4.1. Therapeutic indications

Treatment

ERTAPENEM 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

ERTAPENEM 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.

4.2. Posology and method of administration

Posology

Treatment

Adults and adolescents (13 to 17 years of age): The dose of ERTAPENEM 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 ERTAPENEM 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 ERTAPENEM in children below 3 months of age have not yet been established. No data are available.

Renal impairment

ERTAPENEM 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 ERTAPENEM should be administered, except in cases of severe renal impairment (see Renal impairment).

Method of administration

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

The usual duration of therapy with ERTAPENEM 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.

4.3. Contraindications

• 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).

4.4. Special warnings and precautions for use

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 ERTAPENEM 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.

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 generalized peritonitis and 39 % had infections involving sites other than the appendix including the stomach, duodenum, small bowel, colon, and gallbladder; there were limited numbers of evaluable patients who were enrolled with APACHE II scores ≥ 15 and efficacy in these patients has not been established.

The efficacy of ERTAPENEM 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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

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

4.8. Undesirable effects

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 ERTAPENEM, 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 ERTAPENEM, 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 ERTAPENEM, 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 ERTAPENEM, 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 ERTAPENEM, 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)

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

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 Clostridium 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 Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

4.9. Overdose

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 ERTAPENEM 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.