Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Renascience Pharma Ltd, 11 George Street West, Luton, Bedfordshire, LU1 2BJ, United Kingdom
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).
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.
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.
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.
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.
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.
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.
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).
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.
Cefepime is excreted in human milk in very low quantities, so caution is recommended when administered to the breast-feeding woman.
There are no data on the use of cefepime in human fertility. Reproduction studies in animals did not reveal any effects on fertility.
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).
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.
Uncommon: Oral candidiasis, vaginal infection
Rare: Candidiasis
Common: Anaemia, eosinophilia
Uncommon: Thrombocytopenia, leukopenia, neutropenia
Not known: Aplastic anaemiaa, haemolytic anaemiaa, agranulocytosis
Rare: Anaphylactic reaction, angioedema
Not known: Anaphylactic shock
Not known: State of confusion, hallucination
Uncommon: Headaches
Rare: Convulsions, paraesthesia, digeusia, dizziness
Not known: Coma, stupor, encephalopathy, altered state of conscience, myoclonus
Common: Phlebitis at the infusion site
Rare: Vasodilatation
Not known: Haemorrhage
Rare:__ Dyspnoea
Common: Diarrhoea
Uncommon: Pseudomembranous colitis, colitis, nausea, vomiting
Rare: Abdominal pain, constipation
Not known: Gastrointestinal disorder
Common: Skin rash
Uncommon: Erythema, urticaria, pruritus
Not known: Toxic epidermal necrolysisa, Stevens-Johnson syndrome, erythema multiforme
Uncommon: blood urea increased, blood creatinine increased
Not known: Renal failure, toxic nephropathya
Rare: Genital pruritus
Common: Infusion site reaction, injection site inflammation and pain
Uncommon: Pyrexia, infusion site inflammation
Rare: Chills
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 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.
Cefepime must not be mixed with other medicinal products or solutions except those mentioned in section 6.6 “Special precautions for disposal and other handling”.
There is a physical-chemical incompatibility with metronidazole, vancomycin, gentamicin, tobramycin, netilmicin and aminophylline. In the cases where a concomitant intravenous administration is indicated, these active substances should not be administered together with cefepime or through the same intravenous route.
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