Ertax

Ertax is a white to off-white lyophilized cake.
Each vial contains: 1046 mg Ertapenem (as Ertapenem Sodium) eq. to 1 g.

Pharmacotherapeutic group: Antibacterial for systemic use, carbapenems.
Pharmacology: Pharmacodynamics: 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.
Pharmacokinetics: 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 hour postdose (end of infusion), 9 micrograms/mL at 12 hour postdose, and 1 microgram/mL at 24 hour 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 hour postdose (end of infusion), 13.5 micrograms/mL at 6 hour postdose, and 2.5 micrograms/mL at 12 hour 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 hour postdose (end of infusion), 12.8 micrograms/mL at 6 hour postdose, and 3.0 micrograms/mL at 12 hour 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 hour postdose (end of infusion), 7.0 micrograms/mL at 12 hour postdose, and 1.1 microgram/mL at 24 hour 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 hour postdose (end of infusion), and 6.2 micrograms/mL at 12 hour postdose.
Distribution: Ertapenem is highly bound to human plasma proteins. In healthy young adults (25 to 45 years of age), the protein binding of ertapenem decreases, as plasma concentrations increase, from approximately 95% bound at an approximate plasma concentration of <50 micrograms/mL to approximately 92% bound at an approximate plasma concentration of 155 micrograms/mL (average concentration achieved at the end of infusion following 1 g intravenously).
The volume of distribution (Vdss) of ertapenem in adults is approximately 8 litres (0.11 litre/kg) and approximately 0.2 litre/kg in paediatric patients 3 months to 12 years of age and approximately 0.16 litre/kg in paediatric patients 13 to 17 years of age.
Concentrations of ertapenem achieved in adult skin blister fluid at each sampling point on the third day of 1 g once daily intravenous doses showed a ratio of AUC in skin blister fluid: AUC in plasma of 0.61.
In-vitro studies indicate that the effect of ertapenem on the plasma protein binding of highly protein bound medicinal products (warfarin, ethinyl estradiol, and norethindrone) was small. The change in binding was <12% at peak plasma ertapenem concentration following a 1 g dose. In vivo, probenecid (500 mg every 6 hours) decreased the bound fraction of ertapenem in plasma at the end of infusion in subjects administered a single 1 g intravenous dose from approximately 91% to approximately 87%. The effects of this change are anticipated to be transient. A clinically significant interaction due to ertapenem displacing another medicinal product or another medicinal product displacing ertapenem is unlikely. In-vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
Biotransformation: In healthy young adults (23 to 49 years of age), after intravenous infusion of radiolabelled 1 g ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the ring-opened derivative formed by dehydropeptidase-I-mediated hydrolysis of the beta-lactam ring. In-vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the six major CYP isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.
Elimination: Following administration of a 1 g radiolabelled intravenous dose of ertapenem to healthy young adults (23 to 49 years of age), approximately 80% is recovered in urine and 10% in faeces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged ertapenem and approximately 37% as the ring-opened metabolite.
In healthy young adults (18 to 49 years of age) and patients 13 to 17 years of age given a 1 g intravenous dose, the mean plasma half-life is approximately 4 hours. The mean plasma half-life in children 3 months to 12 years of age is approximately 2.5 hours. Average concentrations of ertapenem in urine exceed 984 micrograms/mL during the period 0 to 2 hours postdose and exceed 52 micrograms/mL during the period 12 to 24 hours post-administration.

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: Intra-abdominal infections; Community acquired pneumonia; Acute gynaecological infections; Diabetic foot infections of the skin and soft tissue.
Prevention: ERTAPENEM is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery.
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 ERTAPENEM is 1 gram (g) given once a day by the intravenous route.
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.
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. 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.
Elderly: The recommended dose of ERTAPENEM should be administered, except in cases of severe 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.

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; however, no information is available on the use of haemodialysis to treat overdose.

Hypersensitivity to the active substance or to any of the excipients.
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).

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. If an allergic reaction to ertapenem occurs, 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.
Concomitant use with valproic acid: The concomitant use of ertapenem and valproic acid/sodium valproate is not recommended.
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. Excipient: This medicinal product contains approximately 6.0 mEq (approximately 137 mg) of sodium per 1.0 g dose which should be taken into consideration by patients on a controlled sodium diet.
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.

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.

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%).

Interactions caused by inhibition of P-glycoprotein-mediated clearance or CYP-mediated clearance of medicinal products are unlikely.
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.

Store at temperatures not exceeding 25°C.
Special Precautions for Storage: This medicinal product does not require any special storage conditions.

Other Beta-Lactams

J01DH03 - ertapenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

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