4.1. Therapeutic indications

Renapime is indicated in the treatment of infections caused by bacteria that are cefepime-sensitive:

- lower respiratory tract infections, including nosocomial pneumonia and community acquired pneumonia, acute bacterial exacerbation of chronic bronchitis and secondary bacterial infection of acute bronchitis;

- uncomplicated and complicated urinary tract infections, including pyelonephritis;

- skin and subcutaneous infections;

- intra-abdominal infections, including peritonitis and biliary tract infections;

- gynaecological infections;

- bacterial meningitis in infants and children;

- In combination with other antibacterial agents in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection;

- Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Renapime can be administered via intravenous use or intramuscular use.

After reconstitution, the solution is yellow to yellow-brown.

The usual dose and the route of administration vary in accordance with the severity of the infection, the renal function and the general conditions of the patient.

The IV route of administration is preferable in the patients with severe infections or in a life-threatening situation, particularly if there is the possibility of shock.

Adults and children weighing > 40 kg with normal renal function:

Severity of the infection

Dosage and route of

administration

Interval between the

doses

Mild to moderate urinary tract infections (UTI)

500 mg to 1 g

IV or IM

every 12 h

Other mild to moderate infections (non UTI)

1 g

IV or IM

every 12 h

Severe infections

2 g IV

every 12 h

Very severe or life-threatening infections

2 g IV

every 8 h

The usual treatment duration is 7 to 10 days; more severe infections can require a more prolonged treatment. In the empirical treatment of febrile neutropenia, the usual treatment duration should not be less than 7 days or until the resolution of the neutropenia.

In patients weighing ≤ 40 kg, the posology indicated for the children is recommended.

Elderly:

No dose adjustment is required in patients with normal renal function; the dose adjustment is recommended in patients with impaired renal function (see section 4.4).

Adults with renal insufficiency:

The cefepime dose should be adjusted to compensate the slower renal elimination rate. In adult patients with mild to moderate renal insufficiency, the initial dose of cefepime recommended should be the same as for patients with normal renal function. The recommended maintenance dose should be in accordance with the instructions of the table below.

When only the serum creatinine values are available, the (Cockcroft and Gault) formula can be used to calculate the creatinine clearance. The serum creatinine should represent a steady-state of renal function:

Man: Creatinine clearance (ml/min) = weight (kg) x (140 - age) 72 x serum creatinine (mg/dl)

Woman: 0.85 x value calculated using the man formula

Creatinine clearance (ml/min)

Recommended maintenance dose

> 50

Usual dose, no dose adjustment is required

2 g, 3x day

2 g, 2x day

1 g, 2x day

500 mg, 2x day

30 to 50

2 g, 2x day

2 g, 1x day

1 g, 1x day

500 mg, 1x day

11 to 29

2 g, 1x day

1 g, 1x day

500 mg, 1x day

500 mg, 1x day

< 10

1 g, 1x day

500 mg, 1x day

250 mg, 1x day

250 mg, 1x day

Haemodialysis*

500 mg, 1x day

500 mg, 1x day

500 mg, 1x day

500 mg, 1x day

*The pharmacokinetic models indicate that it is necessary to reduce the dose in these patients. In patients receiving cefepime and doing haemodialysis, the dose is 1 gram as loading dose in the first day of treatment followed by 500 mg daily for all the infections, except febrile neutropenia which is 1 gram daily. In the dialysis days, cefepime should be administered after dialysis. Cefepime should be administered, whenever possible, at the same time every day.

Patients doing dialysis

In the patient doing dialysis, about 68% of the total quantity of cefepime present in the body in the beginning of the dialysis will be removed during a 3 hour dialysis. In the patient doing continuous ambulatory peritoneal dialysis, cefepime can be administered in the same dosages that are recommended for the patients with normal renal function, i.e. 500 mg, 1 g or 2 g, depending on the severity of the infection, but with an interval of 48 hours between doses.

Children with normal renal function

In the child, the usual recommended dose is:

- Pneumonia, urinary tract infection, skin and subcutaneous tissue infection:

• Children aged more than 2 months and weighing ≤ 40 kg: 50 mg/kg every 12 hours for 10 days; in more severe infections, 8 hours interval between the intakes should be done.

- Bacteraemia that occurs in association with infections, bacterial meningitis and empirical treatment of febrile neutropenia:

• Children aged more than 2 months and weighing ≤ 40 kg: 50 mg/kg every 8 hours for 7 to 10 days.

The experience in children aged less than 2 months is limited. Despite the experience having been obtained with the 50 mg/kg dose, data from pharmacokinetic models obtained in children aged more than 2 months suggest that, in children from 1 month to 2 months old, a dose of 30 mg/kg every 12 or 8 hours can be considered. The administration of Renapime in these patients should be carefully monitored.

In the child weighing > 40 kg, it is recommended to use the dose indicated for adults. The maximum recommended dose for adults (2 g every 8 hours) should not be exceeded. The experience with the intramuscular use in children is limited.

Children with renal insufficiency:

As renal excretion is the main route of elimination of cefepime, the dose should be adjusted in children with renal insufficiency. A dose of 50 mg/kg in children from 2 months to 12 year old and a dose 30 mg/kg in children 1 month to 2 months are comparable to a 2 g dose in the adult.

The same interval between the doses is recommended or the same dose reduction indicated for the renal insufficient adult.

Patients with hepatic function impairment:

No dose adjustment is required in patients with hepatic insufficiency.

4.3. Contraindications

Hypersensitivity to cefepime, to any other cephalosporin or to any of the excipients listed in section 6.1.

History of severe hypersensitivity reaction (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).

4.4. Special warnings and precautions for use

Hypersensitivity reactions

As with all beta-lactam antibacterial agents, severe and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefepime must be discontinued immediately and adequate emergency measures must be initiated.

Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to cefepime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefepime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Cefepime should be administered with caution to patients with a history of asthma or allergic diathesis. The patient must be carefully monitored during the first administration. If an allergic reaction occurs, treatment must be discontinued immediately.

Serious hypersensitivity reactions may require epinephrine and other supportive therapy.

Antibiotics should be administered with caution to patients that have shown some form of allergy, particularly to drugs. If there is an allergic reaction to Renapime, the medicine should be stopped and adequate treatment applied.

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).

As with other antibiotics, the use of Renapime can lead to the development of resistant micro-organisms. If superinfection occurs during treatment, adequate measures should be taken.

Renal impairment

In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency (creatinine clearance ≤ 50 mL/min) or other conditions that may compromise renal function, the dosage of cefepime 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 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 have been reported: reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including non- convulsive status epilepticus), and/or renal failure (see section 4.8 - Undesirable effects). Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommendations.

In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after haemodialysis, however, some cases included a fatal outcome.

Clostridium difficile associated diarrhoea

Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, has been reported in association with the use of nearly all antibiotics including cefepime and may range in severity from mild diarrhoea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of cefepime. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed, ongoing treatment with antibacterial agents, including cefepime, should be discontinued and adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in this situation.

It is known that cefepime is excreted substantially by the kidney and the risk of toxic reactions to this drug can be higher in the patients with renal insufficiency. Because elderly patients are more susceptible to have a decreased renal function, caution should be taken in the selection of the dose and renal function should be monitored (see section 5.2). In elderly patients with renal failure to whom the usual dose of cefepime was administered, severe adverse events occurred (see section 4.8) including reversible encephalopathy (conscience disturbance, including confusion, hallucinations, stupor and coma), myoclonus, convulsions (including non-convulsive status epilepticus) and/or renal failure.

Interference with serological testing

A positive Coombs test, without evidence of haemolysis, has been described in patients treated with cefepime twice daily.

Cephalosporin antibiotics may produce a false-positive reaction for glucose in the urine with copper reduction tests (Benedict's or Fehling's 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.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant treatment with bacteriostatic antibiotics may interfere with the action of beta-lactam antibiotics.

The monitoring of renal function is recommended during the treatment with Renapime if other drugs that have nephrotoxic potential are administered (i.e., aminoglycosides and potent diuretics).

Cephalosporins can potentiate the action of coumarin anticoagulants.

Interaction with diagnostic tests

In patients treated with Renapime 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).

4.6. Fertility, pregnancy and lactation

Pregnancy

In what concerns cefepime there are no sufficient data on its exposure in pregnancy.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, labour or post-natal development (see section 5.3).

This medicinal product should only be prescribed to pregnant women with great caution.

Breastfeeding

Cefepime is excreted in human milk in very low quantities, so caution is recommended when administered to the breast-feeding woman.

Fertility

There are no data on the use of cefepime in human fertility. Reproduction studies in animals did not reveal any effects on fertility.

4.7. Effects on ability to drive and use machines

The effects of the medicinal product on the ability to drive and use machines have not been studied. However, possible adverse reactions like altered state of consciousness, dizziness, confusional state or hallucinations may alter the ability to drive and use machines (see sections 4.4, 4.8 e 4.9).

4.8. Undesirable effects

In clinical trials (N=5598), the more common adverse events were gastrointestinal symptoms and hypersensitivity reactions. The undesirable effects considered as definitively, probably or possibly related to cefepime are listed.

The frequency of adverse reactions listed below, reported during the clinical experience or post-marketing experience, is defined using the following convention:

Very common (≥1/10)

Common (≥1/100 to < 1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (< 1/10,000) and

Not known (cannot be estimated from the available data).

The side effects are presented by decreasing order of severity within each class of frequency.

System organ class

Frequency

MedDRA term

Infections and infestations

Uncommon

Oral candidiasis, vaginal infection

Rare

Candidiasis

Blood and lymphatic system disorders

Common

Anaemia, eosinophilia

Uncommon

Thrombocytopenia, leukopenia, neutropenia

Not known

Aplastic anaemiaa, haemolytic anaemiaa, agranulocytosis

Immune system disorders

Rare

Anaphylactic reaction, angioedema

Not known

Anaphylactic shock

Psychiatric disorders

Not known

State of confusion, hallucination

Nervous system disorders

Uncommon

Headaches

Rare

Convulsions, paraesthesia, digeusia, dizziness

Not known

Coma, stupor, encephalopathy, altered state of conscience, myoclonus

Vascular disorders

Common

Phlebitis at the infusion site

Rare

Vasodilatation

Not known

Haemorrhage

Respiratory, thoracic and mediastinal disorders

Rare

Dyspnoea

Gastrointestinal disorders

Common

Diarrhoea

Uncommon

Pseudomembranous colitis, colitis, nausea, vomiting

Rare

Abdominal pain, constipation

Not known

Gastrointestinal disorder

Skin and subcutaneous tissue disorders

Common

Skin rash

Uncommon

Erythema, urticaria, pruritus

Not known

Toxic epidermal necrolysisa, Stevens-Johnson syndrome, erythema multiforme

Renal and urinary disorders

Uncommon

blood urea increased, blood creatinine increased

Not known

Renal failure, toxic nephropathya

Reproductive system and breast disorders

Rare

Genital pruritus

General disorders and administration site conditions

Common

Infusion site reaction, injection site inflammation and pain

Uncommon

Pyrexia, infusion site inflammation

Rare

Chills

Investigations

Very common

Positive Coombs test

Common

Alkaline phosphatase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, prothrombin time prolonged, partial thromboplastin time prolonged

Not known

False positive glycosuria

a – Adverse reactions generally accepted as being attributable to other compounds of the same class.

The safety profile of cefepime in infants and children is similar to that seen in the adult.

As with other drugs of the class of cephalosporins, 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 which received cefepime doses that exceeded those recommended (see section 4.4).

Such as with other cephalosporins, anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia were reported.

During clinical tests, 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 other frequency) 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 medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In case of severe overdose, especially in patients with renal function impairment, haemodialysis can help remove cefepime from the body (peritoneal dialysis is not useful).

Accidental overdose occurred with the administration of high doses to patients with decreased renal function (see sections 4.2 and 4.4).