Invabex 1 g Powder for solution for injection or infusion.

Adult patients

INVABEX 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 pneumonia (penicillin susceptible strains only) including cases with concurrent bacteraemia, Moraxella catarrhalis. If community acquired pneumonia is caused by Haemophilus influenzae, INVABEX 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

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

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 mu00b2

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

INVABEX may be used for the treatment of infections in adult patients with renal insufficiency. In adult patients whose creatinine clearance is greater than 30 mL/min/1,73 mu00b2, no dosage adjustment is necessary. Adult patients with advanced renal insufficiency (creatinine clearance less than or equal to 30 mL/min/1,73 mu00b2), 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 INVABEX within 6 hours prior to haemodialysis, a supplementary dose of 150 mg is recommended after the haemodialysis session. If INVABEX is given at least 6 hours before haemodialysis, no supplementary dose is needed. No data are available 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 hepatic impairment

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

Elderly

The recommended dose of INVABEX should be administered, except in cases of severe renal impairment (see Patients with renal impairment above).

Method of administration

For instructions on the preparation of INVABEX before administration, see section 6.6. INVABEX may be administered by intravenous (IV) infusion or intramuscular (IM) injection. When administered intravenously, INVABEX should be infused over a period of 30 minutes. The usual duration of therapy with INVABEX is 3 to 14 days, but it may vary according to the type of infection and causative pathogen(s). When clinically indicated, a switch to an appropriate oral antimicrobial medicine may be implemented if clinical improvement has been observed.

• hypersensitivity to ertapenem or to any of the excipients of INVABEX. (see section 6.1)
• hypersensitivity to beta-lactam antibiotics
• patients with known bacterial meningitis, due to lack of sufficient cerebrospinal fluid (CSF) penetration
• INVABEX 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, INVABEX 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 INVABEX. 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 INVABEX, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO INVABEX OCCURS, DISCONTINUE INVABEX IMMEDIATELY.

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH ADRENALINE (EPINEPHRINE), OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION. OTHER THERAPY MAY ALSO BE ADMINISTERED AS INDICATED.

Prescribers must adhere to the principles of antibiotic stewardship.

Hypersensitivity reactions can also progress to Kounis syndrome, (acute coronary syndrome accompanying allergic reaction) and linear IgA associated with the use of beta-lactam antibiotics, including INVABEX.

Superinfection

Prolonged use of INVABEX 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 Antibiotic-associated colitis below.

Antibiotic-associated colitis

Pseudomembranous colitis (antibiotic-associated colitis) has been reported with ertapenem (contained in INVABEX) 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 INVABEX. Treatment with INVABEX 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 antibiotic-associated colitis. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of INVABEX. 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 INVABEX); 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 INVABEX re-examined to determine whether it should be decreased or discontinued.

Encephalopathy

Encephalopathy has been reported with the use of INVABEX (see section 4.8). If ertapenem-induced encephalopathy is suspected (e.g. myoclonus, seizures, altered mental status, depressed level of consciousness), discontinuation of INVABEX 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 INVABEX 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 INVABEX 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 INVABEX 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.

Considerations for use in particular populations

Experience in the use of INVABEX for severe infections is limited. Efficacy has not been established for the use of INVABEX in the treatment of community acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae, or for diabetic foot infections with concurrent osteomyelitis. Caution should be taken with IM administration of INVABEX not to inject it inadvertently into a blood vessel (see section 4.2). Lidocaine (lignocaine) hydrochloride is the diluent for intramuscular administration of INVABEX. Refer to the professional information for lidocaine hydrochloride.

Information on the inactive ingredients

Each vial contains approximately 6,0 millimoles of sodium (approximately 137 mg) which should be taken into consideration by patients on a controlled sodium diet.

Paediatric population

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

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). Ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and is not a substrate for P-glycoprotein-mediated transport. No specific clinical drug interaction studies have been conducted.

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 INVABEX. The lowered valproic acid levels may lead to inadequate seizure control; therefore, concomitant use of INVABEX and valproic acid/sodium valproate is not recommended and alternative antibacterial or anticonvulsant therapies should be considered.

Probenecid

Probenecid inhibits the renal excretion of ertapenem, thereby increasing its plasma concentrations and prolonging its elimination half-life.

Pregnancy

Safety in pregnancy has not been established.

Breastfeeding

Ertapenem is excreted in human milk (see section 5.2). 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.

No studies on the effects on the ability to drive and use machines have been performed. Dizziness and somnolence are possible undesirable effects of INVABEX (see section 4.8). If affected, patients should be warned not to drive or operate machinery.

Summary of the safety profile

Adults

Most adverse experiences reported in clinical studies were described as mild to moderate in severity. Medicine-related adverse experiences were reported in approximately 20 % of patients treated with ertapenem. Ertapenem was discontinued due to adverse experiences thought to be medicine-related in 1,3 % of patients. The most frequent medicine-related adverse experiences reported during parenteral therapy in patients treated with ertapenem were diarrhoea (4,3 %), infused vein complication (3,9 %), nausea (2,9 %) and headache (2,1 %).

Paediatric population (3 months to 17 years of age): The overall safety profile is comparable to that in adult patients. In clinical trials, most frequent medicine-related clinical adverse experiences reported during parenteral therapy were diarrhoea (5,5 %), infusion site pain (5,5 %) and infusion site erythema (2,6 %).

Tabulated list of adverse effects

ADULTS - 18 years of age and older

Paediatric population (3 months to 17 years of age)

System Organ Class Frequency Side effects

Signs and symptoms: No specific information is available on the treatment of overdosage with INVABEX.

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