INVANZ Powder for concentrate for solution for infusion Ref.[8101] Active ingredients: Ertapenem

Hypersensitivity

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

Superinfection

Prolonged use of ertapenem may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Antibiotic-associated colitis

Antibiotic-associated colitis and pseudomembranous colitis have been reported with ertapenem and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents. Discontinuation of therapy with INVANZ and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Seizures

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

Concomitant use with valproic acid

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

Sub-optimal exposure

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

Excipient

This medicinal product contains approximately 6.0 mEq (approximately 137 mg) of sodium per 1.0 g dose which should be taken into consideration by patients on a controlled sodium diet.

Considerations for use in particular populations

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

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 not been established.

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

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

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

Pregnancy

Adequate and well-controlled studies have not been performed in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development, parturition or post-natal development. However, ertapenem should not be used during pregnancy unless the potential benefit outweighs the possible risk to the foetus.

Breast-feeding

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.

Fertility

There are no adequate and well-controlled studies regarding the effect of ertapenem use on fertility in men and women. Preclinical studies do not indicate direct or indirect harmful effects with respect to fertility (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 that dizziness and somnolence have been reported with INVANZ (see section 4.8).

Summary of the safety profile

Adults

The total number of patients treated with ertapenem in clinical studies was over 2,200 of which over 2,150 received a 1 g dose of ertapenem. Adverse reactions (i.e., considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported in approximately 20% of patients treated with ertapenem. Treatment was discontinued due to adverse reactions in 1.3% of patients. An additional 476 patients received ertapenem as a single 1 g dose prior to surgery in a clinical study for the prophylaxis of surgical site infections following colorectal surgery.

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

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

Paediatric population (3 months to 17 years of age)

The total number of patients treated with ertapenem in clinical studies was 384. The overall safety profile is comparable to that in adult patients. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported in approximately 20.8% of patients treated with ertapenem. Treatment was discontinued due to adverse reactions in 0.5% of patients.

For patients who received only INVANZ, the most common adverse reactions reported during therapy plus follow-up for 14 days after treatment was stopped were: diarrhoea (5.2%) and infusion site pain (6.1%).

For patients who received only INVANZ, the most frequently reported laboratory abnormalities and their respective incidence rates during therapy plus follow-up for 14 days after treatment was stopped were: decreases in neutrophil count (3.0%), and elevations in ALT (2.9%) and AST (2.8%).

Tabulated list of adverse reactions

For patients who received only INVANZ, the following adverse reactions were reported during therapy plus follow-up for 14 days after treatment was stopped:

Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

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