Zepilen is indicated for the treatment of serious infections caused by cefazolin-susceptible micro-organisms:

·         respiratory tract infections caused by S. pneumoniae, Klebsiella, H. influenzae, Staph. aureus (penicillin-sensitive and penicillin-resistant) and Beta-hemolytic streptococcus group A.

·         infections of the urinary and genital tract caused by Escherichia coli, P. mirabilis, Klebsiella, some enterococcal and some Enterobacter strains.

·          infections of the biliary tract caused by E. coli, various streptococcal strains, P. mirabilis, Klebsiella and Staph. aureus.

·         skin and soft tissue infections caused by Staph. aureus (penicillin-sensitive and penicillin-resistant), beta-hemolytic group A streptococci and other streptococci strains.

·         bones and joints infections, caused by Staph. aureus.

·         septicemia caused by S. pneumoniae, Staph. aureus (penicillin-sensitive and pencillin resistent), P. mirabilis, Escherichia coli and Klebsiella.

·         endocarditis, caused by Staph. aureus (penicillin-sensitive and penicillin-resistant) and beta-hemolytic streptococcus group A.

·         perioperative prophylaxis.

Posology

The dosage, the route of administration and the dosing interval depends on the severity of the infection, the susceptibility of the detected pathogen and the patient’s condition (e.g. kidney function).

The recommended daily dose for mild to moderate infections is 2 to 6 g, distributed in 2 - 3 doses; if necessary, the dose may be increased to up to 12 g in severe and life-threatening infections.

 

Adults

Infection	Dose	Dosing interval
Pneumococcal pneumonia	500 mg	12 h
Mild infections caused by susceptible gram-positive cocci	250 mg to 500 mg	8h
Acute uncomplicated urinary tract infections	1 g	12h
Moderate to severe infections	500 mg to 1 g	6h to 8h
Severe to life-threatening infections (eg endocarditis, septicemia) *	1 g to 1.5 g	6h

* In rare instances, up to 12 g / day (septicemia).

 

For perioperative prophylaxis, the following dosages are recommended for adults:

a) 1 g i.v. or i.m. 30 min. - 1 hour before the start of the operation.

b) for longer surgical procedures (for example 2 hours or longer) from 0.5 to 1 g i.v. or i.m. during surgery (Administration will be done in accordance with the duration of operation).

c) 0,5 - 1 g i.v. or i.m. every 6 to 8 hours for 24 hours postoperatively or for a period of up to 3-5 days in operations where an infection would present a special risk.

It is important that the pre-operative dose is administered in time (30 minutes to 1 hour) prior to the surgery, so that the appropriate antibiotics are present in serum and tissue; also, in case of risk of infection, cefazolin should be administered at appropriate intervals during the operation, so that sufficient antibiotic doses are provided.

 

Renal impairment

In renal impairment, a suitable dose should be given. The dose should be determined based on the degree of renal impairment, the severity of the infection and the sensitivity of the pathogen.

 

Dosage limitation

Cr Cl= > 55 ml/min Serum creatinine = < 1,5 mg %	Full daily dose
Cr Cl= 35-54 ml/min Serum creatinine = 1,6 - 3mg %	Full daily dose with dosing interval of min. 8 h
Cr Cl= 11 – 34 ml/min Serum creatinine = 3,1 - 4,5	Half the full daily dose at 12 h intervals
Cr Cl= < 10 ml/min Serum creatinine = > 4,6 mg %	Half the full daily dose at 18-24 h intervals

Cr.Cl. = Creatinine Clearance

 

Paediatric population

Paediatric dosing

Weight	25 mg / kg / day 3 single doses		25 mg / kg / day 4 single doses
	Single dose approximately  every 8 hours.	Volume at a conc. of 125 mg / ml	Single dose approximately  every 6 hours.	Volume at a conc. of 125 mg / ml
4,5 kg	40 mg	0,35 ml	30 mg	0,25 ml
9,0 kg	75 mg	0,6 ml	55 mg	0,45 ml
13,5 kg	115 mg	0,9 ml	85 mg	0,7 ml
18.0 kg	150 mg	1,2 ml	115 mg	0,9 m
22,5 kg	190 mg	1,5 ml	140 mg	1,1 ml
Weight	50 mg / kg / day 3 single doses		50 mg / kg / day 4 single doses
	Single dose approximately  every 8 hours.	Volume at a conc. of 225 mg / ml	Single dose approximately  every 6 hours.	Volume at a conc. of 225 mg / ml
4 kg	75 mg	0,35 ml	55 mg	0,25 ml
9 kg	150 mg	0,7 ml	110 mg	0,5 ml
13,5 kg	225 mg	1 ml	170 mg	0,75 ml
18 kg	300 mg	1,35 ml	225 mg	1,0 ml
22,5 kg	375 mg	1,7 ml	285 mg	1,25 ml

 

Infants (over a month) and children:

A total daily dose of 25 - 50 mg / kg body weight, 3 - 4 evenly divided doses, is effective against most mild to moderate infections.

In severe infections, the total daily dose may be increased to 100 mg / kg body weight.

 

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 of creatinine clearance may be determined 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.

 

The safety of cefazolin in premature infants and infants less than one month was not investigated.

 

Method of administration

Zepilen may be administered intramuscularly or intravenously.

The total daily dose for administration is the same for both routes.

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

Not for intrathecal use.

 

• Hypersensitivity to the active substance or other cephalosporins, • Previous serious hypersensitivity reactions to penicillin or any other type of beta-lactam antibiotics

·         Before initiating Zepilen treatment, it should be determined whether the patient has a history of allergic reactions to cephalosporins, penicillins or other drugs.

·         Zepilen should be administrated with caution in patients with penicillin allergy. There are findings that a partial cross-allergy between penicillins and cephalosporins can occur; also, some cases of serious hypersensitivity reactions (including anaphylaxis) were described to both classes. If allergic reactions are observed, Zepilen should be discontinued and the patient treated accordingly.

·         Plasmatic coagulation disorders can rarely occur under cefazolin treatment. Patients at risk are the ones with risk factors that lead to a vitamin K deficiency or other coagulation problems (parenteral nutrition, malnutrition, impaired hepatic and renal function, thrombocytopenia). The same applies to co-morbidities (for example hemophilia, stomach and intestinal ulcers), that can exacerbate bleeding. Therefore, in these cases, the prothrombin time value should be monitored and Vitamin K (10 mg per week) should be used.

·         Caution should be exercised when administering Zepilen in patients who have a history of gastrointestinal disease (ulcerative colitis).

·         Special care is recommended in patients with allergic diathesis or bronchial asthma and hay fever.

·         Severe and persistent diarrhoea (pseudomembranous colitis) may occur and can be life-threatening. In these cases Zepilen should be immediately discontinued and appropriate therapy (for example oral vancomycin, 4 x 250 mg daily) should be initiated. Anti-peristaltic drugs are contraindicated.

·         Prolonged use of Zepilen can cause overgrow of the non-susceptible organisms. A close observation of the patient is therefore essential. If suprainfections occur during treatment, appropriate action should be taken.

·         In patients with low urinary output because of renal impairment, the dosage should be adjusted.

·         Not for intrathecal use.

·         The sodium content of the solution must be taken into account in hypertension and heart failure.

 

This medicinal product contains 2.2 mmol (50 mg) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

·         Co-administration of probenecid may reduce the tubular secretion of cephalosporins resulting in increased and prolonged cephalosporin effects.

·         False-positive reactions with Benedict's reagent, Fehling's solution or Clinitest tablets may occur, but not when using Clinistix test strips and when using the paper Tes-Tape for urine sugar.

·         False positive Coombs test can also occur, including in newborns whose mothers received cephalosporins before delivery.

·         Cefazolin is incompatible with aminoglycosides, amobarbital-Na, ascorbic acid, bleomycin sulfate, calcium glucoheptonate, calcium gluconate, cimetidine, colistin methanesulfonate-Na, erythromycin glucoheptonat, lidocaine HCl, pentobarbital Na, polymyxin B sulfate, tetracyclines (see section 6.2)

Pregnancy

There is insufficient data about the use of cefazolin during pregnancy to assess the possible harmfulness during pregnancy.

 

Breast-feeding

Zepilen should be administered with caution in breast-feeding women as cefazolin is excreted in small amounts into breast milk.

There are no data available regarding cefazolin effects on the ability to drive and use machines.

The following undesirable effects may occur while using Cefazolin.

 

The frequency of each side-effect is given between parentheses, using the following category classification:

·         Very common (³1/10)

·         Common (³1/100 to <1/10)

·         Uncommon (³1/1,000 to <1/100)

·         Rare (³1/10,000 to <1/1,000)

·         Very rare (<1/10,000)

·         Not known (cannot be estimated from the available data).

 

Blood and lymphatic system disorders

Very rare:

·         During treatment with cefazolin extremely rare plasmatic coagulation disorders may occur. Patients at risk are the ones with risk factors and specific therapy, leading to a vitamin K deficiency.

Not known:

·         eosinophilia

·         neutropenia,

·         leukopenia,

·         hemolytic anemia,

·         thrombocytopenia and

·         positive direct and indirect Coombs test.

 

Immune system disorders

Not known:

·         Lyell syndrome and Stevens-Johnson syndrome

·         urticaria

·         anaphylaxis

·         angioneurotic edema.

 

Gastrointestinal disorders

Rare:

·         nausea and vomiting.

Not known:

·         pseudomembranous colitis symptoms during or after antibiotic treatment.

·         loss of appetite, diarrhea and mouth thrush have been reported.

 

Hepatobiliary disorders

Rare:

As with some penicillins and other cephalosporins, isolated cases of transient hepatitis and cholestatic jaundice have been reported.

 

Skin and subcutaneous tissue disorders

Very rare:

·         anaphylactic shock. It can occur up to half an hour after application and requires immediate intensive medical care.

Not known:

·         skin rash with flushing

·         pruritus

·         pruritus vulvae

·         genital pruritus

·         anal pruritus.

 

Renal and urinary disorders

Rare:

·         interstitial nephritis and other kidney injuries have been reported. Most patients who had these side effects were seriously ill and received various drug therapies. Cefazolin function regarding kidney disease is still unclear.

 

Reproductive system and breast disorders

Not known:

·         genital moniliasis and vaginitis.

 

General disorders and administration site conditions

Not known:

·         drug fever

·         pain at the injection site, sometimes with induration, following intramuscular use.

·         phlebitis at the injection site.

 

Investigations

Rare:

·         transient increases in ALT, AST and alkaline phosphatase was observed.

Not known:

·         transient increases in BUN without clinical evidence of renal impairment.

 

Symptoms

Pain, inflammation and phlebitis at the injection site may occur following overdose. Very high doses of parenteral cephalosporins may cause dizziness, paresthesia and headache.

Seizures can occur following overdose with some cephalosporins, particularly in patients with kidney disease.

The following abnormal laboratory results may occur: increase in creatinine, BUN, liver enzymes and bilirubin, a positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leucopenia and prolongation of prothrombin time.

The drug should be discontinued immediately if spasms occur.

 

Management

A treatment with an anticonvulsant may be appropriate. Close monitoring of vital physiological processes, as well as appropriate laboratory tests should be performed.

In case of large overdose, especially in patients with kidney damage, a combination of hemodialysis and hemoperfusion can be useful, if other therapies fail to respond, although no data is available on such use.

 

Pharmacotherapeutic group: Beta-lactam antibiotics, first-generation cephalosporins. ATC code: JO1DB04

 

Mechanism of action

Cefazolin is a semisynthetic cephalosporin antibiotic for parenteral use. The bactericidal effect of cefazolin is based on inhibition of bacterial cell wall synthesis.

 

Microbiology

Cefazolin in vitro effect is generally against the following pathogens:

·         Staphylococcus aureus (including penicillinase-producing strains)

·         Staphylococcus epidermidis (coagulase-negative staphylococci and others)

·         Beta-hemolytic group A streptococci and other streptococci strains

·         Streptococcus pneumoniae

·         Escherichia coli

·         Klebsiella

·         Proteus mirabilis

·         Haemophilus influenzae

·         Enterobacter aerogenes

 

Resistant organisms:

·         Resistant are methicillin-resistant staphylococci, many strains of enterococci, as well as most Enterobacter cloacae strains-and indole-positive Proteus strains (P. vulgaris, P. morganii, P. rettgeri) and Serratia, Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea) and Anaerobes, C. difficile.

 

Resistance Mechanisms

Beta-lactam antibiotics contain a so-called beta-lactam ring that is essential for antimicrobial activity. If this ring is split open, the antibiotic loses its effectiveness. Different bacteria, however, possess enzymes (beta-lactamases) that break the ring open, making them resistant against this type of antibiotics. As with all cephalosporins and other beta-lactam antibiotics, the acquired resistance mechanisms vary per group of bacteria and include: changes in the targets (penicillin-binding proteins, PBPs) enzymatic degradation of the target by beta-lactamases and altered access to the target. There is cross resistance between cephalosporins and penicillins. Gram-negative microorganisms which contain inducible chromosomal beta-bound lactamases, such as Enterobacter spp, Serratia spp, Citrobacter spp and Providentia spp should be regarded as resistant to cefazolin, despite in vitro susceptibility.

 

Breakpoints

According to EUCAST, the following breakpoints have been determined for cefazolin: Non-species related: S≤1 μg / ml, R > 2 μg / ml. The prevalence of resistance can vary geographically and in time for the selected microorganisms and local information on resistance is desirable, particularly when treating severe infections. If necessary, expert advice should be sought, especially when the local prevalence of resistance is such that the use of the agent in at least some types of infections is questionable. The sensitivity of Staphylococcus is derived from the sensitivity to methicillin.

Serum concentrations (ug / ml) after i.m. injection

Dose	After ½ h	After 1 h	After 2 h	After 4 h	After 6 h	After 8 h
250 mg	15,5	17	13	5,1	2,5
500 mg	36,2	36,8	37,9	15,5	6,3	3
1h*	60,1	63,8	54,3	29,3	13,2	7,1

*) Average of the two tests

 

Serum concentrations (ug / ml) after 1 g intravenous injection

After 5 min.	After 15 min.	After 30 min.	After 1 h	After 2 h	After 4 h
188,4	135,8	106,8	73,7	45,6	16,5

 

·         For intravenous administration, the half-life is approximately 1.4 hours.

·         A one-hour intravenous infusion with 3.5 mg cefazolin / kg (about 250 mg) and then two-hour intravenous infusion of 1.5 mg cefazolin / kg (about 100 mg) resulted in a uniform serum levels of about 28 ug / ml during the 3-rd hour of administration.

·         In patients undergoing peritoneal dialysis (2 l / h), the mean serum concentrations after 24 hours of administration of a solution of 50 mg / l or 150 mg / l was 10 or 30 ug / ml.

·         For the 50 mg / l solution concentration, the mean peak plasma concentration was 29 ug / ml (3 patients) and for the 150 mg / l solution concentration, the mean peak plasma concentration was 72 ug / ml (6 patients).

·         The intraperitoneal administration of cefazolin is usually well tolerated.

·         Cefazolin is excreted unchanged in the urine, mainly by glomerular filtration and to a lesser extent by tubular secretion.

·         After intramuscular injection of 500 mg, 56% to 89% of cefazolin administered dose is eliminated by the kidneys within 6 hours, and 80 to nearly 100% is eliminated within 24 hours.

·         After intramuscular administration of 500 mg and 1 g cefazolin, urinary concentrations of more than 1000 or more than 4000 ug / ml are achieved.

·         In patients without biliary obstruction, concentrations high above the serum levels occurs in gallbladder tissues and also in the bile. However, if there is a biliary obstruction, the concentration of the antibiotic in the bile become significantly lower than in serum.

·         Cefazolin crosses the inflamed synovial membrane, and the concentration achieved in the joint space is comparable with the serum concentration.

·         Cefazolin crosses the placenta and is excreted in cord blood and amniotic fluid. It is found in very low concentrations in breast milk.

·         Cefazolin is dialysable (hemodialysis and peritoneal dialysis). The elimination following a 6-hour dialysis is 23%.

No long-term studies in animals regarding mutagenicity or carcinogenic potential were performed. Reproduction studies in rats with doses of 500mg or 1g cefazolin / kg showed no effect on fertility or fetal development.

 

Zepilen contains no excipients.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicines.

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

Cefazolin is incompatible with aminoglycosides, amobarbital-Na, ascorbic acid, bleomycin sulfate, calcium glucoheptonate, calcium gluconate, cimetidine, colistin methanesulfonate-Na, erythromycin glucoheptonat, lidocaine HCl, pentobarbital Na, polymyxin B sulfate, tetracyclines (see section 4.5).

Powder for solution for injection or infusion: 30 months. Reconstituted solution: The reconstituted solution is preferably to be used immediately. Chemical and physical in-use stability after reconstitution for all types of administration has been demonstrated for 24 hours at 2oC–8oC. 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 24hours at 2oC – 8oC, unless reconstitution has taken place in controlled and validated aseptic conditions.

Store below 30°C in the original package.

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

Clear, colourless type I glass vials, sealed with a grey bromobutyl stopper and an aluminium overcap. Each vial contains 1 g of cefazolin as cefazolin sodium. Cartons containing 1, 10, 50 or 100 vials are available.

 

Not all pack sizes may be marketed.

Intramuscular administration

To reconstitute 1 g powder add 2.5 ml water for injection (mean concentration is about 330 mg / ml). Shake well to completely dissolve. The administration is deeply i.m.

 

Intravenous administration

Intravenous injection:

1 g cefazolin is usually reconstituted in at least 10 ml water for injection until it is completely dissolved and slowly, (never less than 3 minutes) injected for 5 min directly into a vein or into the intravenous infusion line.

 

Intravenous infusion:

1g cefazolin is reconstituted in 2.5 ml water for injection until it is completely dissolved and diluted in 50 - 100 ml) of the following diluents:

Ø  0.9% sodium chloride

Ø  0.9% sodium chloride and 5% dextrose

Ø  Lactated Ringer’s solution