Covan Meropenem 500 mg/000 mg Solution

COVAN MEROPENEM is indicated for the treatment, in adults and children, of the following infections caused by single or multiple bacteria sensitive to meropenem and as empiric therapy prior to the identification of the causative organism.

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
• Branhamella catarrhalis
• Klebsiella pneumoniae
• Klebsiella spp.
• Enterobacter cloacae
• Enterobacter spp.
• Acinetobacter

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 complicated infections due to:

• Escherichia coli
• Pseudomonas aeruginosa
• Enterobacter cloacae
• Morganella morganii
• Proteus mirabilis
• Serratia marcescens
• Citrobacter freundii

Pelvic inflammatory disease (including tubo - ovarian abscess) and endometritis due to:

• Staphylococcus aureus (methicillin - susceptible strains only)
• Streptococcus haemolyticus
• Staphylococcus spp. (methicillin - susceptible strains only)
• Staphylococcus spp. (coagulase negative) (methicillin susceptible strains only)
• Streptococcus agalactiae
• Group B
• Pseudomonas aeruginosa
• Streptococcus spp.
• Streptococcus viridians
• Acinetobacter anitratus
• Acinetobacter lwoffii
• Enterobacter aerogenes
• Enterobacter cloacae
• Escherichia coli
• Gardnerella vaginalis
• Klebsiella pneumoniae
• Neisseria gonorrhoeae
• Proteus mirabilis

Skin and skin structure infections in adults due to:

• Escherichia coli
• Klebsiella pneumoniae
• Proteus mirabilis
• Pseudomonas aeruginosa
• Staphylococcus aureus (methicillin susceptible strains only)
• Coagulase negative Staphylococcus (methicillin susceptible strains only)
• Streptococcus agalactiae
• Group A Streptococcus
• Streptococcus viridans
• 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 pneumoniae

Empiric treatment, including initial monotherapy, for presumed bacterial infections in host - compromised neutropenic patients due to:

• Streptococcus sanguis
• Escherichia coli
• Pseudomonas aeruginosa
• Streptococcus epidermidis

Intra - abdominal abscess and peritonitis due to:

• Streptococcus milleri
• Streptococcus mitior
• Enterococcus faecalis
• Escherichia coli
• Klebsiella pneumonia
• Pseudomonas aeruginosa
• Bacteroides fragilis
• Bacteroides ovatus
• Bacteroides distasonis
• Klebsiella oxytoca
• Clostridium perfringens
• Polymicrobial infections

Posology

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

Exceptions:

• Febrile episodes in neutropenic patients - the dose should be 1 g every 8 hours.
• Meningitis - the dose should be 2 g 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.

Use in adults with impaired renal function: Adults with impaired renal function/ with creatinine clearance less than 51 mL/min may require a reduction in dose as given below:

Creatinine clearance

• 26 to 50 mL/min: One unit dose every 12 hours
• 10 to 25 mL/min: One - half unit dose every 12 hours
• < 10 mL/min: One - half unit dose every 24 hours

COVAN MEROPENEM is cleared by haemodialysis. If continued treatment is necessary, the unit dose based on the infection type and severity is recommended at the completion of the haemodialysis procedure to re - institute effective treatment.

Use in adults with hepatic insufficiency: No dosage adjustment is required 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/min.

Paediatrics population: Under 3 months of age: Efficacy and tolerability have not been established. 3 months to 12 years of age: the IV dose is 10 to 40 mg/kg every 8 hours depending on type and severity of infection, the known or suspected susceptibility of the pathogen(s), and the condition of the patient. In children over 50 kg weight, adult dosage should be used. Exceptions: Meningitis - the dose should be 40 mg/kg every 8 hours.

Method of administration

COVAN MEROPENEM should be given as an as an intravenous bolus injection over approximately 5 minutes or by intravenous infusion over approximately 15 to 30 minutes. For instructions on reconstitution and dilution of the medicine before administration, see section 6.6.

COVAN MEROPENEM is contraindicated in patients who have demonstrated hypersensitivity to meropenem or any ingredient of COVAN MEROPENEM. Patients who have a history of hypersensitivity to carbapenems, penicillins, or other beta - lactam antibiotics may also be hypersensitive to COVAN MEROPENEM.

Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8). Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta - lactam antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to beta - lactam antibiotics. If a severe allergic reaction occurs, the medicine should be discontinued and appropriate measures taken. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8).

Overgrowth of non - susceptible organisms such as Enterococcus faecium, strains of Pseudomonas aeruginosa, and Candida species may occur. Prescribers are advised to consider the local prevalence of resistance in these bacteria to penem antibiotics.

Skin reactions: Severe cutaneous adverse reactions (SCAR), such as Stevens - Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking beta - lactam antibiotics. When SCAR is suspected, beta - lactam antibiotics should be discontinued.

Seizures: Seizures have infrequently been reported during treatment with carbapenems, including meropenem (see section 4.8).

Hepatic function monitoring: Hepatic function should be closely monitored during treatment with meropenem due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see section 4.8). Use in patients with liver disease: patients with pre - existing liver disorders should have liver function monitored during treatment with meropenem. 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 meropenem.

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

Use in patients with renal insufficiency: COVAN MEROPENEM should be given with caution in patients with renal impairment (See section 4.2), and the dose reduced appropriately.

Geriatric use: Elderly patients are more likely to have an age - related decrease in renal function, which may require a reduction in dosage in these patients.

Use in patients with central nervous system disorders: Particular care is necessary in patients with epilepsy or brain lesions (see section 4.5).

Paediatric use: Efficacy and tolerability in infants under 3 months old have not been established, therefore COVAN MEROPENEM is not recommended for use below this age.

COVAN MEROPENEM contains sodium:

COVAN MEROPENEM 500 mg IV contains 45 mg sodium (main component of cooking/table salt) in each 500 mg dose. This is equivalent to 2,25 % of the recommended maximum daily dietary intake of sodium for an adult. COVAN MEROPENEM 1 000 mg IV contains 90 mg sodium (main component of cooking/table salt) in each 1 000 mg dose. This is equivalent to 4,5 % of the recommended maximum daily dietary intake of sodium for an adult. COVAN MEROPENEM is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

Probenecid inhibits the renal excretion of meropenem thereby increasing its plasma concentrations and prolonging its elimination half - life. Concurrent administration is not recommended.

COVAN MEROPENEM may reduce serum valproic acid levels. Sub - therapeutic levels may cause loss of seizure control (see section 4.4).

Oral anti - coagulants: Simultaneous administration of meropenem trihydrate 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 normalized ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after coadministration of antibiotics with an oral anti - coagulant medicine.

Pregnancy: The safety of COVAN MEROPENEM in human pregnancy has not been established.

Breastfeeding: COVAN MEROPENEM is detectable at very low concentrations in animal breast milk. It is not known whether COVAN MEROPENEM is distributed into human breast milk and therefore should not be used in breast - feeding women.

COVAN MEROPENEM is not known to interfere with the ability to drive and operate machinery.

a. Summary of the safety profile: In a review of patients treated with meropenem, the most frequently reported meropenem related adverse reactions were diarrhoea, nausea/vomiting and injection site inflammation. The most commonly reported meropenem related laboratory adverse events were thrombocytosis and increased hepatic enzymes.

b. Tabulated risk of adverse reactions: In the table below all adverse reactions are listed by system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class Frequency Event

Infections and Infestations Less frequent Pharyngitis, oral and vaginal candidiasis

Blood and lymphatic disorders Frequent Anaemia, thrombocythemia Less frequent Eosinophilia, leucopenia, neutropenia, thrombocytopenia, agranulocytosis, haemolytic anaemia, decreased haematocrit and haemoglobin

Immune system disorders Less frequent Systemic allergic reactions which may include angioedema and manifestations of anaphylaxis

Endocrine disorders Less frequent Hypoglycaemia

Nervous system disorders Less frequent Headache, convulsions, paraesthesia

Cardiac disorders Frequency not known Kounis syndrome

Vascular disorders Less frequent Shock, visceral vascular disorder

Respiratory, thoracic and mediastinal disorders Less frequent Apnoea, pneumonia

Gastrointestinal disorders Frequent Diarrhoea, nausea and vomiting Less frequent Constipation, bleeding, bleeding events (black, bloody stools; black, bloody vomit; nosebleed), gastrointestinal haemorrhage, haemoperitoneum, pseudomembranous colitis (see section 4.4).

Hepatobiliary disorders Frequent Increases in serum transaminases, alanine amino transferase (ALT), aspartate amino transferase (ASI), bilirubin, alkaline phosphatase and lactic dehydrogenase.

Skin and subcutaneous tissue disorders Less frequent Skin rash, pruritus, urticaria Frequency not known Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome), acute generalised exanthematous pustulosis (AGEP), erythema multiforme, Stevens - Johnson Syndrome, toxic epidermal necrolysis (TEN) and linear IgA disease.

Renal and urinary system disorders Less Frequent Increased serum creatinine, blood urea increased

General disorders and administration site conditions Frequent Inflammation at site of injection Less frequent Thrombophlebitis, pain at site of injection

Investigations Frequency not known Partial thromboplastin time and prothrombin time (INR) may be prolonged or shortened Positive direct or indirect antiglobulin (Coombsu2019) test

Paediatric population: COVAN MEROPENEM may be used in children over 3 months of age. There is no evidence of an increased risk of any adverse drug reaction in children based on the limited available data. All reports received were consistent with events observed in the adult population.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (Who - umc.org) found on SAHPRA website. For reporting side effects directly to the holder of the certificate of registration, contact +27 11635 0134 or email [email protected].

Accidental overdosage could occur during therapy particularly in patients with renal impairment. In the event of an overdose, the medication should be discontinued and symptomatic and supportive care administered until COVAN MEROPENEM can be eliminated through the kidneys. In patients with renal impairment, haemodialysis will remove COVAN MEROPENEM and its metabolite.