutions should be diluted in sodium chloride 9 mg/mL (0.9 %) solution immediatelyafter preparation.

INVANZ must be reconstituted and then diluted prior to administration.

Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of water for injection or sodiumchloride 9 mg/mL (0.9 %) solution to yield a reconstituted solution of approximately 100 mg/mL.

Shake well to dissolve. (See section 6.4.)

For a 50 mL bag of diluent: For a 1 g dose, immediately transfer contents of the reconstituted vial to a50 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 chloride9 mg/mL (0.9 %) solution and discard. Transfer the contents of the reconstituted 1 g vial of INVANZto the 50 mL vial of sodium chloride 9 mg/mL (0.9 %) solution.

Infusion

Infuse over a period of 30 minutes.

Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of water for injection or sodiumchloride 9 mg/mL (0.9 %) solution to yield a reconstituted solution of approximately 100 mg/mL.

Shake well to dissolve. (See section 6.4.)

For a bag of diluent: Transfer a volume equal to 15 mg/kg of body weight (not to exceed 1 g/day) to abag 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 avial of sodium chloride 9 mg/mL (0.9 %) solution for a final concentration of 20 mg/mL or less.

Infusion

Infuse over a period of 30 minutes.

Compatibility of INVANZ with intravenous solutions containing heparin sodium and potassiumchloride has been demonstrated.

The reconstituted solutions should be inspected visually for particulate matter and discolouration priorto administration, whenever the container permits. Solutions of INVANZ range from colourless topale 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.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/02/216/001

EU/1/02/216/002

Date of first authorisation: 18 April 2002

Date of latest renewal: 22 December 2011

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.