Merobax 500 mg/000 mg Solution

MEROBAX is indicated for treatment of the following infections, caused by single or multiple susceptible bacteria and as empiric therapy prior to the identification of the causative organisms:

• Acute exacerbation of chronic bronchitis and pneumonia due to: Staphylococcus aureus (methicillin susceptible strains only), Streptococcus pneumoniae, Streptococcus spp., Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Pseudomonas aeruginosa, Moraxella (Branhamella) catarrhalis, Klebsiella spp, Enterobacter cloacae, Enterobacter spp., Acinetobacter spp.
• Pneumonia in children due to: Staphylococcus aureus (methicillin susceptible strains only), Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa.
• Urinary tract infections in adults and children, including complicating infections due to: Enterobacter cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, Citrobacter freundii.
• Pelvic inflammatory disease (including tubo-ovarian abscess) and endometritis due to: Enterococcus faecalis, Staphylococcus aureus (methicillin susceptible strains only), coagulase-negative Staphylococcus spp. (methicillin susceptible strains only), Streptococcus agalactiae (Group B), Streptococcus viridans, Streptococcus spp., Escherichia coli, Neisseria gonorrhoeae, Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae, Proteus mirabilis, Acinetobacter anitratus, Acinetobacter lwoffii, Gardnerella vaginalis, Bacteroides fragilis group, Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus.
• Skin and skin structure infections in adults due to: Staphylococcus aureus (methicillin susceptible strains only), coagulase-negative Staphylococcus spp (methicillin susceptible strains only), Streptococcus pyogenes (Group A), Streptococcus agalactiae, Streptococcus viridans, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Peptostreptococcus spp.
• Meningitis in adults and children due to: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis.
• Septicaemia in adults and children due to: Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumonia.
• Empiric treatment, including initial monotherapy, for presumed bacterial infections in host-compromised neutropenic patients due to: Streptococcus epidermidis, Streptococcus mitis, Streptococcus sanguinis, Escherichia coli.
• Intra-abdominal abscess and peritonitis due to: Streptococcus milleri, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa, Bacteroides fragilis group (including Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus), Clostridium perfringens, Streptococcus mitior.
• Polymicrobial infections. In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside should be administered concomitantly.

Posology

Adults: Usual dose: 500 mg to 1 000 mg is administered by intravenous infusion every 8 hours, depending on the type or severity of the infection, the known or suspected susceptibility of the pathogen(s) and the condition of the patient.

Dose exceptions:

• Febrile episodes in neutropenic patients u2013 the dose should be 1 000 mg every 8 hours.
• Meningitis u2013 the dose should be 2 000 mg every 8 hours.

Caution may be required in using beta-lactam antibiotics in critically ill patients with known or suspected Pseudomonas aeruginosa lower respiratory tract infections. Concomitant use of an aminoglycoside is recommended. Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa.

Special populations

Dosage schedule for adults with impaired renal function

The dosage should be reduced in patients with creatinine clearance less than 51 ml/minute, as scheduled below.

Creatinine clearance (ml per minute) Dose (based on u201cunitu201d dose range of 500 mg to 2 000 mg every 8 hours u2013 see above) Frequency

• 26 u2013 50 one unit dose every 12 hours
• 10 -25 one-half unit dose every 12 hours
• < 10 one-half unit dose every 24 hours

Dosage for the treatment of adults on haemodialysis: MEROBAX is cleared from the circulation by haemodialysis. If continued treatment with MEROBAX is necessary, the required dose should be used at completion of the haemodialysis cycle to re-institute effective treatment. There is no experience with peritoneal dialysis.

Adults with hepatic insufficiency

No dosage adjustment is necessary in patients with impaired hepatic metabolism.

Elderly

No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 ml/minute.

Paediatric population

Safety and efficacy in babies under 3 months have not been established. For infants and children over 3 months and up to 12 years of age: The intravenous dose is 10 u2013 40 mg/kg every 8 hours, depending on the type and severity of the infection, the known or suspected susceptibility of the pathogen(s) and the condition of the patient. For children > 50 kg: The dosage as indicated for adults should be used. Dose exceptions: Meningitis: The dose should be 40 mg/kg every 8 hours. There is no experience in children with renal impairment.

Method of administration

MEROBAX should be given as an intravenous bolus injection* over approximately 5 minutes or by intravenous infusion** over approximately 15-30 minutes.

* For instructions on reconstitution of MEROBAX before administration, see section 6.6.

** For further dilution for infusion, see section 6.6. See instructions for compatibility and stability in sections 6.2, 6.3 and 6.6.

In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose should be administered for at least 10 days.

MEROBAX is contraindicated in:

• Patients with hypersensitivity to meropenem or any of the other ingredients of MEROBAX (see section 6.1).
• Patients hypersensitive to carbapenems, penicillins or other beta-lactam antibacterials (e.g., cephalosporins, imipenem) may be hypersensitive to meropenem as in MEROBAX.
• Pregnancy and lactation (see section 4.6).

Prescribers must adhere to the principles of antibiotic stewardship. The selection of meropenem to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial medicine based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial medicines and the risk of selecting for carbapenem-resistant bacteria.

Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. resistance: Prescribers are advised to consider the local prevalence of resistance in these bacteria to penem antibiotics.

Paediatric use: Efficacy and tolerability in infants under 3 months of age have not been established and MEROBAX is only approved for children over 3 months of age (see section 4.2).

Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions have been reported (see sections 4.3 and 4.8). Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to meropenem (see section 4.3). Before initiating therapy with MEROBAX, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If a severe allergic reaction occurs, MEROBAX should be discontinued and appropriate measures taken.

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalised exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem (see section 4.8). If signs and symptoms suggestive of these reactions appear, MEROBAX should be withdrawn immediately, and an alternative treatment should be considered.

Antibiotic-associated colitis: Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial medicines, including meropenem, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of MEROBAX (see section 4.8). Discontinuation of therapy with MEROBAX and the administration of specific treatment for Clostridium difficile should be considered. Medicines that inhibit peristalsis should not be given.

Seizures: Seizures have infrequently been reported during treatment with carbapenems, including meropenem as in MEROBAX. Special care is necessary in patients with central nervous system (CNS) disorders such as epilepsy (see section 4.8).

Hepatic function monitoring: Hepatic function should be closely monitored during treatment with MEROBAX due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see section 4.8). Patients with pre-existing liver disorders should have liver function monitored during treatment with MEROBAX. There is no dose adjustment necessary (see section 4.2).

Direct antiglobulin test (Coombs test) seroconversion: A positive direct or indirect Coombs test may develop during treatment with MEROBAX.

Concomitant use with valproic acid/sodium valproate/valpromide: The concomitant use of MEROBAX and valproic acid/sodium valproate/valpromide is not recommended (see section 4.5).

No specific interaction studies other than probenecid were conducted.

Probenecid: Probenecid inhibits the renal excretion of MEROBAX thereby increasing its plasma concentrations and prolonging the elimination half-life. As the potency and duration of action of MEROBAX dosed without probenecid are adequate, the co-administration of probenecid with MEROBAX is not recommended.

The potential effect of meropenem on the protein binding of other medicines or metabolism has not been studied. However, the protein binding is so low that no interactions with other compounds would be expected on the basis of this mechanism.

Valproate/valproic acid: Valproic acid plasma levels may be reduced by meropenem when it is co-administered with carbapenem medicines, resulting in a 60-100 % decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, co-administration of valproic acid/sodium valproate/valpromide with carbapenem medicines is not considered to be manageable and therefore should be avoided (see section 4.4).

Oral anti-coagulants: Simultaneous administration of MEROBAX with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti-coagulant medicines, including warfarin, in patients who are concomitantly receiving antibacterial medicines. The risk may vary with the underlying infection, age, and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of antibiotics with an oral anti-coagulant.

Paediatric population: Interaction studies have only been performed in adults.

Pregnancy: The safety in pregnant women has not been established. MEROBAX should therefore not be used during pregnancy (see section 4.3).

Breastfeeding: Meropenem is detectable at very low concentrations in animal breast milk. Small amounts of meropenem have been reported to be excreted in human milk. MEROBAX should not be used in breastfeeding mothers, or mothers should not breastfeed their babies if treatment with MEROBAX is deemed essential for them.

Fertility: There is no data on fertility and the use of MEROBAX.

No studies on the effect on the ability to drive and use machines have been performed. However, when driving or operating machines, it should be considered that headache, paraesthesia and convulsions have been reported for meropenem.

Summary of the safety profile: Meropenem-related adverse reactions most frequently reported were diarrhoea, rash, nausea/vomiting, injection site inflammation, thrombocytosis and increased hepatic enzymes.

Tabulated summary of adverse reactions: In the table below all adverse reactions are listed by system organ class and frequency: frequent; less frequent; and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class Frequency Event

Infections and infestations Less frequent Oral and vaginal candidiasis, pharyngitis

Blood and the lymphatic system disorders Frequent Thrombocythaemia Less frequent Agranulocytosis, haemolytic anaemia, thrombocytopenia, neutropenia, leukopenia, eosinophilia, lymphadenopathy, positive direct or indirect antiglobulin test may develop

Immune system disorders Less frequent Anaphylaxis (see sections 4.3 and 4.4), angioedema

Metabolism and nutrition disorders Less frequent Hypoglycaemia

Psychiatric disorders Less frequent Delirium

Nervous system disorders Frequent Headache Less frequent Paraesthesia, convulsions (see section 4.4)

Vascular disorders Frequency Peripheral vascular disorder

Respiratory, thoracic, and mediastinal disorders Less frequent Epistaxis, apnoea

Gastrointestinal disorders Frequent Diarrhoea, abdominal pain, vomiting, nausea, constipation Less frequent Pseudomembranous colitis, antibiotic-associated colitis (see section 4.4)

Hepatobiliary disorders Frequent Increases in serum transaminases, bilirubin, alkaline phosphatase, lactic dehydrogenase

Skin and subcutaneous tissue disorders Frequent Rash, pruritus Less frequent Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme (see section 4.4), urticaria Frequency unknown Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP) (see section 4.4)

Renal and urinary disorders Less frequent Blood creatinine increased, blood urea increased

General disorders and administration site conditions Frequent Inflammation, pain, thrombophlebitis Less frequent Pain at the injection site

Paediatric population: Meropenem as in MEROBAX is approved for children over 3 months of age. There is no evidence of an increased risk of adverse reactions in children based on the limited available data. All reports were consistent with events observed in the adult population.

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 via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website.

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). In patients with renal impairment relative overdosage is possible if the dose is not adjusted as described in section 4.2.

Treatment is symptomatic and supportive. In normal individuals, rapid renal elimination will occur. In patients with renal impairment, haemodialysis will remove MEROBAX and its metabolite.