INVANZ, INN-Ertapenem

Home , Cefamandole

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINE

{(Invented) name} 1 g powder for solution for injection/infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains cefazolin sodium equivalent to 1 g cefazolin.

Excipient(s) with known effect: Each vial of {(Invented) name} 1 g contains 50.56 mg (2.2 mmol) sodium.

3. PHARMACEUTICAL FORM

Powder for solution for injection/infusion. White or almost white powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Cefazolin is indicated in adults, adolescents, children and infants older than one month for the treatment of the following infections caused by cefazolin-sensitive microorganisms: • skin and soft tissue infections • bone and joint infections

Perioperative prophylaxis: Perioperative administration of cefazolin may reduce the incidence of postoperative infections in contaminated or potentially contaminated surgery.

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.

4.2 Dosage and method of administration

Dosage

The dosage depends on the susceptibility of the micro-organisms and the severity of the disease.

• Adults and adolescents (above 12 years of age and ≥ 40 kg bodyweight). In infections caused by very sensitive gram-positive micro-organisms the usual dosage in adults and adolescents is 1 to 2 g/day in two or three equal doses. • In infections caused by less sensitive gram-positive organisms and gram-negative organisms, the usual dosage is 3 to 4 g/day in three or four equal doses. {(Invented) name} has been administered up to doses of a maximum 6 g/day in cases of severe infections, such as endocarditis.

In adult and adolescent patients with renal insufficiency a lower dosage should be adhered to, in order to avoid accumulation.

This lower dose can be determined by assessing the blood levels. Should this not be possible, the dosage can be determined by BUN and/or creatinine clearance.

After an initial dose of 500 mg the following guidelines can be used as guide for the maintenance

3 dosage.

Maintenance therapy with {(Invented) name} in patients with reduced renal function. Dose Kidney BUN Creatinine Gram- Gram- Serum half- function (mg %) clearance positive negative life-time (ml/min) infections infections (hours) Mild 20-34 70-40 250-500 mg 500 mg-1 g 3-5 impairment every 8 hours every 8 hours Moderate 35-49 40-20 125-250 mg 250-600 mg 6-12 impairment every 12 hours every 12 hours Severe 50-75 20-5 75-150 mg 150-400 mg 15-30 impairment every 24 hours every 24 hours

Also see section 4.4 “Special warnings and precautions for use”

Perioperative prophylaxis In order to avoid a postoperative infection in (possibly) infectious surgeries, these are the recommended dosages: a. 1 g administered 30 minutes to 1 hr prior to surgery. b. For longer operations (2 hours or more), 500 mg to 1 g administered intravenously during the surgery (administration to be amended depending on the duration of the surgery). c. 500 mg to 1 g administered intravenously, every 6 to 8 hours during 24 hours postoperative.

It is important that (1) the perioperative dose is administered shortly prior to the start of the operation (30 mins to 1 hr), so that adequate levels of antibiotic are reached in the serum and tissues at the time of the first surgical incisions; and (2) cefazolin, if need be, is administered at set times during the surgery - at moments of increased exposure to micro-organisms - in order to reach sufficiently high antibiotic levels.

The prophylaxis with cefazolin should reasonably be terminated within 24 hours after the end of the surgery. In surgeries where the risk of infections poses a particularly great risk (open heart surgery or prosthetic arthroplasty) the prophylaxis should be continued up to 3 to 5 days postoperative.

Paediatric population Children and infants older than one month In infections caused by very sensitive gram-positive micro-organisms a dosage of 25 to 50 mg/kg of body weight divided in two or four doses a day will be efficient. In infections caused by less sensitive gram-positive micro-organisms and by the gram-negative causative agent, a dosage of max 100 mg/kg is recommended in three or four equal doses. In children and infants older than one month with renal insufficiency a lower dose may be recommended in order to avoid accumulation. This lower dose can be determined by assessing the blood levels. Should this not be possible, the dosage can be determined by the creatinine clearance according to the following guidelines.

In children and infants older than one month with moderate renal insufficiency (creatinine clearance of 40-20 ml/min) 25 % of the normal daily dosage, divided in doses every 12 hours, will be sufficient.

In children and infants older than one month with severe renal insufficiency (creatinine clearance 20-5 ml/min) 10 % of the normal daily dosage, administered every 24 hours, will be sufficient.

All these guidelines apply after an initial starting dose.

Also see section 4.4 “Special warnings and precautions for use”

Prematures and infants below the age of 1 month As the safety of use in premature babies and infants younger than one month has not been established, the use of {(Invented) name} in these patients is not recommended. Also see section 4.4 “Special warnings and precautions for use”.

Guidelines for paediatric dosage 1 g vial to be prepared with 4 ml of diluent. Dilution = 225 mg/ml.

Weight in kg 25 mg/kg/day in 3 doses 25 mg/kg/day in 4 doses

doses in mg every volume in ml doses in mg every volume in ml 8 hours needed 6 hours needed 5 42 0.2 31 0.15 10 85 0.4 62 0.3 15 125 0.5 94 0.4 20 167 0.7 125 0.5 25 208 0.9 156 0.7 Weight in kg 50 mg/kg/day in 3 doses 50 mg/kg/day in 4 doses

doses in mg every volume in ml doses in mg every volume in ml 8 hours needed 6 hours needed

5 83 0.4 63 0.3 10 166 0.7 125 0.6 15 250 1.1 188 0.8 20 333 1.5 250 1.1 25 417 1.9 313 1.4

Elderly patients No dose adjustments are needed in elderly patients with normal renal function.

Duration of treatment Depends on the course of the disease. In keeping with the general principles of antibiotic therapy, treatment with {(Invented) name} should be continued for at least 2 to 3 days after the fever has subsided or proof has been obtained for the eradication of the causative agent.

Method of administration

{(Invented) name} may be administered intramuscular as well as intravenous.

Intramuscular injection Dissolved in sterile water for injection, according to the following dilution table. Shake well until all the powder has been dissolved. Product after reconstitution is clear, almost colourless solution.

{(Invented) name} must be injected into a major muscle mass. A reconstituted {(Invented) name} solution remains stable for 24 hours in the refrigerator (2°C - 8°C).

Dilution table Content of the vial to be added diluent obtained volume Average concentration 1 g 2.5 ml 3.0 ml 330 mg/ml

Intravenous administration: {(Invented) name} may be administered directly into a vein, either as a continuous or an intermittent 5 drip. The total daily dose is the same as for intramuscular administration. Intermittent and continuous infusion {(Invented) name} can be administered in combination with an existing intravenous therapy, either in the primary drip or in the secondary infusion drip.

1 g {(Invented) name} may be dissolved in 100 ml 9 ml/ml (0.9 %) sodium chloride intravenous solution.

In these intravenous solutions {(Invented) name} remains stable for 24 hours in the refrigerator (2°C - 8°C).

Direct intravenous injection: Dilute 1 g {(Invented) name} solution further with at least 10 ml water for injection, inject slowly during 3 to 5 minutes. In no case should the injection be shorter than 3 minutes. This should be done straight into the vein or into the tube in which the patient is administered the abovementioned intravenous solution. CAUTION: One-off doses of more than 1g need to be administered over thirty to sixty minutes.

4.3 Contraindications • Hypersensitivity to the active substance or to any other cephalosporins. • Prior severe allergic reactions to penicillin or any other type of β-lactam antibiotics. • When administered to children younger than 1 year, cefazolin should not be dissolved in a lidocaine solution.

4.4 Special warnings and precautions for use

• Before the administration of cefazolin, previous hypersensitivity reactions to cephalosporins and penicillins should be investigated. Cephalosporins should not be used in patients known to develop an immediate allergic reaction to cephalosporins. In case of doubt, a doctor should be present during the initial administration in order to be able to treat any anaphylactic reactions. There is a cross- allergy between penicillin and cephalosporin. • When an allergic reaction occurs caused by {(Invented) name}, the administration of the product must be stopped immediately and appropriate treatment for the patient must be sought. • Although cefazolin seldom causes kidney function impairments, it is recommended to examine the kidney function, especially in seriously ill patients, who get maximum amounts administered and in patients who get other potentially nephrotoxic drugs administered at the same time, such as amino glycosides or powerful diuretics (e.g. furosemide or etacrynic acid). In patients with reduced renal functions higher and longer sustained antibiotic concentrations can occur. In connection to that, the total daily dose of {(Invented) name} should be decreased according to the dosage table as indicated in section 4.2 “Dosage and method of administration”. This is also the case for patients with a low diuresis as a consequence of impaired renal function. • Antibiotic-related pseudomembranous colitis may occur. Severe, sustained diarrhoea developed in patients during treatment with this medicine should promote this diagnosis. In this case appropriate treatment should be instituted. See also section 4.8: “Side effects”. • The prolonged use of cefazolin may promote the overgrowth of non-susceptible micro-organisms; it is of paramount importance to monitor the patient constantly. If superinfections should occur, suitable measures must be taken. • Intrathecal administration is contraindicated. Serious intoxication of the central nervous system were reported after intrathecal administration of cefazolin, among which are convulsions. • Paediatric population: As the safety of use in premature babies and infants younger than one month has not been established, the use of {(Invented) name} in these patients is not recommended. See also section 4.2 “Dosage and method of administration”. • In exceptional cases blood coagulation may be impaired during cefazolin treatment. Risk patients are patients with risk factors who cause vitamin K deficiency, or influence other coagulation mechanisms

(parenteral alimentation, dietary deficiencies, reduced hepatic and renal function, thrombocytopenia). Blood clotting may also be impaired in patients with associated conditions (e.g. haemophilia, gastric and duodenal ulcers) which can induce or intensify bleedings. As such, the prothrombin time needs to be monitored in patients displaying this condition. If it is reduced, vitamin K supplements (10 mg/week) are recommended. • This medicinal product contains 50.56 mg of sodium per vial, equivalent to 2.53 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interactions with other medicinal products and other forms of interaction

Contraindicated combinations: Antibiotics: Concomitant administration of bacteriostatic antibiotics could antagonize the working of cefazolin.

Concomitant use not recommended: Probenecid: Probenecid: The renal clearance of cefazolin is reduced when probenecid is given in parallel.

Cautious use: Vitamin K1: Some cephalosporins such as cefamandole, cefazolin and cefotetan can inhibit the intrahepatic metabolism of vitamin K1 and cause a hypothrombinema, especially in case of vitamin K1 deficiency. This may require vitamin K1 supplementation.

Anticoagulants Cephalosporin may very rarely lead to blood clotting disturbances (see section 4.4). If oral anticoagulants or high dosage heparin are concomitantly used, clotting parameters should be carefully monitored.

Nephrotoxic agents: Nephrotoxic effects are enlarged by administration concomitant with other nephrotoxics such as amino glycosides (e.g. gentamicin), polymyxins, ethacrynic acid and furosemide and powerful diuretics. The kidney parameters should be carefully monitored.

Laboratory tests: Coombs tests may give false positive tests during treatment with cephalosporins. This is also the case for patients who are administered cefazolin.

Oral contraceptives: Cefazolin could possibly have a negative effect on the efficacy of hormonal contraceptives. It is recommended to also use a supplementary non hormonal contraceptive.

4.6 Fertility, pregnancy and breast-feeding

Pregnancy

Broad experience with the use of first generation cephalosporins during pregnancy do not indicate a harmful effect on the pregnancy nor on the health of the foetus/newborn. To date there is insufficient experience on the use of cefazolin during pregnancy in humans in order to be able to assess any damage. Cefazolin passes the placenta. Experimental research on animals has not shown any teratogenicity or other reproductive toxicity (see section 5.3).

As a precautionary measure, the use of {(Invented) name} during pregnancy is not recommended, unless it is strictly necessary.

Breast-feeding

Cefazolin is excreted into breast milk at very low concentrations. However, with therapeutic doses, no effects on the newborn are expected. {(Invented) name} can be used during breast-feeding.

Fertility Animal studies have shown no effects on fertility (see section 5.3).

4.7 Influence of the ability to drive and use machines.

Based on the pharmacodynamic profile and/or side effect profile it is very unlikely that cefazolin has an influence on the ability to drive and use machines.

4.8 Side effects

The following side effects could occur when cefazolin is used. The frequency of each side effect is indicated in brackets, using the following categories: 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) Not known (cannot be estimated form the available data)

MedDRA Organ Class Frequency Relevant side effects Infections and infestations Uncommon: Oral thrush (in long-term use) Rare: Genital moniliasis, Vaginitis, Genital candidiasis Blood and lymphatic system disorders Rare: Leucocytosis, Granulocytosis, Monocytosis, Lymphocytopenia, Basophilia, Eosinophilia, Granulocytopenia, Neutropenia, Leukopenia, Thrombocytopenia These effects are reversible. Very rare Blood clotting disturbances and - as a consequence - bleedings. At risk for these side effects are patients with a deficiency of vitamin K or other factors which can cause blood clotting disorders (parenteral alimentation, dietary deficiencies, reduced hepatic and renal function, thrombocytopenia), and patients with associated diseases causing or aggravating haemorrhages (e.g. haemophilia, gastric and duodenal ulcers). Immune system disorders Very rare Oedema in the face, Swollen tongue, Swelling of the larynx with a constriction of the airways, Increased heart rate, Shortness of breath, Fall in blood pressure, Anaphylactic shock. Metabolism and nutrition disorders Rare Increased or decreased serum glucose concentration. Nervous system disorders Uncommon: Convulsions (in patients with renal impairment, who were treated with inadequate high doses) Rare: Dizziness, Malaise, Tiredness Respiratory, thoracic and mediastinal Uncommon: Interstitial pneumonia or pneumonitis disorders Rare: Pleural effusion, dyspnoea or respiratory distress, coughing, rhinitis, Gastrointestinal disorders Rare: Diarrhoea, nausea, loss of appetite (anorexia), vomiting. These symptoms will often disappear during or after the treatment. Hepatobiliary disorders Rare: Transient elevation of serum concentrations of AST, ALT, gamma-GT, bilirubin and/or LDH and alkaline phosphatase, Transient hepatitis, Transient Cholestatic icterus Skin and subcutaneous tissue disorders Uncommon: Exanthema, Erythema, Erythema exudative multiforme, Urticaria, Reversible local permeability of blood vessels, mucous membrane of joints (angioneurotic oedema)

Rare: Stevens-Johnson syndrome, Toxic epidermal necrolysis (Lyell's syndrome) Very rare Anal pruritus, Genital pruritus Renal and urinary disorders

Rare: Transient increase in blood urea nitrogen (BUN), proteinuria, interstitial nephritis, Undefined nephropathies, Nephrotoxicity, mostly in patients who are being treated with another potentially nephrotoxic drug at the same time. General disorders and administration site conditions

Common: Pain at the injection site of the intramuscular administration, sometimes with induration. Uncommon: With intravenous administration thrombophlebitis can occur, Drug-induced fever Rare Chest pain

In cases of grave and persistent diarrhoea during or after treatment with cefazolin, a physician should be consulted because this could be the symptom of a serious disease (pseudomembranous colitis) that must be treated immediately. The patients should refrain from any self-medication with peristaltic inhibiting drugs. The prolonged use of cephalosporins may promote overgrowth of non-susceptible organisms, in particular Enterobacter, Citrobacter, Pseudomonas, Enterococci or Candida.

Tests • Transient elevation of SGOT, SGPT, blood urea and alkaline phosphatase, without clinical indication for hepatic or renal damage.

Data in animals have shown that with cefazolin there is a potential nephrotoxicity. Even though this has not been proven in humans, this possibility must be considered especially in patients who are being administered high doses during prolonged periods of time. Interstitial nephritis and undefined nephropathies have been reported in rare cases. This occurred mostly in critically ill patients receiving additional drugs. The role of {(Invented) name} in the development of interstitial nephritis and other nephropathies has not been established yet.

In rare cases the following side effects were reported during treatment with cephalosporines:

A decreased haemoglobin content and/or haematocrit, Anaemia, Agranulocytosis, Aplastic anaemia, Pancytopenia, Haemolytic anaemia

The following cases were reported during treatment with certain cephalosporins:

Nightmares, dizziness (vertigo), hyperactivity, nervousness or anxiety, insomnia, somnolence, weakness, hot flushes, alteration in colour perception, confusion, activity of epilepsy (epileptogenic 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 national reporting system listed in Appendix V. 10

4.9 Overdose

Symptoms Symptoms of overdosing can consist of pain, inflammation and phlebitis on the injection site. If administered in very high parenteral doses, cephalosporins may cause vertigo, parenthesias and headache. Particularly in patients with impaired renal function, where accumulation can occur, overdosing of some cephalosporins may induce convulsions. Overdosage may be associated with an increase in creatinine, BUN, liver enzymes and bilirubin concentrations and the likelihood of a positive Coombs test, thrombocytosis, thrombocytopenia, eosinophilia, leukopenia and prolonging of the prothrombin time.

Management of an overdose Convulsions necessitate an immediate drug withdrawal of {(Invented) name} . Anticonvulsants may be indicated and the ventilation and perfusion may be beneficial. The vital body functions should be closely monitored. Haemodialysis combined with haemoperfusion may be beneficial in cases of severe overdose, especially in patients with impaired renal function, if no results are achieved in more conservative therapies. Supportive data are lacking however.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other -lactam antibacterials, first generation cephalosporins. ATC-code: J01DB04

Mechanism of action All cephalosporins (β-lactam antibiotics) inhibit the bacterial cell wall production and are selective inhibitors of the peptidoglycan synthesis. The first step in the mode of action is the binding of the drug to the cell receptors (penicillin-binding proteins). After this binding the transpeptidase reaction is inhibited and this blocks the synthesis of peptidoglycan. This process results in the lysis of the bacteria.

Mechanisms of resistance The β-lactam antibiotics contain a so-called β-lactam ring which is essential for the antimicrobial working by splitting that ring, the antibiotic loses its effectiveness. Various bacteria, however, contain enzymes (-lactamases) which can potentially split that ring, making them resistant to this type of antibiotics.

As in all cephalosporins and other β-lactam antibiotics, resistance mechanisms which have been acquired differ per group of bacteria and comprise: alteration in the binding sites (Penicillin-binding Proteins, PBPs), enzymatic degradation of the binding sites by β-lactamases and changes in membrane permeability to the binding sites. Cross resistance of cephalosporins and penicillin occurs. Gram- negative micro-organisms which contain inducible chromosomal encoded β-lactamases, such as Enterobacter spp, Serratia spp, Citrobacter spp and Providentia spp must be considered as being resistant to cefazolin despite in vitro sensitivity.

Breakpoints The following breakpoints have been established by the European Committee for Antimicrobial Susceptibility testing (EUCAST) Clinical MIC Breakpoints (Version 9.0, valid from 2019-01-01) Species Susceptible (≤) Resistant (>) Staphylococcus spp. Note A Note A Streptococcus groups A, B, C and G Note B Note B Viridans group streptococci 0.5 mg / L 0.5 mg / L PK/PD (Non-species related) 1 mg / L 2 mg / L 11

breakpoints

A Susceptibility of staphylococci to cephalosporins is inferred from the cefoxitin susceptibility except for cefixime, ceftazidime, ceftazidime-avibactam, ceftibuten and ceftolozane-tazobactam, which do not have breakpoints and should not be used for staphylococcal infections. Some methicillin-resistant S. aureus are susceptible to ceftaroline and ceftobiprole.

B The susceptibility of streptococcus groups A, B, C and G to cephalosporins is inferred from the benzylpenicillin susceptibility.

The prevalence of resistance may vary geographically and with time for selected micro-organisms and local information on resistance is desirable, particularly when treating severe infections. If necessary, expert advice of a professional should be sought, in particular when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. The susceptibility of Staphylococcus is derived from the susceptibility of methicillin.

SUSCEPTIBLE SPECIES Gram-positive Staphylococcus. aureus (methicillin-susceptible) Staphylococcus epidermidis (methicillin-susceptible)

SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM Haemophilus influenzae+ Neisseria gonorrhoeae Group A, B, C and G - haemolytic streptococci Streptococcus pneumonia

RESISTANT ORGANISMS Citrobacter spp Enterobacter spp (Enterobacter cloacae, Enterobacter aerogenes) Morganella morganii Proteus stuartii Proteus vulgaris Pseudomonas aeruginosa Serratia spp Staphylococcus, methicillin-resistant Indol positive Proteus genuses Enterobacteriaceae spp (Klebsiella pneumoniae) Enterobacteriaceae spp (Proteus mirabilis)

Some germs of a type can be more or less sensitive to the product than is indicated for the majority of these germs. This is why we recommend performing susceptibility tests.

5.2 Pharmacokinetic properties

Absorption Maximum serum levels of 20-40 μg/ml are reached 1 hour after administration of 500 mg intramuscular. After administration of 1 g, the maximum level was reached of 37-63 μg/ml. In a study (in healthy adults) concerning a continuous intravenous infusion with {(Invented) name} in doses of 3.5 mg/kg during one hour (approx. 250 mg) followed by 1.5 mg/kg for the following two hours (approx. 100 mg) the third hour a stable serum concentration of approx. 28 μg/ml was shown. The following table shows the average serum concentration of cefazolin after an intravenous injection of a one-off dose of 1 g.

Serum concentrations after 1 g intravenous (μg/ml)

5 min 15 min 30 min 1 hour 2 hours 4 hours 188.4 135.8 106.8 73.7 45.6 16.5

Biotransformation Cefazolin is not metabolised.

Elimination The serum half-life is about 1 hr and 35 minutes. Cefazolin is excreted with the urine in a biological active form. With an intramuscular dose of 500mg, 56-89 % is excreted in the first six hours, and 80 to almost 100 % within 24 hours. After the intramuscular administration of 500 mg and 1 g, urine levels can be reached of 500 to 4000 μg/ml. Cefazolin is mainly removed from the serum by glomerular filtration; the renal clearance is 65ml/min/1.73 m².

Distribution About 70-86 % is bound to plasma proteins. The distribution volume is approx. 11l/1.73m². If administered to patients who do not show any obstruction to the bile ducts, the bile levels will be generally higher than the blood levels 90 to 120 minutes after the administration of cefazolin. If there is an obstruction however, the concentration of the antibiotic in the bile will be much lower than in the serum. In patients with non-inflamed meninges the concentrations of cefazolin in the liquor cerebrospinalis varies from 0 to 0.4 μg/ml after administration of therapeutic doses. Cefazolin easily penetrates the inflamed membrane synovialis and the concentration reached by the antibiotic in the joint is comparable to the serum levels.

5.3 Preclinical safety data

Cefazolin has a low acute toxicity. Kidney toxicity after repeated administration was observed in rabbits but not in rats or dogs. Cefazolin did not show teratogenic activity or other reproductive toxic effects in rats, mice and rabbits. There are no studies available about mutagenicity and carcinogenicity on cefazolin.

6. PHARMACEUTICAL PROPERTIES

6.1 List of excipients

None

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. Cefazolin is incompatible with amikacin disulfate, amobarbital sodium, ascorbic acid, bleomycin sulfate, calcium glucoheptonate, cimetidine, colistin methanesulfonate sodium, erythromycin, oxytetracyclin, pentobarbital sodium, tetracycline.

6.3 Shelf life

The shelf life is 2 years.

The reconstituted/diluted product is physically-chemically stable for 24 hours in the refrigerator (2°C - 8°C). From microbiological point of view, after dissolving the product should be administered immediately, unless reconstitution has taken place in controlled and validated aseptic conditions. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°С to 8°С.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.

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

6.5 Nature and contents of the container

Type III, colourless glass vials, with rubber stopper and sealed with aluminium cap. Packs of 10 vials.

6.6 Special precautions for disposal

Reconstitution

Intramuscular injection Dissolve in sterile water for the injection, according to the following dilution table. Shake well until all the powder has been dissolved.

Product after reconstitution is clear, almost colourless solution.

{(Invented) name} must be injected into a major muscle mass.

Dilution table Content of the vial to be added obtained average diluent volume concentration 1 g 2.5 ml 3.0 ml 330 mg/ml

Intravenous administration: {(Invented) name} may be administered directly into a vein, either as a continuous or an intermittent drip. The total daily dose is the same as for intramuscular administration.

Intermittent and continuous infusion {(Invented) name} can be administered in combination with an existing intravenous therapy, either in the primary drip or in the secondary infusion drip.

1 g {(Invented) name} may be dissolved in 100 ml 9 mg/ml (0.9 %) sodium chloride intravenous solution.

Direct intravenous injection: Dilute 1 g {(Invented) name} solution further with at least 10 ml water for injection, inject slowly during 3 to 5 minutes. In no case should the injection be shorter than 3 minutes. Done straight into the vein or into the tube in which the patient is administered the abovementioned.

CAUTION: One-off doses of more than 1g need to be administered over thirty to sixty minutes.

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

7. MARKETING AUTHORIZATION HOLDER:

<[To be completed nationally]> {Name and address} <{tel}> <{fax}> <{e-mail}>

8. MARKETING AUTHORIZATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

{(Invented) name} 1 g powder for solution for injection/infusion Cefazolin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains cefazolin sodium equivalent to 1 g cefazolin.

3. LIST OF EXCIPIENTS

The sodium content is 50.56 mg (2.2 mmol) per gram of product. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for solution for injection/infusion 10 vials

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use. Intravenous or intramuscular injection after reconstitution or intravenous infusion after dilution. For single use only.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP Read the leaflet for the shelf life of the reconstituted medicine.

9. SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from light. For storage conditions after reconstitution and dilution of the medicinal product, see package leaflet.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

{Name and Address} <{tel}> <{fax}> <{e-mail}>

12. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

<[To be completed nationally]>

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

<2D barcode carrying the unique identifier included. >

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

{(Invented) name} 1 g powder for solution for injection/infusion Cefazolin i.v. or i.m. use

2. METHOD OF ADMINISTRATION

Read the package leaflet before use. i.v. or i.m. injection after reconstitution or i.v. infusion after dilution. For single use only.

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1 g

6. OTHER

PACKAGE LEAFLET

Package leaflet: Information for the user

{(Invented) name} 1 g powder for solution for injection/infusion

Cefazolin

Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet 1. What {(Invented) name} is and what it is used for 2. What you need to know before you are given {(Invented) name} 3. How to use {(Invented) name} 4. Possible side effects 5. How to store {(Invented) name} 6. Contents of the pack and other information

1. What {(Invented) name} is and what it is used for

{(Invented) name} is a powder for the preparation of an injection solution. {(Invented) name} is used in adults, adolescents, children and infants older than one month to treat certain infections (antibiotic) and belongs to the group of cephalosporins (a particular group of antibiotics)

{(Invented) name} is used to treat bacterial infections caused by cefazolin-susceptible bacteria, e.g: • Infections of skin and soft tissue • Infections of bones and joints • Prevention of possible infection before, during and after surgery

2. What you need to know before you are given {(Invented) name}

Do not use {(Invented) name} • If you are allergic to cefazolin, one of the other cephalosporins or the other ingredient of this medicine (listed in section 6) • If you have ever had an immediate and/or severe allergic reaction to any penicillin or any other type of β-lactam antibiotic. • When administered to children younger than 1 year, cefazolin should not be dissolved in a lidocaine solution.

Warnings and precautions Talk to your doctor or nurse before you are given {(Invented) name} in the following situations: • If in the past you have had an allergic reaction to penicillin or other medicines. It could be you are allergic to cefazolin sodium too. Should an allergic reaction occur, the treatment will have to be stopped, the allergic reaction will have to be treated and the renal function must be monitored. • When an allergic reaction occurs caused by {(Invented) name} , the administration of the product 21

will be stopped immediately. Your doctor will suggest an alternative treatment. • If you are receiving the maximum dosage and you are seriously ill or if you also use other medicines which could possibly be damaging to your kidneys (aminoglycosides or powerful diuretics), your doctor will examine your kidney function and if necessary adjust the dose. • If you are being administered {(Invented) name} during a prolonged time, your doctor will check that there is no overgrowth of non-susceptible bacteria. • Exceptionally, blood coagulation may be impaired during cefazolin treatment. Patients at risk are those with risk factors causing vitamin K deficiency or affecting other blood clotting mechanisms. In addition, blood clotting may be impaired in patients with conditions which can cause or aggravate bleeding, such as haemophilia, gastric and duodenal ulcers. In such cases your blood coagulation will be monitored. • If during treatment you experience severe persistent diarrhoea, you could possibly be suffering from an infection of the membrane of the small and large intestine with damage to the mucous membranes (pseudomembranous colitis). • Cefazolin should not be used in newborns and infants younger than one month as the safety of use has not been established.

Consult your doctor if one of the warnings listed above applies to you, or applied to you in the past.

Other medicines and {(Invented) name} Tell your doctor or pharmacist if you are taking, or have recently taken or might take any other medicines. This also includes medicines which you have obtained without a prescription.

• Contraindicated combinations: Antibiotics: Concomitant use of antibiotics from certain groups (bacteriostatic mode of action) such as tetracyclines and macrolides. These could impair the working of {(Invented) name}, which means {(Invented) name} would not work properly. • Concomitant use is not recommended. Probenecid: If you also use probenecid (for a metabolic disease), as probenecid reduces the renal clearance of cefazolin. • Cautious use: Vitamin K1: If you use vitamin K1, {(Invented) name} could cause an increase in the doses of vitamin K1 Anticoagulants (medicines which prevent blood clotting (oral anticoagulants) or heparin): Cephalosporins may very rarely lead to blood clotting disturbances. If anticoagulants (oral anticoagulants or heparin) in high dosages are concomitantly used, clotting parameters should be carefully monitored. Nephrotoxic agents (damaging to the kidneys) If you are being administered medicines which have a nephrotoxic effect (poisonous for the kidneys) such as certain antibiotics (aminoglycosides, polymyxin B) and certain diuretics (furosemide). If concomitantly used the kidney parameters should be carefully monitored. Oral contraceptives: Cefazolin could possibly have a negative effect on the efficacy of hormonal contraceptives. It is recommended to also use a supplementary non- hormonal contraceptive.

Pregnancy, breast-feeding and fertility If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before you are given this medicine.

Pregnancy To date there is insufficient experience on the use of cefazolin during pregnancy in humans in order to be able to assess any damage. {(Invented) name} should not be used during pregnancy without the 22 advice of a doctor.

Breast-feeding Cefazolin is excreted into the breast milk at a very low concentration.

With normal administration, no effects on the newborn are expected. {(Invented) name} can be used during breast-feeding.

Driving and using machines There are no data about the effect of cefazolin on the ability to drive and use machines. An effect, however, is not probable.

{(Invented) name} contains sodium This medicine contains approximately 50.56 mg of sodium (main component of cooking/table salt) per vial (in each 1.0 g). This is equivalent to 2.53 % of the recommended maximum daily dietary intake of sodium for an adult. This should be taken into consideration by patients on a controlled sodium diet.

3. How to use {(Invented) name}

{(Invented) name} should only be administered by personnel with the necessary qualifications (doctors or other professionals in the health care sector).

Dosage

Adults and adolescents (above 12 years of age and ≥ 40 kg bodyweight) In infections caused by very sensitive gram-positive micro-organisms the usual dosage in adults and adolescents is 1 to 2 g/day in two or three equal doses. In infections caused by less sensitive gram-positive organisms and gram-negative organisms, the usual dosage is 3 to 4 g/day in three or four equal doses. {(Invented) name} is administered up to doses of a maximum 6 g/day in cases of severe infections.

In adult and adolescent patients with renal insufficiency a lower dosage should be adhered to. The dosage is determined based on the blood levels or kidney function values.

As a precaution against infections: • Before surgery: 1 g administered 30 minutes to 1 hr prior to surgery. • During surgery: for longer operations (2 hours or more) 500 mg to 1 g will be administered intraoperatively for the duration of the surgery. • After surgery: 500 mg to 1 g every 6 to 8 hours for 24 hours.

Use in children and infants older than one month In infections caused by very sensitive micro-organisms a dosage of 25 to 50 mg/kg divided in two or four doses a day will be efficient. In infections caused by less sensitive micro-organisms a dosage of a max 100 mg/kg is recommended in three or four equal doses. In children and infants older than one month with renal insufficiency a lower dose may be recommended in order to avoid accumulation. This lower dose can be determined by assessing the blood levels. Should this not be possible, the dosage can be determined by monitoring the determined values of the kidney function (creatinine clearance) according to the following guidelines.

In children and infants older than one month with moderate renal insufficiency (creatinine clearance of 40-20 ml/min, 25 % of the normal daily dosage, divided in doses every 12 hours, will be sufficient. 23

In children and infants older than one month with severe renal insufficiency (creatinine clearance 20-5 ml/min) 10 % of the normal daily dosage, administered every 24 hours, will be sufficient.

All these guidelines apply after an initial starting dose. See also heading 2: “Warnings and precautions”.

Premature babies and infants younger than one month As the safety of use in premature babies and infants younger than one month has not been established, the use of {(Invented) name} in these patients is not recommended.

Guidelines for paediatric dosage

1 g vial to be prepared with 4 ml of diluent = 225 mg/ml.

Elderly patients No dose adjustments are needed in elderly patients with normal renal function.

Administration

{(Invented) name} is administered via an injection in the muscle (intramuscular administration) or via an infusion in the vein (intravenous administration). Before administration, {(Invented) name} needs to be reconstituted.

The following solutions may be used for reconstitution: - sterile water for injection - 9 mg/ml (0.9 %) sodium chloride for injection

This is done according to the reconstitution rates described in section “The following information is intended for medical or healthcare professionals only”. Shake well until all the powder has been dissolved.

Administration in a muscle (intramuscular) {(Invented) name} must be injected into a major muscle mass.

Administration in a vein (intravenous) {(Invented) name} may be administered directly into a vein, either as a continuous drip or an intermittent drip. The total daily dose is the same as for intramuscular administration.

Intermittent and continuous infusion {(Invented) name} can be administered in combination with an existing intravenous therapy, either in the primary drip or in the secondary infusion drip.

If you use more {(Invented) name} than you should When too much {(Invented) name} has been administered, immediately contact your doctor or pharmacist. High doses of {(Invented) name} can lead to convulsions, especially in patients with impaired renal function. In such cases, the treatment with {(Invented) name} needs to be stopped and the condition needs to be treated. Vital functions will be monitored. 24

If you forget to use {(Invented) name} If you think you have not been given a dose, you must tell your doctor or pharmacist immediately. You should not be given a double dose to make up for a forgotten dose.

If you stop using {(Invented) name} It is very important you finish the course, even if you are already feeling better. If not all the bacteria are killed, the condition could return.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Skin and subcutaneous tissue disorder Uncommon (may affect up to 1 in 100 people): Skin rash (exanthema), reddening of the skin (erythema), skin rash with moist irregular red spots (erythema exudative multiforme), skin rash with excessive itching and formation of small bumps (urticaria), reversible local permeability of the blood vessels, mucous membranes or joints (angio neurotic oedema).

Rare (may affect up to 1 in 1,000 people): Severe allergic reaction with (high) fever, red spots on the skin, joint pains and/or inflammation of the eye (Stevens-Johnsons syndrome), Severe, acute (allergic) reaction combined with fever and blisters on the skin (Lyell’s syndrome).

Very rare (may affect up to 1 in 10,000 people): Anal itching (anal pruritus), genital itching (genital pruritus),

Immune system disorder Very rare (may affect up to 1 in 10,000 people): Fluid accumulation (oedema) in the face, swollen tongue, swelling of the larynx, with constriction of the airways, increased heart rate, shortness of breath, drop in blood pressure, shock (strong drop in blood pressure, pale skin, restlessness, weak fast pulse, moist skin, reduced consciousness) caused by a sudden strong vascular widening as a result of serious allergic reaction for certain excipients (anaphylactic shock).

Infections and parasitic conditions Uncommon (may affect up to 1 in 100 people): Yeast infection (candidiasis) of the oral mucosa (oral thrush) (in long term use).

Rare (may affect up to 1 in 1,000 people): Yeast infection of the reproductive organs (genital monoliasis), infection of the vagina (vaginitis), yeast infection of the reproductive organs (genital candidiasis).

Blood and lymphatic system disorders Rare (may affect up to 1 in 1,000 people): Too many white blood cells (leucocytosis, granulocytosis, monocytosis, basophilia, eosinophilia), shortage of white blood cells in combination with a heightened sensitivity to infections (lymphocytopenia, neutropenia, granulocytopenia, leukopenia), shortage of blood cells in combination with bruises and a tendency for bleeding (thrombocytopenia). These effects are reversible. 25

Very rare (may affect up to 1 in 10,000 people): Blood clotting disturbances and - as a consequence - bleedings. At risk for these side effects are patients with a deficiency of vitamin K or other factors which can cause blood clotting disorders (parenteral alimentation, dietary deficiencies, reduced hepatic and renal function, thrombocytopenia), and patients with associated diseases causing or aggravating haemorrhages (e.g. hemophilia, gastric and duodenal ulcers).

Hepatobiliary disorders Rare (may affect up to 1 in 1,000 people): Transient inflammation of the liver (hepatitis), transient jaundice (cholestatic icterus).

Nervous system disorders Uncommon (may affect up to 1 in 100 people): Seizures, convulsions have occurred in particular in patients with impaired renal function who were treated with doses not amended to their situation.

Rare (may affect up to 1 in 1,000 people): Dizziness, generally feeling unwell (malaise), tiredness. These symptoms will disappear during or after the treatment.

Gastrointestinal disorders Rare (may affect up to 1 in 1,000 people): Diarrhoea, nausea, loss of appetite (anorexia), vomiting. These symptoms will disappear during or after the treatment.

In cases of grave and persistent diarrhoea during or after treatment with cefazolin, a doctor should be consulted because this could be the symptom of a serious disease (pseudomembranous colitis) that must be treated immediately. The patients should refrain from any self- medication with peristaltic inhibiting drugs.

Renal and urinary disorders Rare (may affect up to 1 in 1,000 people): Transient increase of certain values of the renal function (blood urea nitrogen (BUN)), protein loss via urine (proteinuria), inflammation of the kidneys in combination with blood in the urine, fever and pain in the sides (interstitial nephritis), undefined kidney conditions (nephropathies), poisoning of the kidneys (nephrotoxicity), mostly in patients who are treated concomitantly with another potentially nephrotoxic medicine.

General disorders and administration site conditions Common (may affect up to 1 in 10 people): Pain at the injection site of the intramuscular administration, sometimes with sensitive subcutaneous hardening of the tissue (induration).

Uncommon (may affect up to 1 in 100 people): In intravenous administration, inflammation of the vein with the formation of a blood clot, often felt as a painful somewhat hard string with red skin on top (thrombophlebitis) can occur, drug-induced fever.

Rare (may affect up to 1 in 1,000 people): Chest pain.

Respiratory, thoracic and mediastinal disorders Uncommon (may affect up to 1 in 100 people): Lung disease (interstitial pneumonia), benign inflammation of a part of the lung (pneumonitis). 26

Rare (may affect up to 1 in 1,000 people): Difficulty in breathing (pleural effusion, dyspnea), respiratory distress, coughing, inflammation of the nasal mucous (rhinitis).

Metabolism and nutrition disorders Rare (may affect up to 1 in 1,000 people): Increased or decreased serum glucose concentration.

In case you experience a side effect which is not listed in this leaflet or which you experience as being severe, please inform your doctor or pharmacist.

In rare cases the following side effects were reported during treatment with cephalosporines: A decreased haemoglobin concentration and /or haematocrit (blood volume), blood shortage (anaemia), very serious blood condition (shortage of white blood cells) combined with a sudden high fever, severe throat pain and ulcers in the mouth (agranulocytosis), haemolytic anaemia due to postponed production of red blood cells (aplastic anaemia), reduction of all types of cells in the blood (pancytopenia), haemolytic anaemia as a result of too many blood cells being destroyed in the blood (haemolytic anaemia).

The following cases were reported during treatment with certain cephalosporines: Nightmares, dizziness (vertigo), hyperactivity, nervousness or anxiety, insomnia, somnolence, weakness, hot flushes, alteration in colour perception, confusion, activity of epilepsy (epileptogenic activity).

Reporting of side effects If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store {(Invented) name}

Keep {(Invented) name} out of reach and sight of children. This medicine does not require any special temperature storage conditions. Store in the original package in order to protect from light.

Expiry date: Do not use {(Invented) name} after the expiry date which is stated on the label and carton after “EXP”. The expiry date refers to the last day of that month.

6. Contents of the pack and other information

What {(Invented) name} contains - The active substance is cefazolin. A vial of {(Invented) name} 1 g powder for the solution for injection/infusion, contains cefazolin sodium, which corresponds with 1 g cefazolin. Please 27

also see section 2 {(Invented) name} contains sodium. - There are no other excipients.

What X looks like and contents of the pack {(Invented) name} is white or almost white powder in type III, colourless glass vials, with rubber stopper and sealed with aluminium cap. {(Invented) name} is supplied in packaging of 10 vials.

Marketing Authorization Holder and Manufacturer

Marketing authorisation holder: <[To be completed nationally]> {Name and address} <{tel}> <{fax}> <{e-mail}>

Manufacturer: <[To be completed nationally]> {Name and address} <{tel}> <{fax}> <{e-mail}>

This medicinal product is authoris ed in the Member States of the EEA under the following name : <[To be completed nationally]>

This leaflet was last approved in {MM/YYYY}.

------The following information is intended for medical or healthcare professionals only:

Reconstitution

Intramuscular injection Dissolve in sterile water for the injection according to the following dilution table. Shake well until all the powder has been dissolved.

After reconstitution {(Invented) name} is a clear almost colourless solution.

{(Invented) name} must be injected into a major muscle mass.

Dilution table Content of the vial to be added obtained average diluent volume concentration 1 g 2.5 ml 3.0 ml 330 mg/ml

Intermittent and continuous infusion {(Invented) name} can be administered in combination with an existing intravenous therapy, either in the primary drip or in the secondary infusion drip.

1 g {(Invented) name} may be dissolved in 100 ml 9 mg/ml (0.9 %) sodium chloride intravenous solution.

Direct intravenous injection: Dilute 1 g {(Invented) name} solution further with at least 10 ml water for injection, inject slowly during 3 to 5 minutes. In no case should the injection be shorter than 3 minutes. Done straight into the vein or into the tube in which the patient is administered the abovementioned.

CAUTION: One-off doses of more than 1g need to be administered over thirty to sixty minutes.

Incompatibility

This medicinal product must not be mixed with other medicinal products except those mentioned in section Reconstitution. Cefazolin is incompatible with amikacin disulfate, amobarbital sodium, ascorbic acid, bleomycin sulfate, calcium glucoheptonate, cimetidine, colistin methanesulfonate sodium, erythromycin, oxytetracyclin, pentobarbital sodium, tetracycline.

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