Msd-Ertapenem 1 g Powder for injection

MSD-ERTAPENEM is indicated for the treatment of adult patients with 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 pneumoniae (penicillin susceptible strains only) including cases with concurrent bacteraemia, Moraxella catarrhalis. If Community Acquired Pneumonia is caused by Haemophilus influenzae, MSD-ERTAPENEM 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.

Paediatric use

Safety and effectiveness of MSD-ERTAPENEM in paediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in paediatric patients, and additional data from comparator-controlled studies in paediatric patients 3 months to 17 years of age with the following infections:

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

Posology

The dose of MSD-ERTAPENEM in patients 13 years of age and older is 1 gram (g) given once a day. The usual dose of MSD-ERTAPENEM in patient 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1g/day). The usual duration of therapy with MSD-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.

Method of administration

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

Dosage Guidelines for Adults and Paediatric Patients with Normal Renal Function ** and Body Weight

** defined as creatinine clearance u02c3 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

Renal impairment

MSD-ERTAPENEM 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.

Haemodialysis

In a clinical study, 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 MSD-ERTAPENEM within 6 hours prior to haemodialysis, a supplementary dose of 150 mg is recommended following the haemodialysis session. If MSD-ERTAPENEM is given at least 6 hours prior to haemodialysis, no supplementary dose is needed. There are no data in patients undergoing peritoneal dialysis or hemofiltration. 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)

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

No dosage adjustment is recommended in patients with impaired hepatic function (see section 5.1 Pharmacokinetics, Hepatic insufficiency). The recommended dose of MSD-ERTAPENEM can be administered without regard to age (13 years of age and older) or gender.

MSD-ERTAPENEM is contraindicated in patients with known bacterial meningitis and hypersensitivity to any component of this product or to other medicines in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.

Due to the use of lidocaine (lignocaine) hydrochloride as a diluent, MSD-ERTAPENEM administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anaesthetics of the amide type and in patients with severe shock or heart block. (Refer to the prescribing information for lidocaine hydrochloride.)

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

MSD-ERTAPENEM is not recommended in the treatment of meningitis due to lack of sufficient CSF penetration.

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS INCLUDING MSD-ERTAPENEM. 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 MSD-ERTAPENEM, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO MSD-ERTAPENEM 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 and other CNS adverse experiences have been reported during treatment with MSD-ERTAPENEM (see below and section 4.8). During clinical investigations in adult patients treated with MSD-ERTAPENEM (1 g once a day), seizures, irrespective of drug relationship, occurred in 0,5 % of patients during study therapy plus 14 days follow-up period. These experiences have occurred most commonly in 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 MSD-ERTAPENEM re-examined to determine whether it should be decreased or discontinued.

Pseudomembranous colitis (antibiotic-associated colitis) has been reported with MSD-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 MSD-ERTAPENEM. Treatment with MSD-ERTAPENEM 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.

Lidocaine (Lignocaine) hydrochloride is the diluent for intramuscular administration of MSD-ERTAPENEM. Refer to the prescribing information for lidocaine (lignocaine) hydrochloride.

Prolonged use of MSD-ERTAPENEM 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.

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 MSD-ERTAPENEM is necessary, supplemental anti-convulsant therapy should be considered (see section 4.5).

Caution should be taken when administering MSD-ERTAPENEM intramuscularly, to avoid inadvertent injection into a blood vessel (see section 4.2).

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. Drug interactions caused by inhibition of P-glycoprotein-mediated drug clearance or CYP-mediated drug clearance are unlikely (see section 5.2 Distribution and Metabolism).

No specific clinical drug interaction studies have been conducted.

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. MSD-ERTAPENEM 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).

Pregnancy

Safety in pregnancy has not been established.

Breastfeeding

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

There are no data to suggest that MSD-ERTAPENEM affects the ability to drive and operate machinery.

Adult patients

The total number of patients treated with ertapenem in clinical studies was over 1 900 of which over 1 850 received a 1 g dose of MSD-ERTAPENEM. Most adverse experiences reported in these clinical studies were described as mild to moderate in severity. Medicine related adverse experiences were reported in approximately 20 % of patients treated with MSD-ERTAPENEM. MSD-ERTAPENEM was discontinued due to adverse experiences thought to be drug-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 %).

The following drug-related adverse experiences were reported during parenteral therapy in adult patients treated with ertapenem: very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u22651/1 000, < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (u2264 1/10 000), including isolated reports, not known (cannot be estimated from available data).

Common

• Nervous system disorders: headache
• Vascular disorders: infused vein complication, phlebitis/thrombophlebitis
• Gastrointestinal disorders: diarrhoea, nausea, vomiting.

Uncommon

• Nervous system disorders: dizziness, somnolence, insomnia, seizure, confusion
• Cardiac and vascular disorders: extravasation, hypotension
• Respiratory, thoracic and mediastinal disorders: dyspnoea
• Gastrointestinal disorders: oral candidiasis, constipation, acid regurgitation, C. difficile - associated diarrhoea, dry mouth, dyspepsia, anorexia
• Skin and subcutaneous tissue disorders: erythema, pruritus
• General disorders and administration site conditions: abdominal pain, taste perversion, asthenia/fatigue, candidiasis, oedema/swelling, fever, pain, chest pain
• Reproductive system and breast disorders: vaginal pruritus.

In clinical studies, seizure was reported during parenteral therapy in 0,2 % of patients treated with MSD-ERTAPENEM. 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, drug-related adverse experiences in patients treated with MSD-ERTAPENEM included those listed above as well as rash and vaginitis at an incidence of u2265 1,0 % (common) and allergic reactions, malaise and fungal infections at an incidence of u02c3 0,1 % but < 1,0 % (uncommon).

Paediatric patients

The total number of paediatric patients treated with MSD-ERTAPENEM in clinical studies was 384. 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 %).

The following medicine-related adverse experiences were reported during parenteral therapy in paediatric patients treated with MSD-ERTAPENEM:

Common

• Gastrointestinal disorders: diarrhoea, vomiting
• General disorders and administration site conditions: infusion site erythema, infusion site pain, infusion site phlebitis, infusion site swelling
• Skin and subcutaneous tissue disorders: rash.

Additional medicine-related adverse experiences that were reported during parenteral therapy in u02c3 0,5 % but < 1,0 % of patients treated with MSD-ERTAPENEM in clinical studies include: infusion site induration, infusion site pruritus, infusion site warmth and phlebitis.

In the paediatric clinical studies, the majority of the patients had parenteral therapy followed by a switch to an appropriate oral antimicrobial. During the entire treatment period and a 14-day post-treatment follow-up period, drug-related adverse experiences in patients treated with MSD-ERTAPENEM were no different than those listed above.

Post-marketing adverse events

The following post-marketing adverse experiences have been reported:

• Immune system disorders: anaphylaxis including anaphylactoid reactions
• Psychiatric disorders: altered mental status (including agitation, aggression, delirium, disorientation, mental status changes)
• Nervous system disorders: depressed level of consciousness, dyskinesia, gait disturbance. hallucinations, myoclonus, tremor, encephalopathy (recovery may be prolonged in patients with renal impairment)
• Gastrointestinal disorders: teeth staining
• Skin and subcutaneous tissue disorders: Acute Generalised Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), urticaria, hypersensitivity vasculitis
• Musculoskeletal, connective tissue and bone disorders: muscular weakness.

Laboratory test findings

Adult patients

The most frequently observed medicine-related laboratory abnormalities during parenteral therapy in patients receiving MSD-ERTAPENEM 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 MSD-ERTAPENEM were no different than those listed above.

Other medicine-related laboratory abnormalities included the following: increases in direct serum bilirubin (conjugated), total serum bilirubin, eosinophils, indirect serum bilirubin (unconjugated), PTT, urine bacteria, serum urea, serum creatinine, serum glucose, monocytes, urine epithelial cells, urine red blood cells; decreases in segmented neutrophils, white blood cells, haematocrit, haemoglobin and platelet count.

Paediatric patients

The most frequently observed medicine-related laboratory abnormality during parenteral therapy in patients receiving MSD-ERTAPENEM was decreases in neutrophil count. Other medicine-related laboratories abnormalities during the entire treatment period plus 14-day follow-up included the following: elevations in ALT, elevations in AST, decreases in white blood cells and increase in eosinophils.

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