INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo RANZOL 250 Injection
RANZOL 500 Injection
RANZOL 1 g Injection

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

RANZOL 250 Injection
RANZOL 500 Injection
RANZOL 1 g Injection

COMPOSITION:
Ranzol 250 Injection
Each vial contains:
Sterile Cefazolin Sodium USP equivalent to
Cefazolin 250 mg
Ranzol 500 injection
Each vial contains:
Sterile Cefazolin Sodium USP equivalent to Cefazolin 500 mg
Ranzol 1 g Injection
Each vial contains:
Sterile Cefazolin Sodium USP
equivalent to Cefazolin 1 g

PHARMACOLOGICAL CLASSIFICATION:
A 20.1. 1 Broad and Medium Spectrum Antibiotics

PHARMACOLOGICAL ACTION:
The bactericidal action of cefazolin results from inhibition of cell well synthesis. Cefazolin is active against the following organisms in vitro and in clinical infections. (In vitro sensitivity does not necessarily mean in vivo efficacy).
Staphylococcus aureus (including penicillinase producing strains), Staph. epidermidis, Group A beta-hemolytic streptococci and other strains of streptococci, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella species, Enterobacter aerogenes and Haemophilus influenzae.
Most strains of methicillin resistant Staph. aureus, indole-positive Proteus, Enterobacter cloacae, Morganella morganii and Providencia rettgeri are resistant. Serratia, Pseudomonas, and Acinetobacter calcoaceticus are almost uniformly resistant to cefazolin.
Pharmacokinetics:
Cefazolin is well absorbed after intramuscular administration. The half life of cefazolin is 1,4 hours - 1,8 hours. Cefazolin is excreted unchanged in the urine, primarily by glomerular filtration and, to a lesser degree, by tubular secretion. Following intramuscular injection of 500 mg, 56% to 89% of the administered dose is recovered within 6 hours and 80% to nearly 100% in 24 hours. Cefazolin achieves peak urine concentrations greater than 1000 mcg/mL and 4000 mcg/mL respectively following 500 mg and 1 g intramuscular doses.

INDICATIONS:
Cefazolin is indicated in the treatment of the following serious infections due to susceptible organisms:
Respiratory tract infections - due to S. pneumoniae, Klebsiella species, H. influenzae, S. aureus and group A beta- hemolytic streptococci. The agent of choice for streptococcal infection and prevention of rheumatic fever is penicillin.
Genito-urinary tract infections including prostatitis and epididymitis - due to E. coli, P. mirabilis, Klebsiella species and some strains of enterobacter and enterococci.
Skin and soft tissue infections - due to Staphylococcus aureus, group A beta-hemolytic streptococci and other strains of streptococci.
Biliary tract infections - due to E. coli and Klebsiella species.
Bone and joint infections - due to Staphylococcus aureus.
Septicaemia - due to Streptococcus pneumoniae, Staphylococcus aureus, Proteus mirabilis, E. coli, and Klebsiella species.
Endocarditis - due to Staphylococcus aureus and group A beta-haemolytic streptococci.
Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organisms to cefazolin.
Perioperative prophylaxis - Cefazolin is useful in preoperative, intraoperative and post operative prophylaxis in various surgical procedures. This is especially effective in reducing the post operative infections due to contaminated or potentially contaminatedsurgical procedures.
The preoperative use of cefazolin also may be effective in surgical patients in whom infection of the operative site would present a serious risk.
The prophylactic administration of cefazolin should usually be discontinued within a 24 hour period after the surgical procedure.

CONTRA-INDICATIONS:
Cefazolin is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
The safety in pregnancy and lactation has not been established. Since safety for use in premature infants and in infants-under 1 month of age has not been established, the use of cefazolin in these patients is not recommended.

WARNINGS:
Pseudomembranous colitis has been reported with broad spectrum antibiotics including Ranzol, therefore, it is important to consider its diagnosis in patients who develop diarrhoea in association with its use. Such colitis may be life-threatening and appropriate measures should be taken, including discontinuation of the antibiotic.
Cefazolin should be given cautiously to penicillin sensitive patients. There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and the cephalosporins. Before cefazolin therapy is instituted, careful inquiry should be made concerning previous hyprsensitivity reactions of cephalosporins and penicillins. Any patient who has demonstrated some form of allergy particularly to medicines should receive antibiotics cautiously and no exception should be made in this regard to cefazolin.

DOSAGE AND DIRECTIONS FOR USE:
Ranzol may be administered intramuscularly or intravenously after reconstitution. Total daily dosages are the same for either route of administration.
Intramuscular administration: Reconstitute the contents with sterile water for injection, 250 mg and 500 mg vials may be reconstituted using 2 mL of sterile water for injection. For 1 g vial, use 2,5 to 3 mL sterile water for injection for reconstitution. Shake well until dissolved. Ranzol should be injected into a large muscle mass.
Intravenous administration: Ranzol may be administered by intravenous injection or by continuous or intermittent infusion. Total daily dosages remain the same as for intramuscular injection.
Intermittent intravenous infusion: Ranzol can be administered along with primary intravenous fluid management programs in a volume control set or in a separate, secondary IV bottle. Reconstituted 250 mg, 50 mg or 1 g of cefazolin may be diluted in 50 to 100 mL of one of the following intravenous solutions: 0,9% Sodium Chloride Injection, 5% or 10% Dextrose Injection 5% Dextrose in Compound Sodium Lactate Injection, 0,9% Sodium Chloride and 5% Dextrose Injection, 0,45% Sodium Chloride and 5% Dextrose Injection and Compound Sodium Lactate Injection, 5% or 10% Invert sugar in Water for Injection.
Direct intravenous injection: Dilute 250 mg, 500 mg or 1 g reconstituted cefazolin in a minimum of 10 mL sterile water for injection and inject slowly over a period of 3-5 minutes. Do not inject in less than 3 minutes.
Dosage - The usual adult dosages are given below *.

USUAL ADULT DOSAGE OF CEFAZOLIN
Type of Infection Dose Frequency Route of Administration
Pneumococcal pneumonia 500 mg q8h - q12h IV Infusion
Mild infections caused by susceptible Gram positive cocci 250 to 500 mg q8h IV Infusion
Acute uncomplicated urinary tract infections 1 g q12h IV Infusion
Moderate to severe infections 500 mg to 1 g q6h-q8h IV Infusion
Severe, life-threatening
infections (eg endocarditis, septicemia)
1 g to 1,5 g q6h IV Infusion
* In rare instances doses up to 12 g of Ranzol per day have been used.
Dosage adjustment for patients with reduced renal function - Ranzol may be used in patients with reduced renal function with the following dosage adjustments: Patients with a creatinine clearance of > 55 mL/min or a serum creatinine of < 1,5 mg % can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1,6 to 3,0 mg % can also be given full doses, but the dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL min or serum creatinine of 3,1 to 4,5 mg % should be given one half the usual dose every 12 hours. Patients with creatinine clearance rates of < 10 mL/min or serum creatinine of
> 4,6 mg % should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection.
Perioperative prophylactic use: To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended doses are as follows:
A) 1 g IV or IM administered one half to 1 hour prior to the start of surgery.
B) For lengthy operative procedures of 2 hours or longer 0,5 to 1 g IV or IM during surgery. (Administration modified according to the duration of operative procedure.)
C) 0,5 to 1 g IV or IM every 6 to 8 hours for 24 hours postoperatively.
It is important that the preoperative dose be given just prior to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of the initial surgical incision and if exposure to infectious organisms is likely, cefazolin must be administered at appropriate intervals during surgery in order that sufficient levels of the antibiotic be present when needed.
In surgery in which infection may be particularly devastating, the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.
In children over 1 month, the total daily dosage of 25 to 50 mg/kg body weight in 3 or 4 equally divided dosage is effective for mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg of body weight for severe infections. For paediatric dosage guidelines see table below:

PEDIATRIC DOSAGE GUIDE FOR CEFAZOLIN
Weight 25 mg/kg/day divided into 3 doses 25 mg/kg/day divided into 4 doses
Kg Approximate
single dose
(mg q8h)
Vol (mL) needed with dilution of 125 mg/mL Approximate
single dose
(mg q6h)
Vol (mL) needed with dilution of 125 mg/mL
4,5
9
13,6
18,1
22,7
        40 mg
        75 mg
        115 mg
        150 mg
        190 mg
        0,35 mL
        0,6 mL
        0,9 mL
        1,2 mL
        1,5 mL
        30 mg
        55 mg
        85 mg
        115 mg
        140 mg
        0,25 mL
        0,45 mL
        0,7 mL
        0,9 mL
        1,1 mL
       
Weight 50 mg/mL/day divided into 3 doses 50 mg/mL/day divided into 4 doses
Kg Approximate
single dose
(mg q8h)
Vol (mL) needed with dilution of 225 mg/mL Approximate
single dose
(mg q6h)
Vol (mL) needed with dilution of 225 mg/mL
4,5
9
13,6
18,1
22,7
        75 mg
        150 mg
        225 mg
        300 mg
        375 mg
        0,35 mL
        0,70 mL
        1,00 mL
        1,35 mL
        1,70 mL
        55 mg
        110 mg
        170 mg
        225 mg
        285 mg
        0,25 mL
        0,50 mL
        0,75 mL
        1,00 mL
        1,25 mL
In children with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in divided doses every 12 hours should be sufficient. In children with moderate impairment (creatinine clearance of 40-20 mL/min), 25% of the normal daily dosage given every 12 hours should be adequate. In children with severe renal impairment (creatinine clearance of 20-5 mL/min), 10'% of the normal daily dose given every 24 hours should be sufficient. All dosage recommendations apply after an initial loading dose is administered.
In the treatment of beta-haemolytic streptococcal infections a therapeutic dose must be administered for at least 10 days.
Directions for use
In those situations in which the medicine and diluent have been mixed, but not immediately administered to the patient, the admixture may be stored under the following conditions:
Reconstituted Ranzol diluted in Sterile Water for injection, 5% Dextrose Injection, or 0,9% Sodium Chloride Injection. is stable for 24 hours at room temperature and for 10 days if stored under refrigeration (2 to 8°C).
Solutions of cefazolin in Sterile Water for Injection, 5'% Dextrose Injection, or 0,9% Sodium Chloride Injection that are frozen immediately after reconstitution in the original vials are stable for as long as 12 weeks if stored at -20°C. Once thawed, these solutions are stable for 24 hours at room temperature or for 10 days stored under refrigeration (2 to 8°C). If the product is warmed, care should be taken to avoid heating it after the thawing is complete. Once thawed the solution should not be refrozen.
Secondary Diluents-Solutions of cefazolin for infusion in 10% Dextrose Injection, 5 % Dextrose in Lactated Ringer's Injection, 5% Dextrose and 0,9% Sodium Chloride Injection, Lactated Ringer's Injection or 5% or 10% Invert; Sugar in Sterile Water for Injection should be used within 24 hours after dilution if stored at room temperature or within 96 hours if stored under refrigeration (2 to 8°C).
Prior to administration, parenteral medicines should be inspected visually for particulate matter and discoloration whenever solution and container permit.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side Effects
The following adverse reactions have been reported with cefazolin:
Hypersensitivity: Drug fever. skin rash, vulvar pruritus, eosinophilia and anaphylaxis have occurred.
Haematologic: Neutropenia, leukopenia, thrombocythemia and positive direct and indirect Coombs' tests have occurred.
Renal and Hepatic: Transient rise in blood urea levels has been observed without clinical evidence of renal impairment. Interstitial nephritis and other renal disorders have been reported. Most patients experiencing these reactions have been seriously ill and were receiving multiple medicine therapies. The role of cefazolin in the development of nephropathies has not been determined.
Transient rise in AST, ALT, and alkaline phosphatase levels has been observed rarely. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported.
Gastrointestinal: Nausea, vomiting, diarrhoea, oral thrush and anorexia have been reported. Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment in less frequent instances.
Others: Pain on intramuscular injection sometimes with induration, has occurred infrequently. Rarely phlebitis at the site of injection has been reported. Other reactions include genital and anal pruritus, genital moniliasis and vaginitis.
Precautions
If an allergic reaction to cefazolin occurs the medicine should be discontinued and the patient treated with the usual agents.
Prolonged use of cefazolin may result in the overgrowth of non susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.
Cefazolin should be administered with caution in patients with impaired renal function, as in these patients lower daily dosage is required.
Broad spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
Interactions
Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently resulting in increased and more prolonged cephalosporin blood levels.
The efficacy of oestrogen-containing contraceptives may be decreased by the concomitant administration of Ranzol.
Laboratory Test Interactions
A false positive reaction for glucose in the urine may occur with Benedict's solution, Fehling's solution, or Clinitest tablets but not with enzyme based tests such as Clinistix and Tes-Tape.
Positive direct and indirect antiglobulin tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See side effects. Treatment is symptomatic and supportive.

IDENTIFICATION:
Ranzol 250 Injection
White to off-white, practically odourless, crystalline powder filled in 5 mL clear glass USP type III vials sealed with gray butyl rubber plug and tear off aluminium seal embossed with 'RANBAXY'. Ranzol 500 Injection
White to off-white, practically odourless crystalline powder filled in 5 mL clear glass USP type III vials sealed with gray butyl rubber plug and tear off aluminium seal embossed with 'RANBAXY 500 mg.
Ranzol 1 g Injection
White to off-white, practically odourless crystalline powder filled in 10 mL clear glass USP type III vials sealed with gray butyl rubber plug and tear off aluminium seal embossed with 'RANBAXY'.
On reconstitution a clear colourless to pale yellow solution is formed.

PRESENTATION:
Ranzol 250 Injection: Cartons containing 5 or 50 clear glass USP type III vials
Ranzol 500 Injection: Cartons containing 5 or 50 clear glass USP type III vials.
Ranzol 1 g Injection: Cartons containing 5 or 50 clear glass USP type III vials

STORAGE INSTRUCTIONS:
Store below 25°C, protected from light, moisture and freezing.
Reconstituted solution to be used within 24 hours if stored below 25°C and within 96 hours if stored at 2-8°C, in original vial.
KEEP OUT CF REACH OF CHILDREN.

REGISTRATION NUMBERS:
Ranzol 250 Injection: 30/20.1.1/0331
Ranzol 500 Injection: 30/20.1.1/0332
Ranzol 1 g Injection: 30/20.1.1/0333

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
RANBAXY (SA) (PTY) LTD
Lincoln House
Epsom Downs Office Park
13 Sloane Street
Epsom Downs
BRYANSTON

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
February 1997

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