ertapenem: prescribing information – dosing, contraindications, interactions, side effects

Treatment
INVANZ is indicated in paediatric patients (3 months to 17 years of age) and in adults for the treatment of the following infections when caused by bacteria known or very likely to be susceptible to ertapenem and when parenteral therapy is required (see 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)
Prevention
INVANZ is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery (see section 4.4).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology
Treatment
Adults and adolescents (13 to 17 years of age): The dose of INVANZ is 1 gram (g) given once a day by the intravenous route (see section 6.6).
Infants and children (3 months to 12 years of age): The dose of INVANZ is 15 mg/kg given twice daily (not to exceed 1 g/day) by the intravenous route (see section 6.6).

Prevention
Adults: To prevent surgical site infections following elective colorectal surgery, the recommended dosage is 1 g administered as a single intravenous dose to be completed within 1 hour prior to the surgical incision.
Paediatric population
The safety and efficacy of INVANZ in children below 3 months of age have not yet been established.
No data are available.
Renal impairment
INVANZ may be used for the treatment of infections in adult patients with mild to moderate renal impairment. In patients whose creatinine clearance is  30 mL/min/1.73 m2, no dosage adjustment is necessary. There are inadequate data on the safety and efficacy of ertapenem in patients with severe renal impairment to support a dose recommendation. Therefore, ertapenem should not be used in these patients (see section 5.2.). There are no data in children and adolescents with renal impairment.
Haemodialysis
There are inadequate data on the safety and efficacy of ertapenem in patients on haemodialysis to support a dose recommendation. Therefore, ertapenem should not be used in these patients.
Hepatic impairment
No dosage adjustment is recommended in patients with impaired hepatic function (see section 5.2).
Elderly
The recommended dose of INVANZ should be administered, except in cases of severe renal impairment (see Renal impairment).
Method of administration
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 and severity of infection and causative pathogen(s). When clinically indicated, a switch to an appropriate oral antibacterial agent may be implemented if clinical improvement has been observed.
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 of beta-lactam antibacterial agent (e.g., penicillins or cephalosporins).

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)

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, postoperative wound infection, urinary tract infection Blood and lymphatic system disorders Rare: Neutropenia, thrombocytopenia Immune system disorders Rare: Allergy Not known: Anaphylaxis including anaphylactoid reactions Metabolism and nutrition disorders Uncommon: Anorexia Rare: Hypoglycaemia Psychiatric disorders Uncommon: Insomnia, confusion Rare: Agitation, anxiety, depression Not known: Altered mental status (including aggression, delirium, disorientation, mental status changes) Not known: Altered mental status (including aggression)

Adults 18 years of age and older
Children and adolescents
(3 months to 17 years of age)
Nervous system disorders
Common: Headache
Uncommon: Dizziness, somnolence, taste perversion, seizure (see section 4.4)
Rare: Tremor, syncope
Not known: Hallucinations, depressed level of consciousness, dyskinesia, myoclonus, gait disturbance, encephalopathy (see section 4.4) Uncommon: Headache Not known: Hallucinations Eye disorders Rare: Scleral disorder

Cardiac disorders
Uncommon: Sinus bradycardia
Rare: Arrhythmia, tachycardia

Vascular disorders
Common: Infused vein complication, phlebitis/thrombophlebitis
Uncommon: Hypotension
Rare: Haemorrhage, increased blood pressure
Uncommon: Hot flush, hypertension
Respiratory, thoracic and mediastinal disorders
Uncommon: Dyspnoea, pharyngeal discomfort
Rare: Nasal congestion, cough, epistaxis, rales/rhonchi, wheezing

Gastrointestinal disorders
Common: Diarrhoea, nausea, vomiting
Uncommon: Constipation, acid regurgitation, dry mouth, dyspepsia, abdominal pain Rare: Dysphagia, faecal incontinence, pelvic peritonitis Not known: Teeth staining Common: Diarrhoea Uncommon: Faeces discoloured, melaena Hepatobiliary disorders Rare: Cholecystitis, jaundice, liver disorder

Skin and subcutaneous tissue disorders
Common: Rash, pruritus
Uncommon: Erythema, urticaria
Rare: Dermatitis, desquamation, hypersensitivity vasculitis
Not known: Acute Generalised
Exanthematous Pustulosis
(AGEP), Drug Rash with
Eosinophilia and Systemic
Symptoms (DRESS syndrome)
Common: Diaper dermatitis
Uncommon: Erythema, rash, petechiae
Musculoskeletal and connective tissue disorders
Rare: Muscle cramp, shoulder pain
Not known: Muscular weakness

Renal and urinary disorders

Rare: Renal insufficiency, acute renal insufficiency

Pregnancy, puerperium and perinatal conditions
Rare: Abortion

Reproductive system and breast disorders
Rare: Genital bleeding

Adults 18 years of age and older
Children and adolescents
(3 months to 17 years of age)
General disorders and administration site conditions
Uncommon: Extravasation, asthenia/fatigue, fever, oedema/swelling, chest pain
Rare: Injection-site induration, malaise
Common: Infusion site pain
Uncommon: Infusion site burning, infusion site pruritus, infusion site erythema, injection site erythema, infusion site warmth Investigations

Chemistry
Common: Elevations in ALT,
AST, alkaline phosphatase
Uncommon: Increases in total serum bilirubin, direct serum bilirubin, indirect serum bilirubin, serum creatinine, serum urea, serum glucose Rare: Decreases in serum bicarbonate, serum creatinine, and serum potassium; increases in serum LDH, serum phosphorus, serum potassium Common: Elevations in ALT and AST Haematology Common: Elevation in platelet count Uncommon: Decreases in white blood cells, platelet count, segmented neutrophils, haemoglobin and haematocrit;
increases in eosinophils, activated partial thromboplastin time, prothrombin time, segmented neutrophils, and white blood cells Rare: Decrease in lymphocytes;
increases in band neutrophils, lymphocytes, metamyelocytes, monocytes, myelocytes; atypical lymphocytes Common: Decreases in neutrophil count Uncommon: Increases in platelet count, activated partial thromboplastin time, prothrombin time, decreases in haemoglobin Urinalysis Uncommon: Increases in urine bacteria, urine white blood cells, urine epithelial cells, and urine red blood cells; urine yeast present Rare: Increase in urobilinogen Miscellaneous Uncommon: Positive Clostridioides difficile toxin 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.

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

Sodium
This medicinal product contains approximately 137 mg sodium per 1.0 g dose, equivalent to 6.85 % of the 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 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).

No specific information is available on the treatment of overdose with ertapenem. Overdosing of ertapenem is unlikely. Intravenous administration of ertapenem at a 3 g daily dose for 8 days to healthy adult volunteers did not result in significant toxicity. In clinical studies in adults, inadvertent administration of up to 3 g in a day did not result in clinically important adverse reactions. In paediatric clinical studies, a single intravenous (IV) dose of 40 mg/kg up to a maximum of 2 g did not result in toxicity.
However, in the event of an overdose, treatment with INVANZ should be discontinued and general supportive treatment given until renal elimination takes place.
Ertapenem can be removed to some extent by haemodialysis (see section 5.2); however, no information is available on the use of haemodialysis to treat overdose.
5.
PHARMACOLOGICAL PROPERTIES

General properties
Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems, ATC code: J01DH03 Mechanism of action Ertapenem inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). In Escherichia coli, affinity is strongest to PBPs 2 and 3.
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of ertapenem exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in pre-clinical PK/PD studies.
Mechanism of resistance
For species considered susceptible to ertapenem, resistance was uncommon in surveillance studies in Europe. In resistant isolates, resistance to other antibacterial agents of the carbapenem class was seen in some but not all isolates. Ertapenem is effectively stable to hydrolysis by most classes of beta- lactamases, including penicillinases, cephalosporinases and extended spectrum beta-lactamases, but not metallo-beta-lactamases.
Methicillin-resistant staphylococci and enterococci are resistant to ertapenem, owing to PBP target insensitivity; P. aeruginosa and other non-fermentative bacteria are generally resistant, probably owing to limited penetration and to active efflux.
Resistance is uncommon in Enterobacteriaceae and ertapenem is generally active against those with extended-spectrum beta-lactamases (ESBLs). Resistance can however be observed when ESBLs or other potent beta-lactamases (e.g., AmpC types) are present in conjunction with reduced permeability, arising by the loss of one or more outer membrane porins, or with up-regulated efflux. Resistance can also arise via the acquisition of 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 as quinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based cross-resistance between ertapenem and these substances. However, micro-organisms may exhibit resistance to more than one class of antibacterial agents when the mechanism is, or includes, impermeability to some compounds and/or an efflux pump.

Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for ertapenem and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory- concentration-mic-breakpoints_en.xlsx The prescribers are informed that local MIC breakpoints, if available, should be consulted.
Microbiological susceptibility

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

Area under the plasma concentration curve (AUC) of ertapenem in adults increases nearly dose- proportionally over the 0.5 to 2 g dose range.
There is no accumulation of ertapenem in adults following multiple intravenous doses ranging from 0.5 to 2 g daily.
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a 15 mg/kg (up to a maximum dose of 1 g) dose in patients 3 to 23 months of age were 103.8 micrograms/mL (Cmax) at 0.5 hours postdose (end of infusion), 13.5 micrograms/mL at 6 hours postdose, and 2.5 micrograms/mL at 12 hours postdose.
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a 15 mg/kg (up to a maximum dose of 1 g) dose in patients 2 to 12 years of age were 113.2 micrograms/mL (Cmax) at 0.5 hours postdose (end of infusion), 12.8 micrograms/mL at 6 hours postdose, and 3.0 micrograms/mL at 12 hours postdose.
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a 20 mg/kg (up to a maximum dose of 1 g) dose in patients 13 to 17 years of age were 170.4 micrograms/mL (Cmax) at 0.5 hours postdose (end of infusion), 7.0 micrograms/mL at 12 hours postdose, and 1.1 microgram/mL at 24 hours postdose.
Average plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a 1 g dose in three patients 13 to 17 years of age were 155.9 micrograms/mL (Cmax) at 0.5 hours postdose (end of infusion), and 6.2 micrograms/mL at 12 hours postdose.
Distribution