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Vulmizolin 1 g, plo. ino.

1.  NAME OF MEDICINAL PRODUCT

VULMIZOLIN 0,5
VULMIZOLIN 1,0
plv. ino 10x1g

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Vulmizolin 0,5:     cefazolinum natricum 0.525 g is equivalent to cefazolinum 0.5 g 

Vulmizolin 1,0:     cefazolinum natricum 1.05 g is equivalent to cefazolinum 1.0 g 

                            1 g of the substance contains 48.3 mg i.e. 2.1 mmol Na

 3. pharmaceutical form

Powder for solution for injection

Description: white or almost white powder

4. clinical particulars

4.1. Therapeutic indications

Treatment of severe infections which are induced by gram-positive and gram-negative microbes sensitive to cefazolin. Treatment of infections of respiratory and urogenital tract, biliary tract, skin and soft tissues, ostheomyelitis, septicemia. Preoperative prophylaxis.

4.2. Posology and method of administration

Doses depend on severity and localization of infection.

A d u l t s : in pneumococcal pneumonia 500 mg each 12 hours, in infections induced by gram-positive microbes 250 – 500 mg each 6 hours, in acute uncomplicated infections of urogenital tract 1 g each 12 hours, in medium severe and severe infections 500 mg up to 1 g each 6 to 8 hours intramuscularly or by intravenous injection, or by infusion. In endocarditis it is possible to apply even 6 g daily intravenously.

C h i l d r e n : the total daily dose is 25, 50 in heavy infections up to 100 mg/kg of body weight divided into three to four partial doses applied intramuscularly, intravenously or by infusion.

P r e o p e r a t i v e   p r o p h y l a x i s : usual dose for adults is 1 to 2 g intravenously or 1 g intramuscularly, in children the dose per kg of body weight is chosen in dependence on expected infection risk and length of operative intervention, 30 to 60 minutes before surgery intervention.

 Approximate schedule according to the kind of surgery intervention is indicated in the following table:

Type of operation

Dose before operation

Postoperative dose / interval

Duration of prophylaxis

Cardio-surgery

2 g i.v.

1 g i.v. / 6 - 8 h

24 h max. 48 h

Vascular surgery

2 g i.v.

1 g i.v. / 6 - 8 h

24 h

Orthopedics and accidental surgery

2 g i.v.

1 g i.v. / 6 - 8 h

24 h max. 48 h

Surgery of chest and esophagus

1 g i.v.

1 g i.v. / 8 h

max. 24 h

Cervix-facial surgery

2 g i.v.

1 g i.v. / 8 h

24h max. 48 h

Gastro-duodenal and biliary surgery

2 g i.v.

If duration of operation is more than 2 h + 1 g i.v.

Gynecology and obstetrics

2 g i.v.

1 g i.v. / 8 h

24 h

 

In regard to biological half-life of cefazoline (2 h) one application per operative intervention lasting 2 – 3 hours is sufficient. In increased risk of infection it is possible to apply during 24 hours 500 mg up to 1 g of Vulmizolin each 6 to 8 hours.

In renal insufficiency it is necessary to adjust the dosing of Vulmizolin. The starting dose is equivalent to normal single dose (0.5 – 1.0 g), the subsequent doses and dosing intervals are adjusted according to the clearance values of endogenous creatinine.

 

Clearance of endogenous creatinine per 24 h

Single dose in mg

 

Interval between doses in h

mL / min

recom. mL / s

Medium severe infections

Heavy infections

 

above 70

above 1.17

without adjustment

8

40 - 70

0.67 – 1.17

500

1250

12

20 - 40

0.33 – 0.67

250

600

12

5 - 20

0.08 – 0.33

150

400

24

under 5

under 0.08

75

200

24

 

4.3. Contraindications

Hypersensitivity to beta-lactam antibiotics

 4.4. Special warnings and special precautions for use

Cross hypersensitivity to beta-lactam antibiotics occurs in 20 % of treated patients with known hypersensitivity, i.e. 1 % of population. Skin tests are not reliable indicators of cross hypersensitivity in known hypersensitivity to other beta-lactam antibiotics. In long-lasting application there is a risk of pseudomembranous colitis and nephrotoxicity.

4.5. Interaction with other medicinal products and other forms of interaction

In concomitant application of heparin in high doses, per oral anticoagulants and other substances which influence the system of blood coagulation, it is necessary to monitor the values of blood coagulation. Probenecid increases the plasmatic level and subsequently shortens the elimination half-life of cefazolin.

Vulmizolin should not be combined with antimicrobial substances with bacteriostatic action (tetracyclines, erythromycin, sulfonamides, chloramphenicol), because antagonistic effect cannot be excluded.

Risk of nephrotoxicity is increased with the combination with aminoglycoside antibiotics, furosemide, etacrynic acid and cisplatinum.

4.6. Pregnancy and lactation

Pregnancy is relative contraindication. Studies on rats, mouses and rabbits with the doses 25 times exceeding the doses recommended for human, did not show any teratogenic effect. However the studies on human have not been performed and no damage of fetus by cefazolin is known up to now. Despite of this the application to pregnant women must be considered. Vulmizolin crosses the placental barrier. In mother milk and amniotic fluid it reaches low concentrations. In breastfed infant there is a possibility of sensibilization and the development of diarrhea and other undesirable effects cannot be excluded.

 4.7. Effects on ability to drive and use machines

Effects on ability to drive and use machines are not expected.

4.8. Undesirable effects

Skin and total allergic symptoms (exanthema, drug fever, pruritus vulvae), changes of blood count (eosinophilia, neutropenia, leucopenia, thrombocytopenia), lower and temporary increase of values of transaminases (S-AST and S-ALT), urea, alkali phosphatase (S-ALP), gastrointestinal difficulties (nausea, vomiting, diarrhea, candidiasis in mouth), painfulness and induration at the site of i.m. application, phlebitis, genital-anal pruritus, mycosis, colpitis. In long-time application there is a risk of occurrence of pseudomembranous colitis. Risk of anaphylactic reaction and risk of nephrotoxicity increases, if high doses are applied.

4.9. Overdose

LD50 in animals after i.v. application

   mouse

4 - 5 g . kg-1

   rat

2.4 – 3.7 g . kg-1

   rabbit

2.5 g . kg-1

   dog

2.2 g . kg-1

 

Toxic signs and overdose symptoms include pain, phlebitis at application site. Parenteral application of unsuitable high doses may induce dizziness, paresthesia, headache. Overdosing may occur also at application of low doses to patients with impaired renal function, or in interaction with other medicinal products etc.

Treatment of overdosing consists in immediate interruption of application, assurance of breathing (if required, also by artificial ventilation), assurance of heart activity and blood circulation with the target to maintain vital functions of patient. In indicated cases also start of anticonvulsive therapy.


5. PHARMACOLOGICAL PROPERTIES

 5.1. Pharmacodynamic properties

Pharmacotherapeutic group: antibiotic, cephalosporin of 1st generation

ATC code: J01DB04

Cephalosporin semi-synthetic bactericidal antibiotic with wide spectrum of activity. Cefazolin similarly as all beta-lactam antibiotics, blocks the synthesis of cell wall of sensitive bacteria. It is resistant against effect of some beta-lactamases similarly as other cephalosporins of 1st generation, with which it has identical antibacterial activity.

A n t i m i c r o b i a l   s p e c t r u m : well sensitive in vitro are streptococci of A, B, C and G group and others, pneumococci, staphylococci (including the strains producing penicillinase), (MIC G+ cocci 0.1 – 1.0 µg/L) haemophili and strains of gram-negative intestinal sticks isolated from patients out of hospital: Escherichia coli, Proteus mirabilis, Klebsiella sp. (strains isolated in hospital may be resistant). Cefazolin is not effective against the strains of gram-negative bacteria producing line of beta-lactamases (Enterobacter cloacae, Citrobacter freundii, Proteus vulgaris, Providencia rettgeri, Bacteroides fragilis, Serratia sp., Pseudomonas sp., Acinetobacter sp. and others), all enterococci, pneumococci resistant to penicillin and staphylococci resistant to oxacillin (methicillin).

 

5.2. Pharmacokinetic properties

Maximum serum concentrations are reached in about one hour after intramuscular application. After application of 1 g dose the level in plasma reaches about 64 µg/mL, distribution volume 0.14 ± 0.4 L.

 

Concentrations in serum (µg/mL) after intramuscular application

Dose

0.5 h

1 h

2 h

4 h

6 h

8 h

0.25 g

15.5

17

13

5.1

2.5

-

0.5 g

36.2

36.8

37.9

15.5

6.3

3

1 g

60.1

63.8

54.3

29.3

13.2

7.1

 

 

Concentrations in serum (µg/mL) after intravenous application of 1 g

5 min

10 min

30 min

1 h

2 h

4 h

188.4

135.8

106.8

73.7

45.6

16.5

About 80 % of the dose is bound to proteins of blood plasma regardless of the size of applied dose, biological half-life is 1.8 ± 0.4 hour; therapeutic level is kept in blood about 8 hours. The level is higher in bile than in blood serum.

The concentrations of cefazolin in body liquids and tissues:

Body liquid or tissue

Dose of cefazolin

Concentration µg / mL resp. µg / g

Chamber liquor

1 g i.m.

0.5 – 0.9

Bile

4 x 0.5 g i.m.

92.1 – 94.0 +

1.6 – 8.1 ++

Mucosa

(maxillary side sinus)

0.5 g i.m.

3.5

Synovial fluid

1 g i.m.

65

Sputum

3 g i.v.

1 – 1.8

Tonsils

0.25 g i.m.

0.5 g i.m.

3.4

7.6

Notes:             + = patients without closure of biliary tract

                        ++= patients with closure of biliary tract

Cefazolin is excreted in unchanged form (80 – 90 %) by kidneys. In therapeutic doses it penetrates the joint area, passes placental barrier; in mother milk and amniotic fluid it reaches low concentrations.


6. pharmaceutical particulars

6.1. List of excipients

None.

6.2. Incompatibilities

The medicinal product is incompatible with aminoglycosides, ascorbic acid, sodium salt of amobarbital and pentobarbital, amikacin sulfate, bleomycin sulfate, colistin mesilate, gluconate and glucoheptonate calcium, cimetidine, erythromycin glucoheptonate and tetracyclines. In treatment by Vulmizolin the false positive Coombs´ test or false positive result of determination of glucose by Fehling reagent may occur.

6.3. Shelf-life

2 years

6.4. Special precautions for storage

Store below 25 °C, keep on dry place, protect from light.

The prepared solution of Vulmizolin is stable 24 hours kept in refrigerator (2 – 8 °C).

6.5. Nature and contents of container

Vial with crimp, rubber stopper, aluminium crimp cap, paperboard box.

Package size:   1, 10, 50 injection vials of 0.5 g

                        1, 10, 50 injection vials of 1.0 g

6.6. Special precautions for disposal and other handling

For intramuscular injection into vial with 1 g (0.5 g) of Vulmizolin add 4 to 6 mL (2 to 3 mL) of water for injection or NaCl isotonic solution. Injection has to be applied into place with larger amount of muscular mass.

For intravenous injection dilute 1 g (0.5 g) of Vulmizolin firstly in 2 mL (1 mL) of water for injection and then dilute to the total volume of minimum 10 mL. Apply slowly (2 to 3 minutes).

For intravenous infusion dilute the prepared injection solution with 50 to 100 mL of usually used basic infusion solutions. It is applied for 20 – 30 minutes.


7. MARKETING AUTHORISATION HOLDER

BB Pharma a.s., Pod Višňovkou 1662/21, Prague, Czech Republic

8. MARKETING AUTHORISATION NUMBER

15/0034/85-S, 15/034/85-S/C

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

1985/

10. DATE OF REVISION OF THE TEXT

September 2013