Data Sheet

CEFROM

Cefpirome Sulphate Sterile Powder for injection 0.25g, 0.5g, 1g, 2g vials.

Presentation

Cefpirome Sulphate is a white to pale yellowish, crystalline sterile powder supplied in vials for intravenous injection. CEFROM is available in 0.5g, 1g and 2g vials.

Uses

Actions

Cefpirome is a bactericidal β-lactamase-stable cephalosporin antibiotic. As a β-lactam, it acts by disturbing the synthesis of the main bacterial cell-wall polymer, peptidoglycan. It is bactericidal at low concentrations against an extremely broad spectrum of gram-negative and gram-positive pathogens because it penetrates the cell wall of bacteria extremely rapidly and binds to the target enzymes (penicillin-binding proteins) with high affinity.

Cefpirome is very stable against hydrolysis by broad spectrum plasmid-mediated and chromosomally-mediated β-lactamases and compared to third generation cephalosporins, has a lower affinity for these enzymes and is less likely to select active hyper producer mutants.

Furthermore cefpirome is more active against de-repressed mutants producing high level of cephalosporinase than third generation cephalosporins. Cefpirome shows synergistic activity with aminoglycosides against many bacteria.

Antibacterial Activity

The following organisms show in-vitro sensitivity to cefpirome:

GRAM-POSITIVE: Staphylococcus aureus (incl. penicillin-resistant strains), coagulase -negative Staphylococcus spp. (incl. penicillin-resistant but not methicillin-resistant strains), Streptococcus

Groups A (Streptococcus pyogenes ), B ( Streptococcus agalactiae ), C, F and G, Streptococcus mitis, Streptococcus sanguis, Streptococcus viridans, Streptococcus pneumoniae, Propionibacterium acnes, Peptostreptococcus anaerobius, Corynebacterium diphtheriae, Corynebacterium pyogenes.

GRAM-NEGATIVE: Citrobacter spp., Escherichia coli, Salmonella spp., Shigella spp., Klebsiella spp. (indole-positive and indole-negative), Enterobacter spp., Hafnia alvei, Serratia spp., Proteus mirabilis, Proteus vulgaris, Proteus rettgeri, Morganella morganii, Providencia spp., Yersinia enterocolitica, Pasteurella multocida, Haemophilus influenzae, Haemophilus ducreyi, Moraxella catarrhalis, Neisseria meningitidis, Neisseria gonorrhoeae, Aeromonas hydrophila.

Most strains of the following species show sensitivity to cefpirome in vitro:

GRAM-POSITIVE: Enterococcus faecalis, Clostridium spp.

GRAM-NEGATIVE: Pseudomonas aeruginosa, Pseudomonas spp. (non-aeruginosa), Acinetobacter spp., Bacteroides fragilis (non-β-lactamase-producing strains).

Most strains of the following species are resistant to cefpirome in vitro:

GRAM-POSITIVE: Enterococcus faecium, Listeria monocytogenes,

Clostridium difficile, Staphylococcus spp., (methicillin resistant strains).

GRAM-NEGATIVE : Xanthomonas maltophilia, Fusobacterium varium, Bacteroides fragilis (β-lactamase-producing strains).

Infections caused by the following pathogens have been successfully treated in clinical trials:

GRAM-POSITIVE: Staphylococcus aureus and coagulase-negative Staphylococcus spp. ( Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hominis, Staphylococcus warneri ), haemolytic and non-haemolytic streptococci, Streptococcus pyogenes (Group A), streptococci of serogroups B and F , Streptococcus pneumoniae, Streptococcus agalactiae, streptococci of the viridans group, Enterococcus faecalis, Corynebacterium spp.

GRAM-NEGATIVE: Escherichia coli, Enterobacter spp., indole-positive and indole-negative Klebsiella spp. and Proteus spp., Morganella morganii, Providencia spp., Citrobacter spp., Salmonella spp., Hafnia alvei, Serratia marcescens, Pasteurella multocida, Haemophilus influenzae and other Haemophilus species , Moraxella catarrhalis, Neisseria spp., Alcalagines spp., Pseudomonas aeruginosa and other Pseudomonas species, Acinetobacter calcoaceticus, Bacteroides spp.

Pharmacokinetics

Bioavailability and Absorption

Bioavailability after i.m. administration was greater than 90%.

Distribution

The average peak (C_5min) serum level after single i.v. doses of 1.0g was 80-90 mg/L. Pharmacokinetics were dose linear. The volume of distribution was 14-19L. No accumulation was seen after multiple dosing. The elimination half-life in serum was 1.8-2.2h.

Serum protein binding was less than 10% and was dose independent.

Rapid penetration into the following body tissues and fluids was observed:

Peak plasma levels were above the MICs for commonly encountered pathogens.

Biotransformation and Excretion

Cefpirome was principally eliminated by the kidney; 80-90% of the administered drug was recovered in the urine. Radioactive counts recovered in the urine consisted of 98-99% unchanged cefpirome Approximately 30% of a 1.0g dose was eliminated by haemodialysis.

Special Groups:

Elderly (>65 years)

The C_5min serum level after a single i.v dose of 2.0g to healthy elderly subjects was 174 mg/L. The elimination half-life in serum was 3.4h, and urinary excretion of the unchanged product was 71% after 24h. In patients older than 65 years, C_5min after i.v. doses of 1.0 and 2.0g amounted to 127.1 and 231.1 mg/L respectively.

The elimination half-lives after the same doses amounted to about 4.5 hours.

Renally Impaired Patients

The average elimination half-lives after single doses of 2.0g i.v. to patients with different degrees of renal impairment were as follows:

Dose adjustments are required in renally impaired patients only at creatinine clearance levels below 50 ml/min.

Cystic Fibrosis Patients

The pharmacokinetics of cefpirome were not altered in adult cystic fibrosis patients.

Indications

Hospital and community-acquired infections caused by bacterial organisms sensitive to cefpirome.

Lower respiratory tract infections (bronchopneumonia, lobar pneumonia); complicated upper (pyelonephritis) and lower urinary tract infections; skin and soft tissue infections (cellulitis wound infections); bacteraemia/septicaemia and severe infections in intensive care patients; infections in neutropenic and immunocompromised patients.

Cefpirome is to be used by the parenteral route, the dosage, mode of administration and duration of treatment depending upon the severity of the infection, sensitivity of the pathogens, condition of the patient and renal function.

Dosage and Administration

The following dosages are recommended for moderate to severe infections in patients with normal renal function:

For urinary tract and skin and soft tissue infections, the unit dose may be increased to 2.0g in very severe cases.

Dosage in Patients with Impaired Renal Function

Cefpirome is excreted principally by the kidney. The dose must therefore be reduced in patients with impaired renal function to compensate for the slower excretion.

The following doses are recommended for creatinine clearance.

Dosage in Elderly Patients

No adjustment is required unless renal impairment is present.

Intravenous Injection

The contents of one vial of 1.0 or 2.0g cefpirome are dissolved in 10 or 20 ml sterile water for injection respectively, and then injected over 3-5 minutes either directly into a vein or into the distal section of a clamped-off infusion tube. For patients with renal impairment, 0.25 or 0.5g cefpirome are dissolved in 2 or 5 ml of water for injection respectively.

Short Intravenous Infusion

The contents of one 1.0 or 2.0g vial of cefpirome are dissolved in 100 ml sterile water for injections and then infused over 20-30 minutes. The following infusion solutions may also be used: 0.9% sodium chloride solution, Ringer's solution, standard electrolyte infusion, 5 to 10% glucose solution, 5% fructose solution, 6% glucose + 0.9% sodium chloride solution.

Effervescence occurs on dissolution of cefpirome, and the vial has to be tipped gently from side to side for approximately 1 minute before cefpirome is completely dissolved. A pale yellow, clear solution is formed when the sterile powder is dissolved in water for injection.

The vials containing the solvent and powder for reconstitution should be held horizontal when preparing the infusion solution, and the cannula should be inserted rapidly. The amount of 100 ml solvent must be adhered to as precisely as possible.

Instructions for Use/Handling

The vials are manufactured under slight negative pressure. The negative pressure facilitates the addition of the solvent. Carbon dioxide is released when the solvent and the powder for reconstitution are mixed, and an increase in pressure occurs. The solution may still contain bubbles of carbon dioxide, but these have no adverse effects on efficacy.

Children

Cefpirome should not be used in children until adequate clinical experience has been gained.

Contraindications

Absolute

Hypersensitivity to cephalosporins

Relative

Possibility of cross-sensitivity in patients hypersensitive to penicillin.

Warnings and Precautions

This product should not ordinarily be given to those known to be allergic to penicillin or to cephalosporins especially if they have experienced an allergic or urticarial reaction.

Renal Insufficiency

The dosage of CEFROM should be adjusted according to the patient's creatinine clearance rate (see DOSAGE and ADMINISTRATION).

Renal Function

Caution should be exercised if cefpirome is administered together with aminoglycosides or loop diuretics. Renal function must be monitored in all such cases.

Pseudomembranous Colitis

Severe and persistent diarrhoea occurring during treatment or in the initial weeks thereafter, has been observed during treatment with antibiotics of several different classes. This may be symptomatic of pseudomembranous colitis (in most cases due to Clostridium difficile ) which may be fatal. This is a rare complication with cephalosporins. Once pseudomembranous colitis is diagnosed or suspected, treatment must be stopped immediately and specific antibiotic therapy must be started without delay (e.g. oral vancomycin or metronidazole). Products which may cause faecal stasis are contraindicated.

Superinfection

As with other antibiotics, the use of cefpirome, especially if prolonged, may result in overgrowth of non-susceptible organisms, including fungi. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pregnancy and Lactation

The safety of this medicinal product for use in human pregnancy has not been established. Cefpirome should, therefore, not be used during pregnancy. Evaluation of experimental animal studies has not indicated direct or indirect harmful effects with respect to reproduction, development of the embryo or foetus, the course of gestation and perinatal and postnatal development. Nursing mothers should not be treated with cefpirome pending further clinical experience.

Effects on Ability to Drive & Use Machines

There is no evidence that cefpirome impairs the ability to drive or operate machines.

Adverse Effects

Cefpirome is generally well tolerated. The overall incidence of adverse events possibly related to treatment (12.5%) was comparable to that of other cephalosporins used in the clinical trials. Cefpirome was discontinued in 5.1% of cases (5% for comparator cephalosporins).

The following adverse events have been reported with cefpirome:

Hypersensitivity Reactions

Angio-oedema, bronchospasm, malaise, possibly culminating in shock, may rarely occur (see PRECAUTIONS).

Cutaneous

Rash, pruritis, urticaria. As with other cephalosporins, isolated cases of bullous eruptions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported.

Effects on the Gastrointestinal Tract

Nausea and vomiting, abdominal pain, diarrhoea. The possibility of pseudomembranous colitis should be considered in patients in whom severe, persistent diarrhoea occurs during treatment or in the initial weeks thereafter.

Effects on Liver Function

Increased plasma levels of ASAT, ALAT, gamma-GT, LDH, bilirubin and/or alkaline phosphatase. These laboratory abnormalities, which may also be explained by the infection, may rarely exceed twice the upper limit of normal range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic.

Effects on Renal Function

Slight increases in serum creatinine were observed in clinical trials, but were only rarely a reason for discontinuing treatment. Interstitial nephritis has been observed in rare instances during treatment with other cephalosporins and the possibility of its occurrence with cefpirome should be borne in mind. Acute renal failure may occur in rare cases.

Changes in Blood Constituents

Thrombocytopenia; eosinophilia; very rarely, haemolytic anaemia. As with other β-lactam antibiotics, neutropenia and, more rarely, agranulocytosis may develop during treatment with cefpirome, particularly if given over long periods. For courses of treatment lasting longer than 10 days, the blood count should therefore be monitored.

Local Reactions

Phlebitis, thrombophlebitis and pain at the site of injection.

Central Nervous System

Very few cases of convulsions have been reported. Reversible encephalopathy (eg. impairment of consciousness, abnormal movements, convulsions) may occur with high doses of β-lactams including cefpirome, especially in patients with renal insufficiency

Cardiovascular System

Haemorrhage, ecchymosis, altered rhythm.

Respiratory

Dyspnoea.

Body as A Whole

Malaise, superinfection (see WARNINGS and PRECAUTIONS).

Others

Headache, fever, taste and/or smell disturbances shortly after injection.

Interactions

Medicine Interactions

Although there is no evidence that cefpirome adversely affects renal function at normal therapeutic doses, cephalosporin antibiotics may potentiate the nephrotoxic effects of certain medicines (e.g. aminoglycosides, loop diuretics) if administered concomitantly.

Probenecid interferes with the renal tubular transfer of cephalosporins, delaying their excretion and thereby increasing their plasma concentrations.

Other Interactions

A positive Coombs test result may be obtained in rare cases during treatment with cefpirome. Glycosuria should be determined by enzymatic methods during treatment as non-enzymatic methods may give a false-positive result.

Cefpirome gives a strong, creatinine-like reaction in creatinine assays based on the picrate method. The use of an enzyme method is recommended to avoid falsely high levels of creatinine. If an enzyme method is not available, blood sampling should be done immediately before administration of cefpirome or not earlier than 6h after, when the serum level is expected to be below the interference limit. Assays based on the picrate method should not be used in patients with creatinine clearance of < 50 ml/min.

Overdose

So far, there is no clinical experience with overdoses of cefpirome. There is a risk of reversible encephalopathy with high dose of β-lactam antibiotics including cefpirome.

Serum levels of cefpirome can be reduced by peritoneal dialysis and haemodialysis. Approximately 50% of the amount of cefpirome present in the body is eliminated by a 4 hour haemodialysis session.

Pharmaceutical Precautions

Incompatibilities

Cefpirome should not be administered in sodium bicarbonate solution.

Special Precautions for Storage

Store finished product (sterile powder) below +25°C. Protect from light.

Reconstituted Finished Product

As a general rule, cefpirome solutions should be used as soon as possible after reconstitution. They may be kept for up to 6 hours at room temperature in indoor light (do not expose to direct sunlight), or for 24 hours protected from light in a refrigerator at between +2° and +8°C, when prepared in Water for Injection or isotonic sodium chloride solution

Some intensification of colour may occur on storage of the reconstituted solution. However, provided the recommended storage conditions are observed, this does not indicate a change in potency or safety.

Medicine Classification

Prescription Medicine

Package Quantities

Single vials

Further Information

Sensitivity Testing

Sensitivity using the method recommended by the National Committee for Clinical Laboratory Standards, USA is as follows: