Cefazolin 2g Powder for solution for infusion/injection

Cefazolin is indicated for the treatment of the following infections caused by cefazolin-susceptible micro-organisms.
- Skin- and soft tissue infections
- Bone and joint infections

Perioperative prophylaxis. For surgical operations with increased risk of infections with anaerobic pathogens, e.g. colorectal surgery, a combination with an appropriate drug with activity against anaerobes is recommended.

The use of cefazolin should be limited to cases where parenteral treatment is needed.

Susceptibility of causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.

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

The dosage as well as the method of administration are dependent on the location and severity of the infection and on the clinical and bacteriological progress. Local therapeutic guidance should be taken into consideration.

Posology

Adults and adolescents (above 12 years of age and ≥ 40 kg bodyweight)

Infections caused by sensitive microorganisms:

1 g to 2 g cefazolin per day, divided into 2-3 equal doses.

Infections caused by moderately sensitive microorganisms:

3g to 4g cefazolin per day, divided into 3-4 equal doses.

In severe infections, doses up to 6 g per day can be administered in three or four equal doses (one dose every 6 to 8 hours).

Special dosage recommendations

Perioperative prophylaxis
 • To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended doses are: 1 g cefazolin 30 – 60 minutes before surgery.
 • In case of long surgical procedures (2 hours or more), additional 0.5 to 1 g cefazolin during the intervention
 • Prolonged continuation of administration beyond the surgical intervention should be supported by national official guidance.

It is important that:
 (1) the preoperative dose is given just (30 minutes to 1 hour) prior to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision, and
 (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

Adult patients with renal impairment

Adults with renal impairment may need a lower dose to avoid overlapping.

This lower dose may be guided by determining blood levels. If not possible, the dosage can be established based on creatinine clearance.

Cefazolin maintenance therapy in patients with renal impairment

In haemodialysis patients, the treatment schedule depends on the dialysis conditions.

Paediatric population

Infections caused by sensitive microorganisms

A dose of 25-50 mg/kg bodyweight, divided into 2 to 4 equal doses per day is recommended (one dose every 6, 8 or 12 hours).

Infections caused by moderately sensitive microorganisms.

A dose of up to 100 mg/kg bodyweight, divided into 3 or 4 equal doses per day is recommended (one dose every 6 or 8 hours.

Premature babies and infants below the age of 1 month

Since safety of use in premature babies and infants less than 1 month of age has not been established, use of cefazolin in these patients is not recommended. See also section 4.4.

Guidelines for paediatric dosage

Intravenous injection

The content of 1 vial (2000 mg cefazolin) is dissolved in 10 ml of a compatible solvent (i.e. concentration approx. 180 mg / ml). The respective volume of this solution to be used is indicated in Table 1 in addition to the dose in mg.

Intravenous administration of lidocaine solutions must be strictly avoided.

Table 1: Appropriate volumes for intravenous injection for paediatric patients for Cefazolin 2 g powder for solution for injection/infusion

For volumes less than 1 ml, please use a 0.5 ml syringe for better dosing accuracy.

Intravenous infusion

The dosage can be given as intravenous infusion, using the reconstituted and further diluted solution (10 mg / ml) described in section 6.6.

Paediatric patients with renal impairment

Children with renal impairment (like adults) may need a lower dose to avoid overlapping.

This lower dose may be guided by determining blood levels. If not possible, the dosage may be determined based on creatinine clearance, according to the following guidelines.

In children with moderate impairment (creatinine clearance 40 – 20 ml / min), 25% of the normal daily dose, divided into doses every 12 hours are sufficient.

In children with severe impairment (creatinine 20 – 5 mL / min) will be 10% of normal daily dose, given every 24 hours are sufficient.

All these guidelines are valid after an initial starting dose. See also section 4.4.

Elderly patients

No dose adjustment is required in elderly patients with normal renal function.

Method of administration

Cefazolin 2 g powder for solution for injection/infusion may be administered by slow intravenous injection or by intravenous infusion after dilution. Single doses exceeding 1 g should be given as intravenous infusion.

The volume and type of diluent to be used for the reconstitution is dependent upon the method of administration.

For instructions on the reconstitution of the medicinal product before administration, see section 6.6.

If lidocaine is used as a solvent, the resulting solution should never be administered intravenously (see section 4.3). The information in the Summary of Product Characteristics of lidocaine should be considered.

Duration of treatment

The duration of the treatment depends on the severity of the infection as well as on the clinical and bacteriological progress.

• Hypersensitivity to the active substance.
• History of severe hypersensitivity (e.g. anaphylactic reaction) to other beta-lactam antibiotics (penicillins, monobactams and carbapenems).

Contraindications to lidocaine must be excluded before intramuscular injection of cefazolin when lidocaine solution is used as a solvent (see section 4.4). See information in the Summary of Product Characteristics of lidocaine, especially contraindications. Cefazolin solutions containing lidocaine should never be administered intravenously.

Hypersensitivity

Before therapy is initiated, it must be ascertained that the patient has shown no previous hypersensitivity following administration of cephalosporins, penicillins or other medicinal substances. Cefazolin should be administered with caution in patients with a tendency to allergies. Cross-allergies between penicillins and cephalosporins have been documented.

As with all beta-lactam antibacterial agents severe hypersensitivity reactions including fatal outcome have uncommonly been reported. In the event of severe hypersensitivity reactions, treatment with cefazolin must be discontinued immediately and adequate emergency measures must be initiated.

Prior to administration, it should be determined whether the patient has a past history of severe hypersensitivity reactions to cefazolin, other cephalosporins or any other type of beta-lactam agent. Cefazolin should be used with caution in patients with a history of hypersensitivity reactions to other beta-lactams categorized as non-serious.

Cases of Kounis syndrome have been reported in patients treated with cefazolin. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

Antibiotic-associated pseudomembranous colitis

In cases of severe and persistent diarrhoea, considerations should be given to the possibility of antibiotic- related pseudomembranous colitis. This condition can be life-threatening and therefore, treatment with cefazolin should be stopped immediately and appropriate therapy should be administered; antiperistaltic agents are contraindicated. See also section 4.8 Undesirable effects.

Renal impairment

In patients with renal impairment, the dose and/or dosing frequency should be adjusted to the degree of renal dysfunction (see section 4.2). Although cefazolin rarely causes renal dysfunction, it is recommended that renal function be monitored, especially in severely ill patients receiving maximum doses and in patients receiving potentially nephrotoxic agents, such as aminoglycosides or potent diuretics (e.g. furosemide), at the same time.

Intrathecal use

Not for intrathecal administration. Severe intoxication of the central nervous system (including convulsions) has been reported following intrathecal administration of cefazolin.

Bacterial resistance and superinfections

Long-term treatment of cefazolin can result in cefazolin-resistant bacteria. Patients should be closely monitored for potential superinfections. If these occur, appropriate measures should be taken.

Coagulation disorders

Treatment with cefazolin may lead to coagulation disorders in exceptional cases. Risk factors are vitamin K deficiency in patients or the effect of other coagulation mechanisms (parenteral nutrition, malnutrition, impaired hepatic and renal function, thrombocytopenia). Blood clotting may also be impaired in the case of associated diseases (haemophilia, gastric and duodenal ulcers) that may cause or aggravate bleeding. Therefore, patients with these conditions should be monitored for their prothrombin time. If there is a significant reduction, a vitamin K supplement (10 mg / week) should be administered.

Hypertension or heart failure

In patients with hypertension or heart failure the sodium content of the solution for injection should be taken into account.

Use of lidocaine:

In case a lidocaine solution is used as a solvent, cefazolin solutions must only be used for intramuscular injection. Contraindications to lidocaine, warnings and other relevant information as detailed in the Summary of Product Characteristics of lidocaine must be considered before use (see section 4.3).

The lidocaine solution should never be administered intravenously.

Paediatric population

Premature babies and infants below the age of one month

Cefazolin must not be given to preterm babies and infants below the age of one month, as there has been no adequate relevant experience to date.

Cefazolin contains sodium

This medicinal product contains 101.2 mg sodium per vial, equivalent to 5% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

Antibiotics

The potential for antagonistic effects that have been observed in vitro with antibiotics with a bacteriostatic action (e.g. tetracyclines, sulphonamides, erythromycin, chloramphenicol) should be considered when these antibiotics are to be co-administered with cefazolin.

Probenecid

The renal clearance of cefazolin is reduced with concomitant administration of probenecid.

Vitamin K1

Some cephalosporins such as cefamandole, cefazolin and cefotetan can cause interference in vitamin K1 metabolism, especially in cases of vitamin K1 deficiency. This may require vitamin K1 replacement.

Anticoagulants

Cephalosporins can, in very rare cases, lead to coagulation cause bleeding disorders (section 4.4). During concomitant use with oral anticoagulants (e.g. warfarin or heparin) in high doses, coagulation parameters must be monitored.

In a large number of cases, an increase in oral anticoagulant activity has been reported in patients receiving antibiotics. Infection and inflammation, age and general condition of the patient are likely to constitute risk factors.

Under these circumstances, it is difficult to establish which role the infectious disease and its treatment play when INR imbalance occurs. However, some classes of antibiotics are more implicated, particularly fluoroquinolones, macrolides, cyclins, cotrimoxazole and some cephalosporins.

Nephrotoxic substances

It cannot be excluded that the nephrotoxic effect of antibiotics (e.g. aminoglycosides, colistin, polymyxin B), iodine-containing contrast agents, organoplatinum compounds, high-dose methotrexate, some antiviral drugs (e.g. aciclovir, foscarnet), pentamidine, ciclosporin, tacrolimus and diuretics (e.g. furosemide) is increased.

When co-administered with cefazolin, kidney function tests must be carefully monitored.

Laboratory tests

In laboratory tests, there may be a false-positive reaction for urinary glucose when using Benedict's solution or Fehling's solution in patients treated with cefazolin. Cefazolin has no effect on enzymatic measurements of glucose in urine.

The indirect and direct Coombs' test can also give false-positive results. This may also apply to newborn babies whose mothers have been receiving cephalosporins.

Pregnancy

Animal studies do not indicate direct or indirect harmful effects on reproductive toxicity. Cefazolin should only be administered in pregnancy, especially during the first trimester, after careful benefit-risk assessment because there is insufficient experience and cefazolin crosses the placenta.

It is preferable to avoid the use of cefazolin during pregnancy, unless it is absolutely necessary.

Breast-feeding

Cefazolin is excreted in maternal milk at very low concentrations and therefore it should only be used after careful benefit/risk assessment. If diarrhoea or candidiasis should occur in the infant during breastfeeding, the mother should not breastfeed her infant during treatment, or else treatment with cefazolin should be discontinued.

Fertility

Animal studies have shown no effects on fertility.

Cefazolin has no influence on the ability to drive and use machines. However, adverse reactions may occur (see also section 4.8) which may affect the ability to drive and use machines.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The frequencies of adverse reactions are categorized as: 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).

A physician should be consulted in the event of severe and persistent diarrhoea during or after treatment with cefazolin, as such diarrhoea may be a symptom of a serious disease (pseudomembranous colitis) that must be treated immediately. Patients should not, under any circumstances, take anti-peristaltic agents as self-medication (see section 4.4)..

Prolonged use of cephalosporins may result in overgrowth cefazolin-resistant bacteria, especially Enterobacter, Citrobacter, Pseudomonas, Enterococci and Candida. This may lead to superinfections or potential colonization with resistant organisms or yeasts (see section 4.4).

Studies

Transient elevation of AST, ALT, blood urea and alkaline phosphatase without clinical evidence of renal or hepatic damage.

Animal data has shown that cefazolin has a potentially nephrotoxic effect. Although this has not been demonstrated in humans, the possibility should however be taken into account, especially in patients receiving high doses over a prolonged period. Interstitial nephritis and unspecified nephropathy has been reported in rare cases. The patients affected were seriously ill and were receiving several medications. The role of cefazolin in the development of interstitial nephritis or other nephropathies has not been established.

In rare cases, the following have been reported during treatment:
 • Decreased haemoglobin levels and/or haematocrit levels, anaemia, agranulocytosis, aplastic anaemia, pancytopenia, haemolytic anaemia

The following cases have been reported during treatment with certain cephalosporins:
 • Nightmares, dizziness, hyperactivity, nervousness or anxiety, insomnia, drowsiness, weakness, flushing, impaired colour vision, confusion and epileptic activity.

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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms of overdose

An overdose can cause pain, inflammation and phlebitis at the injection site. Parenteral administration of high doses of cephalosporins can cause dizziness, paraesthesia and headache. Following overdose with cephalosporins, convulsions can occur, especially in patients with renal disease.

Following an overdose, the following abnormal laboratory results may occur: increase in creatinine levels, BUN, liver enzyme and bilirubin, a positive Coombs test, thrombocythaemia and thrombocytopenia, eosinophilia, leukopenia and prolongation of prothrombin time.

Treatment of overdose

If convulsions occur, the administration of Cefazolin should be discontinued immediately. Treatment with antiepileptics may be indicated. Vital body functions and parameters should be monitored closely. In case of a severe overdose, where the patient is no longer responsive to other treatments, hemodialysis with hemoperfusion may be effective, although this has not been proven.

Pharmacotherapeutic group:

Antibacterials for systemic use, other beta-lactam antibacterials, first generation cephalosporins.

ATC-code: J01DB04

Mechanism of action

All cephalosporins (beta-lactam antibiotics) inhibit cell wall synthesis and are selective inhibitors of peptidoglycan synthesis. The first step is the binding of the drug to cell receptors (penicillin-binding proteins). After this binding, the transpeptidase reaction is blocked and peptidoglycan synthesis is inhibited. This process leads to bacterial lysis.

Pharmacokinetic/pharmacodynamic relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy is the percentage of the dosing interval during which the free cefazolin concentration exceeds the minimum inhibitory concentration (MIC) of the pathogen (%T>MIC).

Mechanisms of resistance

Beta-lactam antibiotics contain a so-called beta-lactam ring, which is essential for the antimicrobial effect. If this ring is split open, it loses its effect. Various bacteria have enzymes (beta-lactamases) that can split open this ring, thus they become resistant to this type of antibiotic.

As with all cephalosporins and other beta-lactam antibiotics, various mechanisms of resistance may be acquired by groups of bacteria:
 • Changes in the target (penicillin-binding proteins, PBPs), enzymatic degradation of the central structure by beta-lactamases and altered access to the target.
 • There is cross‑resistance between cephalosporins and penicillins. Gram-negative microorganisms contain inducible chromosome-bounded beta-lactamases such as Enterobacter spp., Serratia spp., Citrobacter spp. and Providencia spp.; these should be regarded as resistant to cefazolin despite in vitro susceptibility.

Microbiological susceptibility

The prevalence of acquired resistance for certain strains can vary depending on geographical location and the time of testing. Therefore, information on the local resistance situation is desirable, especially when treating severe infections. If, due to the local resistance situation, efficacy is questionable, expert advice should be sought.

Absorption

IM administration

In human pharmacology, the serum levels of cefazolin and duration of action after intramuscular administration are given in the following table.

*Average of two studies

IV administration

Upon continuous IV infusion (in healthy subjects) of cefazolin at a dose of 3.5 mg/kg for one hour, followed by a dose of 1.5 mg/kg for the next 2 hours, serum levels of about 28 mg/mL were seen in the third hour.

The following table shows the mean serum concentration (μg/ml) of cefazolin after intravenous injection of a single dose of 1 g.

Cefazolin has a mean half-life of about 1.8 hours, which may increase by as much as 15-30 hours in cases of severe renal dysfunction and may be higher in cases of anuria.

Peak plasma concentrations are 63.6 mg/L and 188.4 mg/L, which were achieved after 1-2 hours of continuous IV infusion at a dose of 1 g. The half-life is 100 minutes.

When cefazolin is administered to patients without bile duct obstruction, concentrations far exceeding serum levels occur in the gallbladder tissue and bile.

Cefazolin readily crosses the placental barrier. The amounts of cefazolin in breast milk are low.

The rate of protein binding is 85-90% for human serum under physiological conditions. Diffusion of cefazolin in the cerebrospinal fluid is low.

Biotransformation

Cefazolin is not metabolised.

Elimination

Cefazolin is mainly excreted via the urine, with a small percentage via the bile. Following intramuscular injection of 500 mg, 56% to 89% of the administered dose is eliminated renally within six hours and 80% to almost 100% within 24 hours. Following intramuscular administration of 500 mg and 1 g cefazolin, peak urinary concentrations of more than 1,000 and more than 4,000 μg/ml, respectively, are achieved.

The acute toxicity of cefazolin is low.

Repeated administration of cefazolin to dogs and rats via different routes of injection over a period of 1 to 6 months showed no significant effects on biochemical and haematological values Renal toxicity was observed after repeated doses in rabbits, but not in dogs and rats.

Cefazolin showed no teratogenic or embryotoxic activity. No studies on mutagenicity and carcinogenicity are available.

None

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Cefazolin is incompatible with amikacin disulphate, amobarbital sodium, ascorbic acid, bleomycin sulphate, calcium gluceptate, calcium gluconate, cimetidine hydrochloride, colistimethate sodium, erythromycin gluceptate, kanamycin sulphate, oxytetracycline hydrochloride, pentobarbital sodium, polymyxin-B-sulphate and tetracycline hydrochloride.

Unopened: 3 years

After reconstitution for intravenous injection

The reconstituted solution should be administered immediately after preparation.

After reconstitution and dilution for infusion:

Chemical and physical stability of the diluted product in 9 mg/ml (0.9%) sodium chloride solution at concentrations 20 mg/ml and 40 mg/ml and in 50 mg/ml (5%) glucose solution at concentrations 40 mg/ml has been demonstrated for 4 hours at 25 ± 2 °C and 3 days at 5 ± 3°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 5 ± 3 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Store protected from light.

This medicinal product does not require any special temperature storage conditions.

Keep the vials in the outer carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

20 ml type I, colourless glass vial with bromobutyl rubber stopper and sealed with an aluminium flip-off cap, in a carton.

Pack sizes: 1 or 10 vials per carton.

Not all pack sizes may be marketed.

Preparation of the solution

For each route of administration see the table for addition volumes and solution concentrations, which may be useful when fractional doses are required.

Intramuscular injection

Cefazolin 2 g powder for solution for injection/infusion should not be used for intramuscular administration.

Intravenous injection
Reconstitute Cefazolin with one of the following compatible diluents according to the dilution table that follows:
• water for injections
• 9 mg/mL (0.9%) sodium chloride solution or
• 50 mg/mL (5%) glucose solution
• 100 mg/ml (10%) glucose solution

Reconstitution table for intravenous injection

Cefazolin is to be injected slowly over three to five minutes. In no case should the solution be injected in less than 3 minutes. This should be done directly into the vein or into the tube from which the patient receives intravenous solution.

Single doses exceeding 1 g should be given as an intravenous infusion over 30 to 60 minutes.

Guidelines for paediatric dosage:

The content of 1 vial (2000 mg cefazolin) is dissolved in 10 mL of a compatible solvent (i.e. concentration approx. 180 mg / mL). The respective volume of this solution to be used is indicated in table 1 in addition to the dose in mg.

For the amount of diluent to be added for paediatric population please refer to section 4.2 - Guidelines for paediatric dosage. For volumes less than 1 ml, please use a 0.5 ml syringe for better accuracy of dosing.

Intravenous infusion

Cefazolin should first be reconstituted with water for injection and diluted with one of the following compatible diluents according to the dilution table that follows:
 • 9 mg/mL (0.9%) sodium chloride solution
 • 50 mg/mL (5%) glucose solution

Dilution table for intravenous infusion

Cefazolin solutions containing lidocaine should never be administered intravenously.

As for all parenteral medicinal products, inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and practically free from particles.

The reconstituted product is for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.