Cefepime 1 G/2 G Solution

Adults

CEFEPIME FRESENIUS is indicated in the treatment of the infections listed below when caused by susceptible bacteria. Culture and susceptibility studies should be performed to determine susceptibility of the causative organism(s) to cefepime.

Lower respiratory tract infections: Nosocomial and community - acquired pneumonia caused by Staphylococcus aureus (methicillin susceptible strains), Pseudomonas aeruginosa, Klebsiella species (including Klebsiella pneumoniae), Enterobacter species, Escherichia coli, Proteus mirabilis, Streptococcus pneumoniae (including intermediate penicillin resistant strains), Haemophilus influenzae (including beta - lactamase producing strains), Haemophilus parainfluenzae and Moraxella (Branhamella) catarrhalis (including beta - lactamase producing strains), including cases associated with bacteraemia. When P. aeruginosa is isolated or suspected, combination therapy with an aminoglycoside should be used.

Acute bacterial exacerbation of chronic bronchitis and acute bronchitis due to Streptococcus pneumoniae (including intermediate penicillin resistant strains), Haemophilus influenzae (including beta - lactamase - producing strains), Moraxella (Branhamella) catarrhalis (including beta - lactamase producing strains).

Urinary tract infections: Complicated urinary tract infections caused by Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis and Enterobacter species, including cases associated with bacteraemia. When P. aeruginosa is isolated or suspected, combination therapy with an aminoglycoside should be used. Uncomplicated urinary tract infections due to Escherichia coli, Proteus mirabilis, Klebsiella species and Enterobacter species.

Skin and skin structure infections: Skin and skin structure infections caused by Staphylococcus aureus (methicillin susceptible strains), Streptococcus pyogenes (Group A streptococci), Streptococcus agalactia (Group B streptococci), other u03b2 - haemolytic Streptococcus species, Enterobacter species, Klebsiella species, Proteus mirabilis, Morganella morganii, Escherichia coli, Serratia marcescens and Acinetobacter calcoaceticus.

Intra - abdominal infections: Complicated intra - abdominal infections including peritonitis and biliary tract infections caused by Escherichia coli, sensitive Pseudomonas aeruginosa. Peritonitis is often polymicrobial and may include anaerobic micro - organisms such as Bacteroides species which are resistant to cefepime. When resistant anaerobes are suspected, CEFEPIME FRESENIUS should be combined with an antibiotic effective against these micro - organisms, including cases associated with bacteraemia. In patients who are at risk of mixed aerobic - anaerobic infection, including infections in which Bacteroides fragilis may be present, concurrent therapy with an anti - anaerobic medicine is recommended.

Empiric treatment in febrile neutropenia: CEFEPIME FRESENIUS is indicated for empiric monotherapy of febrile neutropenia. Combination of cefepime with other appropriate medicines should be considered in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, hypotension at presentation, an underlying haematologic malignancy, or severe or prolonged neutropenia) or when called for by host or local epidemiological factors.

Paediatrics

CEFEPIME FRESENIUS is indicated in paediatric patients (2 months and older) for the treatment of the infections listed below when caused by susceptible bacteria, (when P. aeruginosa is isolated or suspected, combination therapy with an aminoglycoside should be used):

Lower respiratory tract infection: Pneumonia caused by S. aureus, S. pneumoniae, H. influenzae.

Urinary tract infections: Caused by E. coli.

Skin and skin structure: Infections caused by Staphylococcus epidermidis, Streptococcus, S. aureus, S. pyogenes.

Empiric treatment in febrile neutropenia: CEFEPIME FRESENIUS is indicated for empiric monotherapy of febrile neutropenia. Combination of CEFEPIME FRESENIUS with other appropriate antimicrobial medicines should be considered in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, hypotension at presentation, an underlying haematologic malignancy, or severe or prolonged neutropenia) or when called for by host or local epidemiological factors.

Posology

CEFEPIME FRESENIUS can be administered either intravenously or intramuscularly. The dosage and route depend upon the severity of the infection, susceptibility of causative organisms, site and type of infection, and upon age and renal function of the patient.

Adults

TABLE 1 : Recommended dosage schedule for adults and paediatric patients > 40 kg (or older than 12 years of age) with normal renal function:

SITE AND TYPE OF INFECTION DOSE FREQUENCY

Mild to moderate urinary tract infections (uncomplicated and complicated) 500 mg - 1g IV or IM 12 - hourly

Mild to moderate infections including bronchitis, skin and skin structure infections 1 g IV or IM 12 hourly

Severe infections including pneumonia, urinary tract infections, complicated intra - abdominal infections, including cases with an associated bacteraemia 2 g IV 12 hourly

Empiric treatment of fever in neutropenic patients 2 g IV 8 hourly

* Usual duration of therapy is 7 - 10 days; more severe infections may require longer treatment. In the treatment of beta - haemolytic streptococcal infections a therapeutic dose should be administered for at least 10 days. For empirical treatment of febrile neutropenia, usual duration of therapy is 7 days or until resolution of neutropenia.

Special populations

Elderly

Dose adjustment is not required, unless there is concurrent renal impairment.

Adults with impaired renal function

In patients with impaired renal function, the dose of CEFEPIME FRESENIUS should be adjusted to compensate for the slower rate of renal elimination. The recommended initial dose of CEFEPIME FRESENIUS in patients with mild to moderate renal impairment should be the same as in patients with normal renal function. The recommended maintenance doses of CEFEPIME FRESENIUS in patients with renal impairment are presented in TABLE 2.

When only a serum creatinine measurement is available, the following formula (Cockcroft and Gault equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Males: Creatinine clearance (ml/min) = Weight (kg) x (140 - age) / (0,82 x serum creatinine (micromole/L))

Females: 0,85 x value calculated using the formula for males.

Maintenance dose schedule for adults and adolescents (>12 years) with renal impairment:

TABLE 2: Maintenance dosing schedule in adult patients with renal impairment

Creatinine clearance (ml/min) Recommended maintenance dosage

> 50 Usual dose, no adjustment necessary

2 g 8 hourly

2 g 12 hourly

1 g 12 hourly

500 mg 12 hourly

30 - 50 1 g 8 hourly

2 g 24 hourly

1 g 24 hourly

500 mg 24 hourly

11 - 29 1 g 12 hourly

1 g 24 hourly

500 mg 24 hourly

500 mg 24 hourly

u2264 10 1 g 24 hourly

500 mg 24 hourly

250 mg 24 hourly

250 mg 24 hourly

Haemodialysis* 500 mg 24 hourly

500 mg 24 hourly

500 mg 24 hourly

500 mg 24 hourly

* Pharmacokinetic modelling indicates that reduced dosing for these patients is necessary.

Patients receiving CEFEPIME FRESENIUS who are undergoing concomitant haemodialysis should be dosed as follows: 1 gram loading dose on the first day of CEFEPIME FRESENIUS therapy and 500 mg per day thereafter. On dialysis days, CEFEPIME FRESENIUS should be administered following dialysis. Whenever possible CEFEPIME FRESENIUS should be administered at the same time each day.

Patients doing dialysis

In patients undergoing haemodialysis, approximately 68 % of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3 hour dialysis period. In patients undergoing continuous ambulatory peritoneal dialysis (CAPD), CEFEPIME FRESENIUS may be administered at the same dose recommended for patients with normal renal function at intervals of 48 hours.

Paediatric population

Paediatrics (aged 2 month up to 12 years with normal renal function and body weight of u2264 40 kg) Pneumonia, urinary tract infections, and skin structure infections: 50 mg/kg twelve hourly for 10 days. For more severe infections, an eight hourly dosage schedule can be used.

Empiric treatment of febrile neutropenia: Patients > 2 months of age with body weight < 40 kg: 50 mg/kg eight hourly for 7 - 10 days. Experience with the use of CEFEPIME FRESENIUS in paediatric patients < 2 months of age is limited. Administration of CEFEPIME FRESENIUS in these patients should be carefully monitored.

For paediatric patients with body weights > 40 kg, adult dosing recommendations apply (see TABLE 1). For patients older than 12 years who are < 40 kg, the dosage recommendations for younger patients < 40 kg should be used. Dosage in paediatric patients should not exceed the maximum recommended dosage in adults (2 g eight hourly). Experience with intramuscular administration in paediatric patients is limited.

Children with impaired renal function

Since urinary excretion is the primary route of elimination of cefepime in paediatric patients (see section 5.2), an adjustment of the dosage of CEFEPIME FRESENIUS should also be considered in patients < 12 years of age with renal impairment.

Method of administration

After reconstitution, CEFEPIME FRESENIUS can be administered via intravenous or intramuscular route. The reconstituted solution is yellow to yellow - brown.

Intravenous (IV) administration: The IV route of administration is preferable for patients with severe or life - threatening infections, particularly if the possibility of shock is present. The prepared solution (see section 6.6 for instructions) should be injected directly into the vein over a period of three to five minutes or injected into the tubing of an administration set while the patient is receiving a compatible IV fluid (see section 6.6 for a list of compatible fluids). For physical and chemical incompatibilities, refer to section 6.6. For intravenous infusion, reconstitute the 1 g, or 2 g vial, as described in section 6.6 for direct IV administration. Dilute it further by adding the appropriate quantity of the resulting solution to an IV container with one of the compatible IV fluids identified in section 6.6. IV infusions of a volume between 50 ml and 100 ml should be administered over a period of approximately 30 minutes.

Intramuscular (IM) administration: CEFEPIME FRESENIUS should be reconstituted with one of the diluents described in section 6.6, then administered by deep IM injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus).

• Hypersensitivity to cefepime or any of the excipients of CEFEPIME FRESENIUS.
• Patients with history of hypersensitivity reactions to the cephalosporin class of antibiotics or beta - lactam antibiotics (e.g. penicillins, monobactams and carbapenems).

Hypersensitivity

Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly to medicines. Severe and occasionally fatal hypersensitivity reactions have been reported. If an allergic reaction to CEFEPIME FRESENIUS occurs, discontinue the medicine and treat the patient appropriately. Severe immediate hypersensitivity reactions may require epinephrine and other supportive therapy.

Colitis and antibiotic - associated colic and diarrhoea

Antibiotic - associated diarrhoea and antibiotic - associated colitis, including pseudomembranous colitis Clostridium difficile - associated diarrhoea, has been reported with nearly all broad - spectrum antibiotics, including CEFEPIME FRESENIUS. It may range in severity from mild diarrhoea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop diarrhoea in association with the use of CEFEPIME FRESENIUS. Careful medical history is necessary since Clostridium difficile associated diarrhoea has been reported to occur over two months after the administration of antibacterial medicines. Mild cases of colitis may respond to discontinuation of CEFEPIME FRESENIUS; moderate to severe cases may require more elaborate management. Medicines inhibiting peristalsis are contraindicated in this situation.

Antibacterial activity of cefepime

Due to the relatively limited spectrum of antibacterial activity of cefepime it is not suitable for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with cefepime (see section 5.1). Use of CEFEPIME FRESENIUS may result in overgrowth of non - susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

Renal impairment

Cefepime is predominantly excreted by the kidney and the risk of toxic reactions to CEFEPIME FRESENIUS is greater in patients with impaired renal function (see section 5.2 and u201cElderly patientsu201d below). Renal function should be monitored carefully if medicines with nephrotoxic potential, such as aminoglycosides and potent diuretics, are administered with CEFEPIME FRESENIUS. In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency (creatinine clearance u2264 50 mL/min) or other conditions that may compromise renal function, the dosage of CEFEPIME FRESENIUS should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal insufficiency or other conditions that may compromise renal function, the maintenance dosage should be reduced when CEFEPIME FRESENIUS is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms (see sections 4.2 and 5.2).

During post - marketing surveillance, the following serious adverse events were reported: reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure (see section 4.8). Most cases occurred in patients with renal impairment who received doses of CEFEPIME FRESENIUS that exceeded recommendations. In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after haemodialysis however, some cases included a fatal outcome.

Elderly patients (65 years and older)

In clinical studies, when elderly patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in younger adult patients unless the patients had renal insufficiency. There was a modest prolongation in elimination half - life and lower renal clearance values compared with those seen in younger people. Dosage adjustments are recommended if renal function is compromised (see section 4.2). Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection and renal function should be monitored (see section 4.8, 5.2 and u201cRenal impairmentu201d above).

Severe adverse events, including reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma) myoclonus, convulsions (including nonconvulsive status epilepticus), and/or renal failure have occurred in elderly patients with renal insufficiency given the usual dose of CEFEPIME FRESENIUS (see section 4.8).

Interference with serological testing

A positive Coombs test, without evidence of haemolysis, has been described in patients treated with CEFEPIME FRESENIUS twice daily (see section 4.5). Cephalosporin antibiotics (including CEFEPIME FRESENIUS) may produce a false - positive reaction for glucose in the urine with copper reduction tests (Benedictu2019s or Fehlingu2019s solution or with Clinitest tablets), but not with enzyme - based tests (glucose oxidase) for glycosuria. Therefore, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used (see section 4.5).

Concomitant treatment with bacteriostatic antibiotics may interfere with the action of beta - lactam antibiotics. Renal function should be monitored if CEFEPIME FRESENIUS is used in combination with potentially nephrotoxic medicines, such as aminoglycosides and potent diuretics. CEFEPIME FRESENIUS may potentiate the action of coumarin anticoagulants (warfarin). The renal excretion of CEFEPIME FRESENIUS may be inhibited by probenecid.

Interaction with diagnostic tests (see section 4.4)

In patients treated with cefepime, a positive Coombs test was described with no evidence of haemolysis. In the glycosuria test, a false - positive result may occur due to reduction of copper (the enzymatic method should preferably be used). False positives are not seen with glucose oxidase methods. For incompatibility information, see section 6.2.

Pregnancy

The safety of CEFEPIME FRESENIUS during pregnancy has not been established.

Breastfeeding

Cefepime is excreted in human breast milk in very low quantities. The safety of CEFEPIME FRESENIUS during lactation has not been established.

Fertility

There is no information available on the effect of CEFEPIME FRESENIUS on fertility.

Dizziness, confusional states and altered state of consciousness may be possible side effects of CEFEPIME FRESENIUS. Patients should be advised not to drive or use machinery if they experience any of these effects.

a. Summary of the safety profile

The most common side effects were gastrointestinal symptoms and hypersensitivity reactions. Adverse events that occurred are listed below by system organ class and frequency of occurrence.

b. Tabulated summary of adverse reactions

System organ class/ Adverse reactions (MedDRA term) Frequency

Infections and infestations Less frequent: Vaginitis, candidiasis (vaginal and oral), Clostridium difficile associated diarrhoea, colitis, pseudomembranous colitis. Frequency not known: Overgrowth of non - susceptible organisms

Blood and lymphatic system disorders Frequent: Anaemia, eosinophilia Less frequent: Thrombocytopenia, leukopenia, neutropenia Frequency not known: Agranulocytosis, aplastic or haemolytic anaemia

Immune system disorders Less frequent: Anaphylactic reaction, angioedema Frequency not known: Anaphylactic shock

Psychiatric disorders Frequency not known: State of confusion, hallucination

Nervous system disorders Less frequent: Headache, convulsions, paraesthesia, dysgeusia, dizziness Frequency not known: Coma, stupor, e ncephalopathy, altered state of consciousness, myoclonus

Vascular disorders Frequent: Phlebitis at the infusion site Less frequent: Vasodilation Frequency unknown: Haemorrhage

Respiratory, thoracic and mediastinal disorders Less frequent: Dyspnoea

Gastrointestinal disorders Frequent: Diarrhoea Less frequent: Nausea, vomiting, abdominal pain, constipation Frequency not known: Gastrointestinal disorder

Hepatobiliary disorders Frequent : Increased alkaline phosphatase, alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin Frequency not known: Hepatitis, cholestatic jaundice

Skin and subcutaneous tissue disorders Frequent: Skin rash Less frequent: Erythema, urticaria, pruritus Frequency unknown: Stevens - Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Renal and urinary disorders Less frequent: Increased blood urea, increased blood creatinine Frequency not known: Renal failure, toxic nephropathy

Reproductive system and breast disorders Less frequent: Genital pruritus

General disorders and administration site conditions Frequent: I nfusion site reaction, injection site inflammation and pain Less frequent: Pyrexia , infusion site inflammation, chills

Investigations Frequent: Coombs test positive, p rolonged prothrombin time, prolonged partial thromboplastin time Frequency not known: False - positive glycosuria

c. Description of selected adverse reactions

Encephalopathy (conscience disorder, including confusion, hallucinations, stupor and coma), convulsions, myoclonus and/or renal failure were reported. Most cases occurred in patients with renal impairment who received cefepime doses that exceeded those recommended (see sections 4.2 and 4.4). Anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia were reported. Changes in laboratory tests were transient in the patients with normal baseline values. The changes that occurred with a frequency between 1 % and 2 % (except when indicated otherwise) were: increased alanine aminotransferase (3,6 %), aspartate aminotransferase (2,5 %), alkaline phosphatase, total bilirubin, anaemia, eosinophilia, increased prothrombin time and thromboplastin time (2,8 %) and positive Coombs test with no haemolysis (18,7 %). The transient increases of uraemia, serum creatinine and thrombocytopenia were observed in 0,5 % to 1 % of the patients. Transient leukopenia and neutropenia were observed (< 0,5 %).

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. Health care 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 SAHPRA website. Healthcare providers are asked to report any suspected adverse drug reactions to the Holder of the Certificate of Registration at the following email address: safety.fksa@fresenius - kabi.com and to the relevant medicineu2019s regulatory authority in the country where the product is marketed.

Treatment should be symptomatic and supportive. In case of severe overdosage, especially in patients with compromised renal function, haemodialysis will aid in the removal of cefepime from the body; peritoneal dialysis is of no value. Accidental overdosing has occurred when large doses were given to patients with impaired renal function (see sections 4.2 and 4.8).