Cefepime

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

* 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.

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.

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. 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.

Cephalosporins can potentiate the action of coumarin anticoagulants.

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

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.

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.

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.

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.

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.

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.

Fertility

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 cefepime 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.

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.

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 anaemia^a, haemolytic anaemia^a, 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 necrolysis^a, Stevens-Johnson syndrome, erythema multiforme

Renal and urinary disorders

Uncommon: blood urea increased, blood creatinine increased

Not known: Renal failure, toxic nephropathy^a

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.

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%).