INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INVANZ® (INVANZ®)

Composition:

Active substance: ertapenem;

1 vial contains ertapenem 1 g;

Excipients: sodium bicarbonate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: solid homogeneous substance, from white to almost white in color, in granular form.

Pharmacotherapeutic group. Antibacterials for systemic use. Beta-lactam antibiotics. Carbapenems. ATC code J01D H03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ertapenem inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). In Escherichia coli, it shows stronger affinity for PBP 2 and PBP 3.

Mechanism of resistance

Strains considered sensitive to ertapenem rarely developed resistance during surveillance studies in Europe. In some resistant strains, resistance to other carbapenem-class antibacterial agents has been observed. Ertapenem is stable against 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 due to insensitivity of target PBPs; P. aeruginosa and other non-fermenting bacteria are generally resistant, likely due to limited penetration and active efflux from the cell.

Resistance among pathogens belonging to the Enterobacteriaceae family is rare, and ertapenem is usually active against extended-spectrum beta-lactamases. However, resistance may occur when extended-spectrum beta-lactamases or other potent beta-lactamases (e.g., AmpC type) are present in combination with reduced permeability due to loss of one or more outer membrane proteins or active efflux mechanisms. Resistance may also arise through acquisition of beta-lactamases with significant carbapenem-hydrolyzing activity (particularly IMP- and VIM-type metallo-beta-lactamases or KPC-type enzymes), although this is a rare phenomenon.

The mechanism of action of ertapenem differs from that of other antibiotic classes, such as quinolones, aminoglycosides, macrolides, and tetracyclines. There is no cross-resistance between ertapenem and these agents. However, microorganisms may exhibit resistance to more than one class of antibacterial agents if the resistance mechanism involves reduced permeability and/or efflux pumps.

Breakpoints

The minimal inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

• Enterobacterales: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L;
• Streptococcus pneumoniae: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L;
• Haemophilus influenzae: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L;
• M. catarrhalis: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L;
• anaerobic Gram-negative microorganisms: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L;
• anaerobic Gram-positive microorganisms: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L;
• Viridans group streptococci: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L;
• non-species-related breakpoints: susceptible ≤ 0.5 mg/L and resistant > 0.5 mg/L.

Note: Susceptibility of staphylococci to ertapenem is determined based on methicillin susceptibility, and susceptibility of streptococci groups A, B, C, and G is determined based on benzylpenicillin susceptibility.

Local MIC breakpoints, if available, should also be taken into account.

Microorganism susceptibility

The prevalence of acquired resistance in specific species may vary over time and by geographic region; therefore, information on local resistance patterns is highly valuable, especially when treating severe infections. Localized outbreaks of infections caused by carbapenem-resistant microorganisms have been reported in the European Union. Approximate susceptibility rates of microorganisms to ertapenem are provided below.

Moderately susceptible strains

Anaerobic Gram-positive microorganisms: methicillin-resistant staphylococci (including Staphylococcus aureus), Streptococcus agalactiae, Streptococcus pneumoniae†, Streptococcus pyogenes.

Anaerobic Gram-negative microorganisms: Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens.

Anaerobic microorganisms: Clostridium strains (except C. difficile), Eubacterium strains, Fusobacterium strains, Peptostreptococcus strains, Porphyromonas asaccharolytica, Prevotella strains.

Strains capable of developing resistance

Aerobic Gram-positive microorganisms: methicillin-resistant staphylococci+#.

Anaerobic microorganisms: Bacteroides fragilis and other species of the B. fragilis group.

Organisms with intrinsic resistance

Aerobic Gram-positive microorganisms: Corynebacterium jeikeium, enterococci, including Enterococcus faecalis and Enterococcus faecium.

Aerobic Gram-negative microorganisms: Aeromonas strains, Acinetobacter strains, Burkholderia cepacia, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobic microorganisms: Lactobacillus strains.

Others: Chlamydia strains, Mycoplasma strains, Rickettsia strains, Legionella strains.

* Satisfactory activity observed in clinical studies.

† The efficacy of Invanz® in the treatment of community-acquired pneumonia caused by penicillin-resistant Streptococcus pneumoniae has not been established.

• Acquired resistance frequency > 50%.

Methicillin-resistant staphylococci (including MRSA) are always resistant to beta-lactams.

Information from clinical studies

Clinical efficacy studies in pediatric practice

Randomized, comparative, multicenter studies involving patients aged 3 months to 17 years primarily assessed safety, followed by evaluation of efficacy of ertapenem use in pediatric practice.

The proportion of patients showing positive clinical response after completion of treatment and those who continued treatment is presented in Table 1.

Table 1

Type of disease†	Age group	Ertapenem		Ceftriaxone
		n/m	%	n/m	%
Community-acquired pneumonia (CAP)	3 to 23 months	31/35	88.6	13/13	100.0
	2 to 12 years	55/57	96.5	16/17	94.1
	13 to 17 years	3/3	100.0	3/3	100.0
Type of disease	Age group	Ertapenem		Ticarcillin/clavulanate
		n/m	%	n/m	%
Intra-abdominal infections (IAI)	2 to 12 years	28/34	82.4	7/9	77.8
	13 to 17 years	15/16	93.8	4/6	66.7
Acute pelvic infections (API)	13 to 17 years	25/25	100.0	8/8	100.0

†9 patients in the ertapenem group (7 patients with cUTI and 2 patients with IAIs), 2 patients in the ceftriaxone group (2 patients with cUTI) and 1 patient with IAIs in the ticarcillin/clavulanate group had secondary bacteremia at the time of enrollment in the study.

n/m – number of patients with positive assessment outcome / number of patients assessed during the post-treatment visit.

Pharmacokinetics.

Plasma concentrations

Mean plasma concentrations of ertapenem after a single 30-minute intravenous infusion of 1 g in healthy young adult volunteers (aged 25 to 45 years) were 155 mcg/mL (Cmax) at 0.5 hours after dose administration (end of infusion), 9 mcg/mL at 12 hours after dose administration, and 1 mcg/mL at 24 hours after dose administration.

The area under the plasma concentration-time curve (AUC) of ertapenem in adults increases almost proportionally with dose over the dose range of 0.5 g to 2 g.

No accumulation of ertapenem was observed in adult patients following multiple intravenous doses ranging from 0.5 g to 2 g per day.

Mean plasma concentrations of ertapenem after a single 30-minute intravenous infusion of 15 mg/kg (up to a maximum dose of 1 g) in patients aged 3 to 23 months were 103.8 mcg/mL (Cmax) at 0.5 hours after dose administration (end of infusion), 13.5 mcg/mL at 6 hours after dose administration, and 2.5 mcg/mL at 12 hours after dose administration.

Mean plasma concentrations of ertapenem after a single 30-minute intravenous infusion of 15 mg/kg (up to a maximum dose of 1 g) in patients aged 2 to 12 years were 113.2 mcg/mL (Cmax) at 0.5 hours after dose administration (end of infusion), 12.8 mcg/mL at 6 hours after dose administration, and 3 mcg/mL at 12 hours after dose administration.

Mean plasma concentrations of ertapenem after a single 30-minute intravenous infusion of 20 mg/kg (up to a maximum dose of 1 g) in patients aged 13 to 17 years were 170.4 mcg/mL (Cmax) at 0.5 hours after dose administration (end of infusion), 7 mcg/mL at 12 hours after dose administration, and 1.1 mcg/mL at 24 hours after dose administration.

Mean plasma concentrations of ertapenem after a single 30-minute intravenous infusion of 1 g in three patients aged 13 to 17 years were 155.9 mcg/mL (Cmax) at 0.5 hours after dose administration (end of infusion) and 6.2 mcg/mL at 12 hours after dose administration.

Distribution

Ertapenem is highly bound to human plasma proteins. In healthy young adult volunteers (aged 25 to 45 years), the plasma protein binding of ertapenem decreases as plasma concentration increases, from approximately 95% binding at a plasma concentration of < 50 mcg/mL to approximately 92% binding at a plasma concentration of 155 mcg/mL (reaching the mean concentration at the end of infusion after intravenous administration of a 1 g dose).

The volume of distribution (Vdss) of ertapenem is approximately 8 liters (0.11 L/kg) in adults, approximately 0.2 L/kg in children aged 3 months to 12 years, and approximately 0.16 L/kg in adolescents aged 13 to 17 years.

Concentrations of ertapenem in blister fluid in adult patients on day 3 of intravenous administration at a dose of 1 g daily indicate that the ratio of AUC in blister fluid to AUC in plasma is 0.61.

In vitro studies indicate that the effect of ertapenem on the plasma protein binding of highly protein-bound drugs (warfarin, ethinyl estradiol, and norethindrone) is negligible. The change in binding is < 12% at the maximum plasma concentration of ertapenem after a 1 g dose. In vivo, administration of probenecid (500 mg every 6 hours) reduced the fraction of ertapenem bound in plasma from approximately 91% to approximately 87% at the end of infusion in patients receiving a single 1 g intravenous infusion. This effect is considered transient. Clinically significant interaction due to displacement of another drug by ertapenem or displacement of ertapenem by another drug is unlikely.

In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin and vinblastine and is not a substrate of this transporter.

Metabolism

In healthy young adult volunteers (aged 23 to 49 years), after intravenous infusion of radiolabeled ertapenem 1 g, plasma radioactivity consisted predominantly of ertapenem (94%). The major metabolite of ertapenem is an open-ring derivative formed by hydrolysis of the beta-lactam ring by dehydropeptidase-I.

In vitro studies using human liver microsomes indicate that ertapenem does not inhibit the metabolism mediated by any of the six major cytochrome isoforms: 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4.

Excretion

After intravenous infusion of radiolabeled ertapenem 1 g in healthy young adult volunteers (aged 23 to 49 years), approximately 80% is excreted in urine and 10% in feces. Of the 80% excreted in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the open-ring metabolite.

In healthy young adult volunteers (aged 18 to 49 years) and patients aged 13 to 17 years receiving a 1 g intravenous infusion, the mean elimination half-life from plasma is approximately 4 hours. The mean elimination half-life from plasma in children aged 3 months to 12 years is approximately 2.5 hours. The mean concentration of ertapenem in urine from 0–2 hours after dose administration exceeds 984 mcg/mL, and from 12–24 hours after dose administration exceeds 52 mcg/mL.

Special patient groups

Gender

Plasma concentrations of ertapenem are similar in males and females.

Elderly patients

Plasma concentrations of ertapenem after intravenous infusion of 1 g and 2 g doses are slightly higher (approximately 39% and 22%, respectively) in healthy elderly volunteers (≥ 65 years) compared to younger patients (< 65 years). In the absence of severe renal impairment, dose adjustment is not required in elderly patients.

Children

Plasma concentrations of ertapenem are comparable in children aged 13 to 17 years and adults after a single 1 g intravenous dose.

After administration of a 20 mg/kg dose (up to a maximum of 1 g), pharmacokinetic parameters in patients aged 13 to 17 years were generally comparable to those in healthy young adult volunteers.

To evaluate pharmacokinetic data following administration of a 1 g dose to all patients in this age group, pharmacokinetic data were scaled to a 1 g dose assuming linearity. Comparison of results indicates that administration of ertapenem 1 g once daily achieves a pharmacokinetic profile in patients aged 13 to 17 years similar to that observed in adult patients. The ratios of area under the curve (patients aged 13 to 17 years vs. adults), concentration at the end of infusion, and concentration within the dosing interval were 0.99, 1.20, and 0.84, respectively.

Plasma concentrations within the dosing interval after intravenous administration of a single 15 mg/kg dose of ertapenem in patients aged 3 months to 12 years are comparable to plasma concentrations within the dosing interval after intravenous administration of a single 1 g dose in adult patients (see "Plasma concentrations" above). The plasma clearance (mL/min/kg) of ertapenem in patients aged 3 months to 12 years is approximately twice that in adults. After administration of a 15 mg/kg dose, the area under the curve and plasma concentration within the dosing interval in patients aged 3 months to 12 years were comparable to those in healthy young adult volunteers receiving a 1 g intravenous dose of ertapenem.

Hepatic impairment

The pharmacokinetics of ertapenem in patients with hepatic impairment has not been established. Due to the limited hepatic metabolism of the drug, hepatic dysfunction is not expected to affect the pharmacokinetics of ertapenem. Therefore, dose adjustment in patients with hepatic impairment is not required.

Renal impairment

After intravenous administration of a single 1 g dose of ertapenem in adults, the AUC of total (bound and unbound) ertapenem and unbound ertapenem is similar in patients with mild renal impairment (Clcr 60–90 mL/min/1.73 m²) and healthy volunteers (aged 25 to 82 years). The AUC of total and unbound ertapenem increases approximately 1.5- and 1.8-fold, respectively, in patients with moderate renal impairment (Clcr 31–59 mL/min/1.73 m²) compared to healthy volunteers. The AUC of total and unbound ertapenem increases approximately 2.6- and 3.4-fold, respectively, in patients with severe renal impairment (Clcr 5–30 mL/min/1.73 m²) compared to healthy volunteers. The AUC of total and unbound ertapenem increases approximately 2.9- and 6-fold, respectively, in patients requiring hemodialysis between dialysis sessions compared to healthy volunteers. After intravenous administration of a single 1 g dose of ertapenem immediately before a hemodialysis session, approximately 30% of the administered dose is recovered in the dialysate. Data on the use of the drug in children with renal impairment are lacking.

There are insufficient data on the safety and efficacy of ertapenem in patients with end-stage renal disease and in patients requiring hemodialysis to make dosage recommendations. Therefore, ertapenem should not be used in these patients.

Clinical characteristics.

Indications.

Treatment

Infections caused by susceptible microbial strains:

• complicated intra-abdominal infections;
• community-acquired pneumonia;
• acute gynecological infections;
• complicated skin and skin structure infections, including diabetic foot infections (diabetic foot);
• complicated urinary tract infections, including pyelonephritis;
• bacterial septicemia.

Prophylaxis

Invanz**®** is indicated in adults for the prevention of surgical site infections associated with elective colorectal surgery.

Contraindications.

Known hypersensitivity to any component of the medicinal product or to other drugs of the same class. Severe hypersensitivity reactions (e.g., anaphylactic reactions, severe skin reactions) to any other type of beta-lactam agents (e.g., penicillins or cephalosporins).

When lidocaine hydrochloride is used as the solvent, intramuscular administration of Invanz® is contraindicated in patients with hypersensitivity to amide-type local anesthetics and in patients with severe shock or complete heart block.

Interaction with other medicinal products and other forms of interaction.

Drug interactions due to inhibition of drug clearance mediated by P-glycoprotein or CYP are unlikely.

Decreased valproic acid levels below the therapeutic range have been reported with concomitant administration of carbapenems and valproic acid. The reduction in valproic acid levels may increase the risk of seizures; therefore, concomitant administration of ertapenem and valproic acid/sodium divalproex is not recommended, and consideration should be given to alternative antibacterial or anticonvulsant therapy.

Special precautions for use.

Hypersensitivity

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in patients with a history of multiple allergen sensitivity. Severe hypersensitivity reactions have been reported in patients with penicillin hypersensitivity who were treated with other beta-lactams. Before initiating therapy with Invanz® it is essential to carefully inquire about the patient’s history of previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens (see section "Contraindications"). If an allergic reaction to Invanz® occurs, the drug should be discontinued immediately (see section "Adverse reactions").

Serious anaphylactic reactions require immediate treatment.

Superinfection

Prolonged use of Invanz® may result in overgrowth of non-susceptible microorganisms. Re-evaluation of the patient’s condition is important. If superinfection develops during therapy, appropriate measures should be taken.

Antibiotic-associated colitis

Antibiotic-associated colitis and pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with ertapenem use. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. Consideration should be given to discontinuing therapy with Invanz® and initiating treatment for Clostridioides difficile-associated infection. Antiperistaltic agents should not be prescribed.

Seizures

Seizures have been reported during clinical trials in adult patients receiving ertapenem (1 g once daily) during treatment or within the 14-day follow-up period. Seizures occurred primarily in elderly patients and in patients with a history of central nervous system (CNS) disorders (e.g., structural brain lesions or history of seizures) and/or renal impairment. Similar effects have been observed during post-marketing use.

Encephalopathy

Encephalopathy has been reported with ertapenem use (see section "Adverse reactions"). If encephalopathy due to ertapenem 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 developing ertapenem-induced encephalopathy, which may prolong treatment duration.

Concomitant use with valproic acid

Concomitant administration of ertapenem and valproic acid/sodium valproate is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Suboptimal exposure

Available data suggest that during surgical procedures lasting longer than 4 hours, patients may receive subtherapeutic concentrations of ertapenem, thus risking ineffective treatment. Therefore, caution should be exercised in such cases.

Recommendations for use in specific patient populations

Experience with ertapenem for the treatment of severe infections is limited. In clinical trials evaluating treatment of community-acquired pneumonia in adult volunteers, 25% of evaluable patients receiving ertapenem had severe disease (defined as pneumonia severity score > III). In clinical trials evaluating treatment of acute gynecological infections in adult volunteers, 26% of evaluable patients receiving ertapenem had severe disease (defined as temperature ≥ 39°C and/or bacteremia); 10 patients had bacteremia. Among evaluable patients in clinical trials evaluating treatment of intra-abdominal infections in adult volunteers, 30% had generalized peritonitis and 39% had infections involving organs beyond the appendix, including the stomach, duodenum, small intestine, large intestine, and gallbladder. The number of evaluable patients included in studies with an APACHE II score ≥ 15 was limited; therefore, efficacy in these patients has not been established.

The efficacy of Invanz® for the treatment of community-acquired pneumonia caused by penicillin-resistant Streptococcus pneumoniae has not been established.

The efficacy of ertapenem for the treatment of diabetic foot infections with associated osteomyelitis has not been established.

Experience with ertapenem use in children under 2 years of age is limited. Particular caution should be exercised when determining microbial susceptibility to ertapenem in this age group. Information on the use of ertapenem in children under 3 months of age is lacking.

Care should be taken when administering Invanz® intramuscularly to avoid accidental intravascular injection (see section "Method of administration and dosage").

When lidocaine hydrochloride is used as a solvent, safety information regarding lidocaine hydrochloride should be considered.

This medicinal product contains approximately 137 mg of sodium per 1 g dose, equivalent to 6.85% of the maximum daily sodium intake of 2 g for adults as recommended by WHO.

Use during pregnancy or breastfeeding.

Pregnancy

Adequate and well-controlled studies of the use of this medicinal product in pregnant women have not been conducted. Animal studies do not indicate a direct or indirect adverse effect on pregnancy, embryonal/fetal development, parturition, or postnatal development. However, ertapenem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding

Ertapenem is excreted in breast milk. Due to the potential for adverse reactions in infants, mothers receiving ertapenem should avoid breastfeeding.

Fertility

Adequate and well-controlled studies to assess the effect of ertapenem on fertility in men and women have not been conducted. Preclinical study results do not indicate a direct or indirect adverse effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect on reaction speed when driving or operating machinery have not been conducted.

However, caution is recommended when driving or operating machinery, due to the potential for adverse nervous system reactions (e.g., dizziness, somnolence).

Administration and Dosage

For intravenous and intramuscular administration.

Infection treatment

The usual dose of Invanz® for adults and children aged 13 years and older is 1 g once daily administered by intravenous injection.

The usual dose of Invanz® for children aged 3 months to 12 years is 15 mg/kg body weight twice daily (dose must not exceed 1 g per day) administered by intravenous infusion.

Invanz® can be administered either by intravenous infusion or by intramuscular injection. When administered intravenously, Invanz® should be infused over 30 minutes. Intramuscular administration of Invanz® may be used as an alternative to intravenous administration.

The usual duration of treatment with Invanz® is from 3 to 14 days, depending on the type of infection and causative pathogens. If clinical improvement is observed, transition to subsequent appropriate oral antimicrobial therapy is acceptable when clinically indicated.

Prophylaxis

For prevention of surgical infections associated with elective colorectal surgery, a single intravenous dose of 1 g of Invanz® is recommended to be administered 1 hour prior to surgery.

Patients with renal impairment

Invanz® can be used for treatment of infections in adult patients with mild or moderate renal impairment. Dose adjustment is not required for patients with creatinine clearance > 30 mL/min/1.73 m². There are insufficient data on the safety and efficacy of ertapenem in patients with severe renal impairment to provide dosing recommendations. Therefore, ertapenem should not be used in these patients. There are no data available in pediatric patients with renal impairment.

Patients undergoing hemodialysis

There are insufficient data on the safety and efficacy of ertapenem in patients undergoing hemodialysis to provide dosing recommendations. Therefore, ertapenem should not be used in these patients.

Patients with hepatic impairment

Dose adjustment is not required for patients with hepatic impairment.

Elderly patients

The recommended dose of Invanz® should be administered, except in cases of severe renal impairment.

INSTRUCTIONS FOR SOLUTION PREPARATION

Preparation of Invanz® solution for intravenous administration in adults and children aged 13 years and older

DO NOT MIX OR ADMINISTER CONCOMITANTLY WITH OTHER MEDICINAL PRODUCTS.

DO NOT USE DILUENTS CONTAINING DEXTROSE.

Prior to administration, Invanz® must be reconstituted and then diluted.

1. Reconstitute the contents of a vial containing 1 g of Invanz® with 10 mL of one of the following diluents: Water for Injection, 0.9% Sodium Chloride Injection, or Bacteriostatic Water for Injection.
2. Shake well to dissolve, then immediately transfer the reconstituted solution into 50 mL of 0.9% Sodium Chloride Injection.
3. The product is stable and suitable for use for up to 6 hours after reconstitution. Infusion duration is 30 minutes.

Preparation of Invanz® solution for intramuscular administration in adults and children aged 13 years and older

Prior to administration, Invanz® must be reconstituted.

1. Reconstitute the contents of a vial containing 1 g of Invanz® by adding 3.2 mL of 1% or 2% Lidocaine Hydrochloride Injection (without epinephrine). Shake the vial well to dissolve the contents.
2. Immediately withdraw the reconstituted solution into a syringe and administer by deep intramuscular injection into a large muscle (e.g., gluteal or lateral thigh muscle).
3. The reconstituted solution for intramuscular injection must be used within 1 hour after preparation.

Note: This reconstituted solution must not be administered intravenously.

Preparation of Invanz® solution for intravenous administration in children aged 3 months to 12 years

DO NOT MIX OR ADMINISTER CONCOMITANTLY WITH OTHER MEDICINAL PRODUCTS.

DO NOT USE DILUENTS CONTAINING DEXTROSE.

Prior to administration, Invanz® must be reconstituted and then diluted.

1. Reconstitute the contents of a vial containing 1 g of Invanz® with 10 mL of one of the following diluents: Water for Injection, 0.9% Sodium Chloride Injection, or Bacteriostatic Water for Injection.
2. Shake well to dissolve, then immediately withdraw the required volume based on 15 mg/kg body weight (dose must not exceed 1 g per day) and dilute in 0.9% Sodium Chloride Injection to a final concentration of 20 mg/mL or less.
3. The product is stable and suitable for use for up to 6 hours after reconstitution. Infusion duration is 30 minutes.

Preparation of Invanz® solution for intramuscular administration in patients aged 3 months to 12 years

Prior to administration, Invanz® must be reconstituted.

1. Reconstitute the contents of a vial containing 1 g of Invanz® by adding 3.2 mL of 1% or 2% Lidocaine Hydrochloride Injection (without epinephrine). Shake the vial well to dissolve the contents.
2. Immediately withdraw the required volume based on 15 mg/kg body weight (dose must not exceed 1 g per day) into a syringe and administer by deep intramuscular injection into a large muscle (e.g., gluteal or lateral thigh muscle).
3. The reconstituted solution for intramuscular injection must be used within 1 hour after preparation.

Note: This reconstituted solution must not be administered intravenously.

Stability of reconstituted solutions and injection solutions

The reconstituted solution, once diluted in 0.9% Sodium Chloride Injection, may be stored at room temperature (25°C) and used within 6 hours, or stored in the refrigerator (2–8°C) for up to 24 hours and used within 4 hours after removal from the refrigerator.

The reconstituted solution for intramuscular injection must be used within 1 hour after preparation.

The Invanz® solution must not be frozen.

Compatibility of Invanz® has been observed with intravenous solutions containing sodium heparin and potassium chloride.

Parenteral medicinal products should always be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. The color of Invanz® solution may vary from colorless to pale yellow. Variability within this range does not affect the potency of the medicinal product.

Children

Due to lack of data, Invanz® is not recommended for use in children under 3 months of age.

Overdose

There is no specific information on the treatment of Invanz® overdose. Overdose with Invanz® is unlikely. Intravenous administration of up to 3 g per day for 8 days in healthy adult volunteers did not result in significant toxic effects. Accidental administration of up to 3 g per day in adult patients during clinical trials did not lead to clinically significant adverse events. In pediatric clinical studies, intravenous administration of single doses up to 40 mg/kg body weight (maximum dose 2 g) did not result in toxic effects.

In the event of Invanz® overdose, the drug should be discontinued and general supportive therapy should be administered until the drug is eliminated by the kidneys.

Invanz® can be partially removed from the body by hemodialysis. However, there is no information available on the use of hemodialysis for the treatment of overdose.

Adverse reactions.

Summary of safety profile

Adults

The total number of patients who received ertapenem during clinical studies was over 2200, of whom more than 2150 received ertapenem at a dose of 1 g. Adverse reactions (i.e., those considered by the investigator as possibly related, probably related, or definitely related to the study drug) occurred in approximately 20% of patients receiving ertapenem. Treatment was discontinued due to adverse reactions in 1.3% of patients. An additional 476 patients received a single 1-g dose of ertapenem prior to undergoing surgical intervention in a clinical study evaluating efficacy in the prevention of surgical infections associated with colorectal surgery.

The most commonly observed adverse reactions in patients during treatment with Invanz® alone and during the 14-day post-treatment follow-up period were diarrhea (4.8%), venous complications at the infusion site (4.5%), and nausea (2.8%).

The most common laboratory abnormalities and their incidence rates observed in patients receiving Invanz® alone during treatment and during the 14-day post-treatment follow-up period included increased alanine aminotransferase (ALT) (4.6%), increased aspartate aminotransferase (AST) (4.6%), increased alkaline phosphatase (3.8%), and increased platelet count (3%).

Children (aged 3 months to 17 years)

A total of 384 pediatric patients received ertapenem during clinical studies. The overall safety profile was comparable to that observed in adult patients. Adverse reactions were reported in approximately 20.8% of patients receiving ertapenem. Treatment was discontinued due to adverse reactions in 0.5% of patients.

The most commonly observed adverse reactions in patients during treatment with Invanz® alone and during the 14-day post-treatment follow-up period were diarrhea (5.2%) and infusion site pain (6.1%). The most common laboratory abnormalities included decreased neutrophil count (3%), increased ALT (2.9%), and increased AST (2.8%).

The following adverse reactions have been reported in patients during treatment with Invanz® alone and during the 14-day post-treatment follow-up period: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Table 2

System Organ Classes	Adults	Children aged 3 months and older
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: hypoglycemia
Psychiatric disorders	Uncommon: insomnia, confusion Rare: anxiety, restlessness, depression Not known: change in mental status (including aggression, delirium, disorientation, psychic disturbances)	Not known: change in mental status (including aggression)
Nervous system disorders	Common: headache Uncommon: dizziness, somnolence, taste alterations, seizures Rare: tremor, syncope Not known: decreased level of consciousness, hallucinations, dyskinesia, myoclonus, gait disturbance, encephalopathy (see section "Special precautions")	Uncommon: headache Not known: hallucinations
Eye disorders	Rare: scleral development abnormalities
Cardiac disorders	Uncommon: sinus bradycardia Rare: arrhythmia, tachycardia
Vascular disorders	Common: infusion site complications, phlebitis/thrombophlebitis Uncommon: arterial hypotension Rare: hemorrhages, increased blood pressure	Uncommon: flushing, arterial hypertension
Respiratory, thoracic and mediastinal disorders	Uncommon: dyspnea, discomfort on swallowing Rare: nasal congestion, cough, epistaxis, wheezing/stridor, whistling respiration
Gastrointestinal disorders	Common: diarrhea, nausea, vomiting Uncommon: constipation, acid regurgitation, dry mouth, dyspepsia, abdominal pain Rare: dysphagia, fecal incontinence, pelvic peritonitis Not known: dental pigmentation	Common: diarrhea Uncommon: change in stool color, melena
Hepatobiliary disorders	Rare: cholecystitis, jaundice, liver disease
Skin and subcutaneous tissue disorders	Common: rash, pruritus Uncommon: erythema, urticaria Rare: dermatitis, desquamation, hypersensitivity vasculitis Not known: acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)	Common: diaper dermatitis Uncommon: erythema, rash, petechiae
Musculoskeletal and connective tissue disorders	Rare: muscle cramps, shoulder pain Not known: muscle weakness
Renal and urinary disorders	Rare: renal failure, acute renal failure
Pregnancy, puerperium and perinatal conditions	Rare: abortion
Reproductive system and breast disorders	Rare: vaginal bleeding
General disorders and administration site conditions	Uncommon: extravasation, asthenia/fatigue, pyrexia, swelling/edema, chest pain Rare: induration at injection site, malaise	Common: pain at infusion site Uncommon: burning at infusion site, pruritus at infusion site, erythema at infusion site, erythema at injection site, feeling of warmth at infusion site
Investigations
Biochemical parameters	Common: increased levels of ALT, AST, alkaline phosphatase Uncommon: increased levels of total bilirubin, direct and indirect bilirubin in serum, creatinine concentration, urea, glucose in serum Rare: decreased concentrations of bicarbonate, creatinine or potassium in serum, increased levels of lactate dehydrogenase (LDH), phosphorus or potassium concentration in serum	Common: increased levels of ALT and AST
Hematological parameters	Common: increased platelet count Uncommon: decreased blood leukocyte count, platelets, segmented neutrophils, decreased hemoglobin and hematocrit, increased eosinophils, activated partial thromboplastin time, prothrombin time, increased segmented neutrophils and leukocytes Rare: decreased lymphocyte count, increased band neutrophils, lymphocytes, metamyelocytes, monocytes, myelocytes, atypical lymphocytes	Common: decreased neutrophil count Uncommon: increased platelet count, activated partial thromboplastin time, prothrombin time, decreased hemoglobin
Urine analysis	Uncommon: increased bacteria, leukocytes, epithelial cells and erythrocytes in urine, presence of yeast fungi in urine Rare: increased urinary urobilinogen excretion
Miscellaneous	Uncommon: positive test for Clostridioides difficile toxins

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

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

Since compatibility studies have not been conducted, Invanz® must not be mixed with other medicinal products except those mentioned in the section "Administration and dosage. Preparation of solution".

Packaging. 1 glass vial of 15 ml capacity in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Unpackaged product, primary packaging, secondary packaging, quality control and batch release:

FAREVA Mirabel, France

Secondary packaging (alternative manufacturer):

Merck Sharp & Dohme B.V., the Netherlands

Manufacturer's address and location of operations.

Route de Marsat, Riom 63963 Clermont-Ferrand Cedex 9, France

Waarderweg 39, 2031 BN Haarlem, the Netherlands