Ertava 1 g Powder for solution for injection or infusion

Adult patients

ERTAVA is indicated for the treatment of adult patients with the following moderate to severe infections, caused by susceptible strains of the designated microorganisms (see section 4.2):

• Complicated intra-abdominal infections due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis.
• Complicated skin and skin structure infections including diabetic lower extremity and diabetic foot infections due to Staphylococcus aureus (methicillin susceptible strains only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Porphyromonas asaccharolytica or Peptostreptococcus species.
• Community acquired pneumonia due to Streptococcus pneumoniae (penicillin susceptible strains only) including cases with concurrent bacteraemia, Moraxella catarrhalis. If community acquired pneumonia is caused by Haemophilus influenzae, ERTAVA should be used only after confirmation of culture and sensitivity results.
• Complicated urinary tract infections including pyelonephritis due to Escherichia coli, including cases with concurrent bacteraemia, or Klebsiella pneumoniae.
• Acute pelvic infections including postpartum endomyometritis, septic abortion and post-surgical gynaecologic infections due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species or Prevotella bivia.

Paediatric patients

ERTAVA is indicated in paediatric patients 3 months to 17 years of age with the following infections (see u201cAdult patientsu201d above for susceptible organisms):

• Complicated intra-abdominal infections
• Complicated skin and skin structure infections
• Community acquired pneumonia
• Complicated urinary tract infections
• Acute pelvic infections

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to ertapenem. Therapy with ERTAVA may be initiated empirically before results of these tests are known; once results become available, antimicrobial therapy should be adjusted accordingly.

Posology

The usual dose of ERTAVA in patients 13 years of age and older is 1 gram (g) given once a day. The usual dose of ERTAVA in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day). The usual duration of therapy with ERTAVA 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. Intramuscular (IM) administration of ERTAVA may be used as an alternative to intravenous (IV) administration in the treatment of those infections for which IM therapy is appropriate. (See u2018Method of administrationu2019).

Dosage guidelines for adults and paediatric patients with normal renal function* and body mass

* Defined as creatinine clearance greater than 90 ml/min/1,73 m2.

u2020 Duration includes a possible switch to an appropriate oral therapy once clinical improvement has been demonstrated.

u00a7 Not to exceed 1 g/day.

u2551 Patients with diabetic foot infections received up to 28 days of treatment (parenteral or parenteral plus oral switch therapy).

Special populations

Patients with renal insufficiency

ERTAVA may be used for the treatment of infections in adult patients with renal insufficiency. In patients whose creatinine clearance is greater than 30 ml/min/1,73 m2, no dosage adjustment is necessary. Adult patients with advanced renal insufficiency (creatinine clearance less than or equal to 30 ml/min/1,73 m2), including those on haemodialysis, should receive 500 mg daily. There are no data in paediatric patients with renal insufficiency.

Patients on haemodialysis

Following a single 1 g IV dose of ertapenem given immediately prior to a haemodialysis session, approximately 30 % of the dose may be recovered in the dialysate. When adult patients on haemodialysis are given the recommended daily dose of 500 mg of ERTAVA within 6 hours prior to haemodialysis, a supplementary dose of 150 mg is recommended after the haemodialysis session. If ERTAVA is given at least 6 hours before haemodialysis, no supplementary dose is needed. There are no data in patients undergoing peritoneal dialysis or haemofiltration. There are also no data in paediatric patients on haemodialysis.

When only the serum creatinine is available, the following formula** may be used to calculate creatinine clearance. The serum creatinine should represent a steady state of renal function.

Males: (weight in kg) x (140 - age in years) / (72) x serum creatinine (mg/100 ml)

Females: (0,85) x (value calculated for males)

** Cockcroft and Gault equation: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976.

Patients with impaired hepatic function

No dosage adjustment is recommended in patients with impaired hepatic function (see section 5.2 Pharmacokinetic properties, Hepatic insufficiency). The recommended dose of ERTAVA may be administered without regard to age (13 years of age and older) or gender.

Method of administration

For instructions on the preparation of ERTAVA before administration (see section 6.6). ERTAVA may be administered by IV infusion or IM injection. When administered intravenously, ERTAVA should be infused over a period of 30 minutes.

• Hypersensitivity to ertapenem or to any of the excipients of ERTAVA.
• Hypersensitivity to beta-lactam antibiotics.
• Patients with known bacterial meningitis, due to lack of sufficient cerebrospinal fluid (CSF) penetration.
• ERTAVA is not recommended in infants under 3 months of age, as no data are available.
• Due to the use of lidocaine (lignocaine) hydrochloride as a diluent, ERTAVA administered intramuscularly is contraindicated in patients with a known hypersensitivity to amide type local anaesthetics and in patients with severe shock or heart block. (Refer to the professional information for lidocaine (lignocaine) hydrochloride.)

Hypersensitivity

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAM ANTIBIOTICS, INCLUDING ERTAVA. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS WHEN TREATED WITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY WITH ERTAVA, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO ERTAVA OCCURS, DISCONTINUE ERTAVA IMMEDIATELY. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE (ADRENALINE), OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION. OTHER THERAPY MAY ALSO BE ADMINISTERED AS INDICATED.

Superinfection

Prescribers must adhere to the principles of antibiotic stewardship. Prolonged use of ERTAVA 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. See u201cAntibiotic-associated colitisu201d below.

Antibiotic-associated colitis

Pseudomembranous colitis (antibiotic-associated colitis) has been reported with ertapenem (contained in ERTAVA) 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 ERTAVA. Treatment with ERTAVA alters the normal flora of the colon and may permit overgrowth of clostridia. It has been demonstrated that a toxin produced by Clostridium difficile is a primary cause of u201cantibiotic-associated colitisu201d. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the ERTAVA. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, parenteral nutrition and treatment with an antibacterial medicine clinically effective against Clostridium difficile colitis. Medicines that inhibit peristalsis should not be given.

Seizures

Seizures and other central nervous system (CNS) adverse experiences have been reported during treatment with ertapenem (as in ERTAVA); see section 4.8. Seizures occur more frequently in elderly patients and those with pre-existing CNS disorders (e.g. brain lesions or history of seizures) and/or compromised renal function. Close adherence to the recommended dosage regimen is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorder. If focal tremors, myoclonus or seizures occur, patients should be evaluated neurologically and the dosage of ERTAVA re-examined to determine whether it should be decreased or discontinued.

Concomitant use with valproic acid

The concomitant use of ERTAVA and valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be enough to overcome this interaction. The concomitant use of ERTAVA and valproic acid or divalproex sodium is not recommended (see section 4.5). Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of ERTAVA is necessary, supplemental anticonvulsant therapy should be considered (see section 4.5).

Sub-optimal exposure

In 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.

Encephalopathy

Encephalopathy has been reported with the use of ertapenem. 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.

Lidocaine (lignocaine) hydrochloride is the diluent for IM administration of ERTAVA. Refer to the professional information for lidocaine hydrochloride. Caution should be taken with IM administration of ERTAVA not to inject it inadvertently into a blood vessel (see section 4.2).

Considerations for use in particular populations

Experience in the use of ERTAVA for severe infections is limited. Efficacy has not been established for the use of ERTAVA in the treatment of community acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae, or for diabetic foot infections with concurrent osteomyelitis.

Paediatric population

There is little experience with ertapenem (as in ERTAVA) 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, ERTAVA is therefore contraindicated in this age group (see section 4.3).

Ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and is not a substrate for P-glycoprotein-mediated transport. Ertapenem does not inhibit metabolism mediated by any of the six major cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Medicine interactions caused by inhibition of P-glycoprotein-mediated medicine clearance or CYP-mediated medicine clearance are unlikely (see section 5.2).

Valproic acid

Decreases in valproic acid levels that may fall below the therapeutic range have been reported when valproic acid or divalproex sodium was co-administered with carbapenem medicines, including ERTAVA. The lowered valproic acid levels may lead to inadequate seizure control (see section 4.4). Concomitant use of ERTAVA and valproic acid/sodium valproate is therefore not recommended and alternative antibacterial or anticonvulsant therapies should be considered.

Pregnancy

Safety in pregnancy has not been established.

Breastfeeding

Ertapenem is excreted in human milk (see section 5.2 u201cDistributionu201d). Safety in nursing mothers has not been established.

Fertility

There are no adequate and well controlled studies regarding the effect of ertapenem on fertility in men and women.

There are no data to suggest that ERTAVA affects the ability to drive and operate machinery. ERTAVA may influence patientsu2019 ability to drive and use machines. Patients should be informed that dizziness and somnolence have been reported with ERTAVA (see section 4.8).

Tabulated list of adverse reactions

ADULTS 18 years of age and older

CHILDREN AND ADOLESCENTS (3 months to 17 years of age)

System organ class / Adverse reactions

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-ucmc.org) found on the SAHPRA website.

No specific information is available on the treatment of overdosage with ERTAVA. In the event of an overdose, ERTAVA should be discontinued and general supportive treatment given until renal elimination takes place. ERTAVA can be removed by haemodialysis; however, no information is available on the use of haemodialysis to treat overdosage.