- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal status
|Zinacef strength||Amount of sodium per vial|
|250 mg||14 mg|
|750 mg||42 mg|
|1.5 g||83 mg|
Table 1. Adults and children ≥ 40 kg
|Community acquired pneumonia and acute exacerbations of chronic bronchitis||750 mg every 8 hours (intravenously or intramuscularly)|
|Soft-tissue infections: cellulitis, erysipelas and wound infections.|
|Complicated urinary tract infections, including pyelonephritis||1.5 g every 8 hours (intravenously or intramuscularly)|
|Severe infections||750 mg every 6 hours (intravenously) 1.5 g every 8 hours (intravenously)|
|Surgical prophylaxis for gastrointestinal, gynaecological surgery (including caesarean section) and orthopaedic operations||1.5 g with the induction of anaesthesia. This may be supplemented with two 750 mg doses (intramuscularly) after 8 hours and 16 hours|
|Surgical prophylaxis for cardiovascular and oesophageal operations||1.5 g with induction of anaesthesia followed by 750 mg (intramuscularly) every 8 hours for a further 24 hours|
Table 2. Children < 40 kg
|Infants and toddlers > 3 weeks and children < 40 kg||Infants (birth to 3 weeks)|
|Community acquired pneumonia||30 to 100 mg/kg/day (intravenously) given as 3 or 4 divided doses; a dose of 60 mg/kg/day is appropriate for most infections||30 to 100 mg/kg/day (intravenously) given as 2 or 3 divided doses (see section 5.2)|
|Complicated urinary tract infections, including pyelonephritis|
|Soft-tissue infections: cellulitis, erysipelas and wound infections|
Renal impairmentCefuroxime is primarily excreted by the kidneys. Therefore, as with all such antibiotics, in patients with markedly impaired renal function it is recommended that the dosage of Zinacef should be reduced to compensate for its slower excretion.
Table 3. Recommended doses for Zinacef in renal impairment
|Creatinine clearance||T1/2 (hrs)||Dose (mg)|
|> 20 mL/min/1.73 m2||1.72.6||It is not necessary to reduce the standard dose (750 mg to 1.5 g three times daily).|
|10-20 mL/min/1.73 m2||4.36.5||750 mg twice daily|
|< 10 mL/min/1.73 m2||14.822.3||750 mg once daily|
|Patients on haemodialysis||3.75||A further 750 mg dose should be given intravenously or intramuscularly at the end of each dialysis; in addition to parenteral use, cefuroxime sodium can be incorporated into the peritoneal dialysis fluid (usually 250 mg for every 2 litres of dialysis fluid).|
|Patients in renal failure on continuous arteriovenous haemodialysis (CAVH) or high-flux haemofiltration (HF) in intensive therapy units||7.912.6 (CAVH) 1.6 (HF)||750 mg twice daily; for low-flux haemofiltration follow the dosage recommended under impaired renal function.|
Hepatic impairmentCefuroxime is primarily eliminated by the kidney. In patients with hepatic dysfunction this is not expected to affect the pharmacokinetics of cefuroxime.
Method of administrationZinacef should be administered by intravenous injection over a period of 3 to 5 minutes directly into a vein or via a drip tube or infusion over 30 to 60 minutes, or by deep intramuscular injection. Intramuscular injections should be injected well within the bulk of a relatively large muscle and not more than 750 mg should be injected at one site. For doses greater than 1.5 g intravenous administration should be used. For instructions on reconstitution of the medicinal product before administration, see section 6.6. 750 mg, 1.5 g powder for solution for infusion (Monovial presentation).For instructions on preparation of the medicinal product before administration, see section 6.6.
Hypersensitivity reactionsAs with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefuroxime 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 cefuroxime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.
Concurrent treatment with potent diuretics or aminoglycosidesCephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide or aminoglycosides. Renal impairment has been reported during use of these combinations. Renal function should be monitored in the elderly and those with known pre-existing renal impairment (see section 4.2).
Overgrowth of non-susceptible microorganismsUse of cefuroxime may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment (see section 4.8).Antibacterial agentassociated pseudomembranous colitis has been reported with use of cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of cefuroxime (see section 4.8). Discontinuation of therapy with cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Intra-abdominal infectionsDue to its spectrum of activity, cefuroxime is not suitable for the treatment of infections caused by Gram-negative non-fermenting bacteria (see section 5.1).
Interference with diagnostic testsThe development of a positive Coomb's Test associated with the use of cefuroxime may interfere with cross matching of blood (see section 4.8).Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed. However, this should not lead to false-positive results, as may be experienced with some other cephalosporins.As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefuroxime sodium.
Important information about excipientsZinacef powder for solution for injection and infusion contains sodium. This should be considered for patients who are on a controlled sodium diet.
Potential nephrotoxic drugs and loop diureticsHigh-dosage treatments with cephalosporins should be carried out with caution on patients who are taking strong-acting diuretics (such as furosemide) or potential nephrotoxic preparations (such as aminoglycoside antibiotics), since impairment of renal function through such combinations cannot be ruled out.
Other InteractionsDetermination of blood/plasma glucose levels: refer to section 4.4.Concomitant use with oral anticoagulants may give rise to increased international normalised ratio (INR).
PregnancyThere are limited amounts of data from the use of cefuroxime in pregnant women. Studies in animals have shown no reproductive toxicity (see section 5.3). Zinacef should be prescribed to pregnant women only if the benefit outweighs the risk.Cefuroxime has been shown to cross the placenta and attain therapeutic levels in amniotic fluid and cord blood after intramuscular or intravenous dose to the mother.
BreastfeedingCefuroxime is excreted in human milk in small quantities. Adverse reactions at therapeutic doses are not expected, although a risk of diarrhoea and fungus infection of the mucous membranes cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from cefuroxime therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
FertilityThere are no data on the effects of cefuroxime sodium on fertility in humans. Reproductive studies in animals have shown no effects on fertility.
|System organ class||Common||Uncommon||Not known|
|Infections and infestations||Candida overgrowth, overgrowth of Clostridium difficile|
|Blood and lymphatic system disorders||neutropenia, eosinophilia, decreased haemoglobin concentration||leukopenia, positive Coomb's test||thrombocytopenia, haemolytic anaemia|
|Immune system disorders||drug fever, interstitial nephritis, anaphylaxis, cutaneous vasculitis|
|Gastrointestinal disorders||gastrointestinal disturbance||pseudomembranous colitis (see section 4.4)|
|Hepatobiliary disorders||transient rise in liver enzymes||transient rise in bilirubin|
|Skin and subcutaneous tissue disorders||skin rash, urticaria and pruritus||erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome, angioneurotic oedema|
|Renal and urinary disorders||elevations in serum creatinine, elevations in blood urea nitrogen and decreased creatinine clearance (see section 4.4)|
|General disorders and administration site conditions||injection site reactions which may include pain and thrombophlebitis|
|Description of selected adverse reactions Cephalosporins as a class tend to be absorbed onto the surface of red cell membranes and react with antibodies directed against the drug to produce a positive Coomb's test (which can interfere with cross matching of blood) and very rarely haemolytic anaemia. Transient rises in serum liver enzymes or bilirubin have been observed which are usually reversible. Pain at the intramuscular injection site is more likely at higher doses. However it is unlikely to be a cause for discontinuation of treatment.|
Paediatric populationThe safety profile for cefuroxime sodium in children is consistent with the profile in adults.
Reporting of suspected adverse reactionsReporting 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.
Mechanism of actionCefuroxime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.
Mechanism of resistanceBacterial resistance to cefuroxime may be due to one or more of the following mechanisms: • hydrolysis by beta-lactamases including (but not limited to) extended-spectrum beta-lactamases (ESBLs), and Amp-C enzymes, that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species; • reduced affinity of penicillin-binding proteins for cefuroxime; • outer membrane impermeability, which restricts access of cefuroxime to penicillin binding proteins in Gram-negative bacteria;• bacterial efflux pumps. Organisms that have acquired resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the mechanism of resistance, organisms with acquired resistance to penicillins may demonstrate reduced susceptibility or resistance to cefuroxime.Cefuroxime sodium breakpointsMinimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
|Streptococcus A, B, C and G||Note4||Note4|
|Non-species related breakpoints1||≤45||>85|
|1 The cephalosporin breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms (including ESBL and plasmid mediated AmpC). Some strains that produce beta-lactamases are susceptible or intermediate to 3rd or 4th generation cephalosporins with these breakpoints and should be reported as found, i.e. the presence or absence of an ESBL does not in itself influence the categorization of susceptibility. In many areas, ESBL detection and characterization is recommended or mandatory for infection control purposes. 2 Breakpoint relates to a dosage of 1.5 g × 3 and to E. coli, P. mirabilis and Klebsiella spp. only 3 Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility except for ceftazidme and cefixime and ceftibuten, which do not have breakpoints and should not be used for staphylococcal infections. 4 The susceptibility of streptococcus groups A, B, C and G to cephalosporins is inferred from the benzylpenicillin susceptibility. 5 Breakpoints apply to daily intravenous dose of 750 mg × 3 and a high dose of at least 1.5 g × 3.|
Microbiological susceptibilityThe prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is known and the utility of the agent in at least some types of infections is questionable.Cefuroxime is usually active against the following microorganisms in vitro.
|Commonly susceptible species|
|Gram-positive aerobes: Staphylococcus aureus (methicillin-suscpetible) $ Streptococcus pyogenes Streptococcus agalactiae|
|Gram-negative aerobes: Haemophilus parainfluenzae Moraxella catarrhalis|
|Microorganisms for which acquired resistance may be a problem|
|Gram-positive aerobes: Streptococcus pneumoniae Streptococcus mitis (viridans group)|
|Gram-negative aerobes: Citrobacter spp. not including C. freundii Enterobacter spp. not including E. aerogenes and E. cloacae Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Proteus mirabilis Proteus spp. not including P. penneri and P. Vulgaris Providencia spp. Salmonella spp.|
|Gram-positive anaerobes: Peptostreptococcus spp. Propionibacterium spp.|
|Gram-negative anaerobes: Fusobacterium spp. Bacteroides spp.|
|Inherently resistant microorganisms|
|Gram-positive aerobes: Enterococcus faecalis Enterococcus faecium|
|Gram-negative aerobes: Acinetobacter spp. Burkholderia cepacia Campylobacter spp. Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Morganella morganii Proteus penneri Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens Stenotrophomonas maltophilia|
|Gram-positive anaerobes: Clostridium difficile|
|Gram-negative anaerobes: Bacteroides fragilis|
|Others: Chlamydia spp. Mycoplasma spp. Legionella spp.|
AbsorptionAfter intramuscular (IM) injection of cefuroxime to normal volunteers, the mean peak serum concentrations ranged from 27 to 35 µg/mL for a 750 mg dose and from 33 to 40 µg/mL for a 1000 mg dose, and were achieved within 30 to 60 minutes after administration. Following intravenous (IV) doses of 750 and 1500 mg, serum concentrations were approximately 50 and 100 µg/mL, respectively, at 15 minutes. AUC and Cmax appear to increase linearly with increase in dose over the single dose range of 250 to 1000 mg following IM and IV administration. There was no evidence of accumulation of cefuroxime in the serum from normal volunteers following repeat intravenous administration of 1500 mg doses every 8 hours.
DistributionProtein binding has been stated as 33 to 50%, depending on the methodology used. The average volume of distribution ranges from 9.3 to 15.8 L/1.73 m2 following IM or IV administration over the dosage range of 250 to 1000 mg. Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in the tonsilla, sinus tissues, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum and aqueous humour. Cefuroxime passes the blood-brain barrier when the meninges are inflamed.
BiotransformationCefuroxime is not metabolised.
EliminationCefuroxime is excreted by glomerular filtration and tubular secretion. The serum half-life after either intramuscular or intravenous injection is approximately 70 minutes. There is an almost complete recovery (85 to 90%) of unchanged cefuroxime in urine within 24 hours of administration. The majority of the cefuroxime is excreted within the first 6 hours. The average renal clearance ranges from 114 to 170 mL/min/1.73 m2 following IM or IV administration over the dosage range of 250 to 1000 mg.
Special patient populations
GenderNo differences in the pharmacokinetics of cefuroxime were observed between males and females following a single IV bolus injection of 1000 mg of cefuroxime as the sodium salt.
ElderlyFollowing IM or IV administration, the absorption, distribution and excretion of cefuroxime in elderly patients are similar to younger patients with equivalent renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in cefuroxime dose selection, and it may be useful to monitor renal function (see section 4.2).
PaediatricsThe serum half-life of cefuroxime has been shown to be substantially prolonged in neonates according to gestational age. However, in older infants (aged >3 weeks) and in children, the serum half-life of 60 to 90 minutes is similar to that observed in adults.
Renal impairmentCefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. C1cr <20 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion (see section 4.2). Cefuroxime is effectively removed by haemodialysis and peritoneal dialysis.
Hepatic impairmentSince cefuroxime is primarily eliminated by the kidney, hepatic dysfunction is not expected to have an effect on the pharmacokinetics of cefuroxime.
PK/PD relationshipFor cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefuroxime for individual target species (i.e. %T>MIC).
Instructions for constitutionTable 4. Additional volumes and concentrations which may be useful when fractional doses are required.
|Additional volumes and concentrations, which may be useful when fractional doses are required|
|Vial size||Routes of administration||Physical State||Amount of water to be added (mL)||Approximate cefuroxime concentration (mg/mL)**|
|250 mg powder for solution for injection|
|250 mg||intramuscular intravenous bolus Intravenous infusion||suspension solution solution||1 mL at least 2 mL at least 2 mL*||216 116 116|
|750 mg powder for solution for injection or infusion|
|750 mg||intramuscular intravenous bolus intravenous infusion||suspension solution solution||3 mL at least 6 mL at least 6 mL||216 116 116|
|1.5 g powder for solution for injection or infusion|
|1.5 g||intramuscular intravenous bolus intravenous infusion||suspension solution solution||6 mL at least 15 mL 15 mL*||216 94 94|
Preparation of solution for intravenous infusionThe contents of the Monovial are added to small volume infusion bags containing 0.9% w/v Sodium Chloride Injection BP, or 5% Dextrose Injection, or another compatible fluid.1. Peel off the removable top part of the label and remove the cap.2. Insert the needle of the Monovial into the additive port of the infusion bag.3. To activate, push the plastic needle holder of the Monovial down onto the vial shoulder until a "click" is heard.4. Holding it upright, fill the vial to approximately two-thirds capacity by squeezing the bag several times.5. Shake the vial to reconstitute the cefuroxime sodium.6. With the vial uppermost, transfer the reconstituted cefuroxime sodium into the infusion bag by squeezing and releasing the bag.7. Repeat steps 4 to 6 to rinse the inside of the vial. Dispose of the empty Monovial safely. Check that the powder has dissolved, and that the bag has no leaks.
Compatibility1.5 g cefuroxime sodium constituted with 15 mL Water for Injection may be added to metronidazole injection (500 mg/100 mL) and both retain their activity for up to 24 hours below 25°C.1.5 g cefuroxime sodium is compatible with azlocillin 1 g (in 15 mL) or 5 g (in 50 mL) for up to 24 hours at 4°C or 6 hours below 25°C.Cefuroxime sodium (5 mg/mL) in 5% w/v or 10% w/v xylitol injection may be stored for up to 24 hours at 25°C.Cefuroxime sodium is compatible with aqueous solutions containing up to 1% lidocaine hydrochloride.Cefuroxime sodium is compatible with the following infusion fluids. It will retain potency for up to 24 hours at room temperature in: 0.9% w/v Sodium Chloride Injection BP 5% Dextrose Injection BP 0.18% w/v Sodium Chloride plus 4% Dextrose Injection BP 5% Dextrose and 0.9% w/v Sodium Chloride Injection BP 5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.225% Sodium Chloride Injection 10% Dextrose Injection 10% Invert Sugar in Water for Injection Ringer's Injection USP Lactated Ringer's Injection USP M/6 Sodium Lactate Injection Compound Sodium Lactate Injection BP (Hartmann's Solution).The stability of cefuroxime sodium in 0.9% w/v Sodium Chloride Injection BP and in 5% Dextrose Injection is not affected by the presence of hydrocortisone sodium phosphate.Cefuroxime sodium has also been found compatible for 24 hours at room temperature when admixed in IV infusion with:Heparin (10 and 50 units/mL) in 0.9% w/v Sodium Chloride Injection BP; Potassium Chloride (10 and 40 mEqL) in 0.9% w/v Sodium Chloride Injection BP.Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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