Ertapenem Aspen 1 g Sterile powder for injection.

Adults

ERTAPENEM ASPEN is indicated for the treatment of the following moderate to severe infections caused by susceptible strains of the designated micro-organisms (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 bacteremia, Moraxella catarrhalis. If Community Acquired Pneumonia is caused by Haemophilus influenzae, ERTAPENEM ASPEN should be used only following 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 post-partum endomyometritis, septic abortion and post-surgical gynaecologic infections due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species or Prevotelia bivia.

Adolescents and children

Safety and effectiveness of ERTAPENEM ASPEN in adolescents and children 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in these patients, and additional data from comparator-controlled studies in patients 3 months to 17 years of age with the following infections (see section 4.2):

• 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 ERTAPENEM ASPEN may be initiated empirically before results of these tests are known; once results become available, antimicrobial therapy should be adjusted accordingly.

Posology

Adults, adolescents and children aged 3 months and older

The dose of ERTAPENEM ASPEN in patients 13 years of age and older is 1 gram (g) given once a day. The usual dose of ERTAPENEM ASPEN in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day). Intramuscular administration of ERTAPENEM ASPEN may be used as an alternative to intravenous administration in the treatment of those infections for which intramuscular therapy is appropriate. The usual duration of therapy with ERTAPENEM ASPEN is 3 to 14 days but varies by the type of infection and causative pathogen(s) (see section 4.1). When clinically indicated, a switch to an appropriate oral antimicrobial may be implemented if clinical improvement has been observed.

Table 1: Dosage guideline for adults and paediatric patients with normal renal function* and body weight

* Defined as creatinine clearance u02c3 90 mL/min/1,73 mu00b2

Special populations

Renal insufficiency

ERTAPENEM ASPEN may be used for the treatment of infections in adult patients with renal insufficiency. In patients whose creatinine clearance is u02c3 30 mL/min/1,73 mu00b2, no dosage adjustment is necessary. Adult patients with advanced renal insufficiency (creatinine clearance u2264 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

Studies have shown that following a single 1 g IV dose of ertapenem given immediately prior to a haemodialysis session, approximately 30 % of the dose was recovered in the dialysate. When adult patients on haemodialysis are given the recommended daily dose of 500 mg of ERTAPENEM ASPEN within 6 hours prior to haemodialysis, a supplementary dose of 150 mg is recommended following the haemodialysis session. If ERTAPENEM ASPEN is given at least 6 hours prior to haemodialysis, no supplementary dose is needed. There are no data in patients undergoing peritoneal dialysis or haemofiltration. There are no data in paediatric patients on haemodialysis.

When only the serum creatinine is available, the following formula may be used to estimate 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)

Hepatic impairment

No dosage adjustment is recommended in patients with impaired hepatic function (see section 5.2).

Age or gender

The recommended dose of ERTAPENEM ASPEN can be administered without regard to age (13 years of age and older) or gender.

Paediatric population

ERTAPENEM ASPEN is not recommended in infants under 3 months of age as no data are available.

Method of administration

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

ERTAPENEM ASPEN is contraindicated in:

• Patients with hypersensitivity to ertapenem or to any excipients in ERTAPENEM ASPEN (see section 6.1).
• Patients with hypersensitivity to other medicines in the same class (carbapenem antibacterials).
• Patients who have demonstrated anaphylactic reactions to beta-lactams (e.g. penicillins or cephalosporins).
• Patients with known bacterial meningitis. ERTAPENEM ASPEN is not recommended in the treatment of meningitis due to lack of sufficient CSF penetration.
• Patients with severe shock or heart block.

ERTAPENEM ASPEN 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, ERTAPENEM ASPEN administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anaesthetics of the amide type (refer to the prescribing information for lidocaine (lignocaine) hydrochloride).

Hypersensitivity

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS INCLUDING ERTAPENEM ASPEN. 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 ERTAPENEM ASPEN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO ERTAPENEM ASPEN OCCURS, DISCONTINUE THE MEDICINE 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.

Seizures

Seizures and other CNS adverse experiences have been reported during treatment with ERTAPENEM ASPEN (see below and section 4.8). During clinical investigations in adult patients treated with ERTAPENEM ASPEN (1 g once a day), seizures, irrespective of medicine relationship, occurred in 0,5 % of patients during study therapy plus 14 days follow-up period. These experiences have occurred most commonly in elderly patients and patients with 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 ERTAPENEM ASPEN re-examined to determine whether it should be decreased or discontinued. See co-administration with valproic acid below and section 4.5.

Antibiotic-associated colitis

Pseudomembranous colitis (antibiotic-associated colitis) has been reported with ERTAPENEM ASPEN 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 ERTAPENEM ASPEN. Treatment with ERTAPENEM ASPEN alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate 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 medicine discontinuation alone. 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.

Superinfection

Prolonged use of ERTAPENEM ASPEN may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patientu2019s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Valproic acid

Co-administration of carbapenems, including ertapenem, to patients receiving 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 sufficient to overcome this interaction. The concomitant use of ertapenem and valproic acid/divalproex sodium is not recommended. 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 ERTAPENEM ASPEN is necessary, supplemental anticonvulsant therapy should be considered (see section 4.5).

Intramuscular administration

Caution should be taken when administering ERTAPENEM ASPEN intramuscularly, to avoid inadvertent injection into a blood vessel (see section 4.2). Lidocaine (lignocaine) hydrochloride is the diluent for intramuscular administration of ERTAPENEM ASPEN. Refer to the prescribing information for lidocaine (lignocaine) hydrochloride.

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, as contained in ERTAPENEM ASPEN, concentrations and consequently to a risk of potential treatment failure. Therefore, caution should be exercised in such unusual cases.

Patients with severe infections

Experience in the use of ERTAPENEM ASPEN in the treatment of severe infections is limited. There were limited numbers of evaluable patients who were enrolled in clinical studies thus efficacy in these patients has not been established.

Community acquired pneumonia

The efficacy of ERTAPENEM ASPEN in the treatment of community acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae has not been established.

Diabetic foot infections

Efficacy of ertapenem in the treatment of diabetic foot infections with concurrent osteomyelitis has not been established.

Paediatric population

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.

Excipients

ERTAPENEM ASPEN contains approximately 6,0 mEq (approximately 137 mg) of sodium per 1 g dose which should be taken into consideration by patients on a controlled sodium diet (see section 6.1).

Valproate

Case reports in the literature have shown that co-administration of carbapenems, including ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction of valproic acid concentrations. ERTAPENEM ASPEN should not be co-administered with valproic acid or divalproex sodium. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures (see section 4.4).

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. In vitro studies in human liver microsomes indicate 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 drug clearance or CYP-mediated drug clearance are unlikely (see section 5.2, Distribution and Biotransformation). No specific clinical medicine interaction studies have been conducted.

Safety in pregnancy and lactation has not been established.

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.

Breastfeeding

Ertapenem is excreted in human milk (see section 5.2, Distribution). Because of the potential for adverse reactions on the infant, mothers should not breastfeed their infants while receiving ERTAPENEM ASPEN.

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.

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

a) Summary of the safety profile

Adult patients: In clinical study patients who received a 1 g dose of ertapenem, most adverse event experiences reported were described as mild to moderate in severity. Medicine related adverse experiences were reported in approximately 20 % of patients treated with ERTAPENEM ASPEN. ERTAPENEM ASPEN was discontinued due to adverse experiences thought to be medicine-related in 1,3 % of patients. The most common 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 %). In adult patients the most frequently observed medicine-related laboratory abnormalities during parenteral therapy in patients receiving ERTAPENEM ASPEN were elevations in ALT, AST, alkaline phosphatase and platelet count. In the majority of clinical studies, parenteral therapy was followed by a switch to an appropriate oral antimicrobial. During the entire treatment period and a 14-day post treatment follow-up period, medicine-related laboratory abnormalities in patients treated with ERTAPENEM ASPEN were no different than those listed above.

b) Tabulated list of adverse reactions

System organ class

Infections and infestations

• Fungal infections, candidiasis, pseudo-membranous enterocolitis, pneumonia, dermatomycosis, postoperative wound infection, urinary tract infection, positive Clostridium difficile toxin

Blood and the lymphatic system disorders

• Elevation in platelet count

Immune system disorders

• Anaphylaxis including anaphylactoid reactions

Metabolism and nutrition disorders

• Anorexia, hypoglycaemia, increases in serum glucose

Psychiatric disorders

• Confusion, agitation, anxiety, depression

Nervous system disorders

• Headache, Dizziness, somnolence, insomnia, seizure, taste perversion, tremor, syncope

Eye disorders

• Scleral disorder

Cardiac disorders

• Sinus bradycardia, arrhythmia, tachycardia

Vascular disorders

• Infused vein complication, phlebitis/ thrombophlebitis

Respiratory, thoracic and mediastinal disorders

• Dyspnoea, pharyngeal discomfort, nasal congestion, cough, epistaxis, rales/rhonchi, wheezing

Gastrointestinal disorders

• Diarrhoea, nausea, vomiting

Oral candidiasis, constipation, acid regurgitation, C. difficile - associated diarrhoea, dry mouth, dyspepsia, abdominal pain, dysphagia, faecal incontinence, pelvic peritonitis

Teeth staining

Hepato-biliary disorders

• Elevations in ALT, AST, alkaline phosphatase

Cholecystitis, jaundice, liver disorder, increases in total serum bilirubin, direct serum bilirubin, indirect serum bilirubin

Skin and subcutaneous tissue disorders

• Erythema, pruritus, Rash

Urticaria, dermatitis, desquamation

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome)

Acute Generalised Exanthematous Pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

• Muscle cramp, shoulder pain

Muscular weakness

Renal and urinary disorders

• Renal insufficiency, acute renal insufficiency, increases in serum creatinine, serum urea, decreases in serum bicarbonate, serum creatinine and serum potassium, increases in serum LDH, serum phosphorus, serum potassium

Increases in urine bacteria, urine white blood cells, urine epithelial cells and urine red blood cells; urine yeast present, increase in urobilinogen

Pregnancy, puerperium and perinatal conditions

• Abortion

Reproductive system and breast disorders

• Vaginitis, Vaginal pruritus, genital bleeding

General disorders and administrative site conditions

• Infusion site erythema, infusion site pain, infusion site phlebitis, infusion site swelling

Asthenia/fatigue, oedema/swelling, fever, pain, chest pain, malaise, infusion site induration, infusion site pruritis, infusion site warmth

1: Medicine related adverse effect reported during parenteral therapy in paediatric patients.

2: Medicine related adverse effect reported during parenteral therapy in both adult and paediatric patients.

Post-marketing adverse events:

System organ class Frequency unknown (cannot be estimated from available data)

Immune system disorders Anaphylaxis including anaphylactoid reactions

Psychiatric disorders Altered mental status, agitation, aggression, delirium, disorientation, mental status changes

Nervous system disorders Depressed level of consciousness, dyskinesia, gait disturbance. hallucinations, myclonus, tremor

Gastrointestinal disorders Teeth staining

Skin and subcutaneous tissue disorders Urticaria, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome)

Musculoskeletal and connective tissue disorders Muscular weakness

c) Description of selected adverse reactions

In clinical studies, seizure was reported during parenteral therapy in 0,2 % of patients treated with ERTAPENEM ASPEN. In the majority of clinical studies, parenteral therapy was followed by a switch to an appropriate oral antimicrobial.

d) Paediatric population

The overall safety profile is comparable to that in adult patients. In clinical trials, the most common medicine-related clinical adverse experiences reported during parenteral therapy were diarrhoea (5,5 %), infusion site pain (5,5 %) and infusion site erythema (2,6 %). In paediatric patients the most frequently observed medicine u2013 related laboratory abnormality during parenteral therapy in patients receiving ERTAPENEM ASPEN was decreases in neutrophil count, and elevations in ALT and AST.

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: https://www.sahpra.org.za/health-products-vigilance/

Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088

Symptoms

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).

Treatment

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