INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
CEFACIDAL 500 mg
CEFACIDAL 1 g

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

CEFACIDAL 500 mg
CEFACIDAL 1 g
Powder for injection

COMPOSITION:
Cefazolin Sodium equivalent to Cefazolin 500 mg or 1 g activity.

PHARMACOLOGICAL CLASSIFICATION
A 20.1.1 - Broad spectrum antibiotic.

PHARMACOLOGICAL ACTION
CEFACIDAL (cefazolin sodium) is a broad-spectrum bactericidal, semi-synthetic cephalosporin for parenteral administration. Chemically cefazolin is the sodium salt of 7-[1-(1H)-tetrazolylacetamide]- 3-[2-(5-methyl-1,3,4-thiadiazolyl)-thiomethyl]-delta³-cephem- 4-carboxylic acid.
CEFACIDAL given intravenously or intramuscularly produces notably high serum levels. Serum binding occurs at a rate of 74%. Cefazolin is resistant to degradation in the body, is virtually not inactivated in the liver, and is primarily excreted in the urine unchanged. Following intramuscular injection of cefazolin 500 mg, 63+17% of the dose was recovered within 6 hours and approximately 80% to 100% within 24 hours. Peak urine concentrations of approximately 1000 micrograms/mL and 4000 micrograms/mL are achieved after intramuscular administration of 500 mg and 1 g doses, respectively. When cefazolin is administered to patients with unobstructed biliary tracts, high concentrations well over serum levels occur in the gallbladder tissue and bile. In the presence of obstruction, however, concentration in the bile is considerably lower than the serum level. Tissue distribution of cefazolin is greatest in the kidney, liver and lungs. The concentration of cefazolin in the joint space when the synovial membrane is inflammed is comparable to the concentration found in the serum due to the ease with which the antibiotic crosses the inflammed membrane.
CEFACIDAL is bactericidal against a wide range of gram-positive and gram-negative micro-organisms.
In vitro sensitivity of gram-positive organisms include:
Penicillinase and Non-penicillinase-producing Staphylococci, beta-haemolytic Streptococci. Streptococcus pneumoniae and Clostridia perfringens. Methicillin-resistant staphylococci are uniformly resistant to cefazolin.
In vitro sensitivity of gram-negative organisms include:
Some strains of Neisseria gonorrhoea, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhosa, Shigella, Corynebacterium diptheriae, Bacillus subtilis.
Most strains of Enterobacter cloacae and indole positive Proteus (P. vulgaris), Enterococcus faecalis Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri) are resistant. Almost uniformly resistant to cefazolin are Serratia, Pseudomonas and Acinetobacter calcoaceticus. In vitro sensitivity does not necessarily imply in vivo efficacy.

INDICATIONS
CEFACIDAL is indicated in the treatment of the following infections when due to susceptible micro-organisms.
Respiratory tract infections:
Tonsillitis, pharyngitis, pneumonia, bronchitis, pulmonary abscess, empyema, pleurisy, sinusitis, laryngitis and otitis media.
Skin, soft-tissue and postoperative infections:
Lymphangitis, abscesses, cellulitis, decubitus ulcers, mastitis. (Surgical procedures should be performed where indicated).
Gastrointestinal tract infections:
Cholangitis, cholecystitis.
Genitourinary tract infection:
Pyelonephritis, cystitis and adnexitis.
Other infections:
Bacteremia, septicemia, endocarditis, osteomyelitis, peritonitis, puerperal sepsis.
NOTE:
Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to CEFACIDAL. If the tests show that the causative organism is resistant of CEFACIDAL, other appropriate therapy should be instituted.

CONTRA-INDICATIONS
Patients hypersensitive to cephalosporins and its derivatives, or any components of the formulation.

DOSAGE AND DIRECTIONS FOR USE
The following dosages are recommended, for administration of constituted CEFACIDAL preferably by intravenous infusion or alternatively by slow intravenous injection (over 3 to 5 minutes) or by intramuscular injection.
For the treatment of mild-to-moderately severe bacterial infections, 1,5 to 2 g per day in equally divided doses, two or three times daily. For the treatment of severe bacterial infection, 3-4 g per day in equally divided doses two or three times daily.
Higher and/or more frequent doses (up to 6 g daily) may be given in very severe, life-threatening infections, but in rare instances, doses of up to 12 grams have been used.
Children:
The following dosage chart is a useful guide* to CEFACIDAL therapy in children.

PERCENTAGE OF ADULT DOSE	AGE AND WEIGHT	TOTAL DAILY DOSE** MAXIMUM
100%	Adult (65 kg)	1,5 g to 6 g
75%	12 years (40 kg)	1,125 g to 4,5 g
50%	7 years (23 kg)	750 mg to 3 g
25%	1 year (10 kg)	375 mg to 1,5 g
20%	4 months (6,5 kg)	300 mg to 1,2 g

For in-between ages, in-between percentages are used e.g. at 10 years, 66% and at three years 33% of the adult dose.
*Using the Percentage Method based on the following formula:

Surface area of child	x 100	= Percentage of adult dose
Surface area of adult

**The recommended total daily dose should be administered in two or three equally divided doses. The maximum range is for very severe life-threatening infections.
The intravenous route by drip infusion is preferable when high doses are to be administered.
Safety and effectiveness for use in premature infants and infants under one month of age has not been established.
Note:
CEFACIDAL may be nephrotoxic if given in excessive doses (more than 6g daily in patients with normal renal function) or if administered without appropriate dosage reduction in patients with renal impairment. Although CEFACIDAL is generally well tolerated in patients with impaired renal function it is nevertheless desirable to adjust the dosage as follows to prevent the accumulation of high blood levels:

Renal impairment:
Dosage adjustment for adults:

CREATININE CLEARANCE         (mL/min)	DOSAGE ADJUSTMENT
> 55	Full doses
35 TO 54	Full doses, but restricted to at least 8 hour intervals
11 TO 34	Half the usual dose every 12 hours
< 10	Half the usual dose every 18 to 24 hours

Dosage adjustment for children:

CREATININE CLEARANCE         (mL/min)	DOSAGE ADJUSTMENT
70 to 40	60% of normal daily dose in equally divided doses every 12 hours
40 to 20	25% of normal daily dose in equally divided doses every 12 hours
20 to 5	10% of normal daily dose every 24 hours.

All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis: (See PHARMACOLOGICAL ACTION).
Treatment should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained.

A MINIMUM OF 10 DAYS TREATMENT IS RECOMMENDED FOR ANY INFECTION CAUSED BY GROUP-A beta-HAEMOLYTIC STREPTOCOCCI TO HELP PREVENT THE OCCURRENCE OF ACUTE GLOMERULONEPHRITIS OR ACUTE RHEUMATIC FEVER.

For administration by intravenous infusion: Use sterile water for injection. Add 2 mL to the 500 mg vial and 4 mL to the 1 g vial. Withdraw the entire contents and add to one of the following intravenous solutions:
0,9% sodium chloride injection
5% or 10% dextrose injection
5% dextrose in lactated Ringers injection
5% dextrose in 0,9% sodium chloride injection (also may be used with 5% dextrose and 0,45% or 0,2% sodium chloride injection)
Lactated Ringers Injections
5% or 10% invert sugar in sterile water for injection
Ringers Injection

For administration by direct intravenous injection: After constitution with 2 mL (500 mg) or 4 mL (1 g) of water for injection, dilute in a minimum of 10 mL of water for injection. Inject solution slowly over 3-5 minutes either directly into a vein or through the tubing for a patients receiving the parenteral fluids mentioned above.

For administration by intramuscular injection: Add 2 mL (500 mg) or 4 mL (1 g) of sterile water for injection, bacteriostatic water for injection or 0,9% sodium chloride injection. Withdraw the entire contents to the vial.

Constituted solutions are stable for 24 hours when kept at room temperature not exceeding 25°C, or for 96 hours when kept in a refrigerator (4-8°C).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Hypersensitivity:
As with all other cephalosporins, CEFACIDAL has the potential for producing allergic reactions, such as rash, pruritus, urticaria, angioedema eosinophilia, drug fever and anaphylaxis were observed.
Haematologic:
Leukopenia, neutropenia, thrombocytopenia, thrombocythemia and positive direct and indirect Coombs' tests have occurred.
Hepatic:
Transient rises in AST (SGOT), ALT (SGPT) and alkaline phosphatase levels have been observed rarely. Transient hepatitis and cholestatic jaundice have been reported rarely.
Renal:
Transient rise in blood urea levels have been observed without clinical evidence of renal impairment. Interstitial nephritis and other renal disorders have been reported rarely. Most patients experiencing these reactions had been seriously ill and were receiving multiple drug therapies. The role of cefazolin in the development of nephropathies has not been determined.
Gastrointestinal:
Symptoms of pseudomembranous colitis may appear either during or after antibiotic therapy. Nausea and vomiting have been reported rarely. Anorexia, diarrhoea and oral candidiasis have been reported.
Other:
CEFACIDAL is well tolerated when administered by intravenous infusion, and the incidence of phlebitis with CEFACIDAL is low.
Although pain was infrequently reported after intramuscular injection, it was seldom severe. Cefazolin rarely produced tenderness, induration or fever.
Other reactions include genital and anal pruritis, genital candidiasis and vaginitis.
In patients with a history of cephalosporin or penicillin allergy, CEFACIDAL should be used with caution. There is evidence of partial cross-allergenicity of the penicillins and the cephalosporins and there are instances of patients who have had fatal anaphylactoid reactions after parenteral use. These require immediate emergency treatment.
Any patient who has demonstrated some form of allergy, particularly to medicine, should receive antibiotics cautiously and then only when absolutely necessary.
Pseudomembranous colitis has been reported with cephalosporins and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea after the administration of CEFACIDAL. Should colitis be diagnosed, therapeutic measures should be initiated.
Intrathecal administration of CEFACIDAL is not recommended. There have been reports of severe central nervous system toxicity including seizures when cefazolin was administered intrathecally.
A reduced dose may be appropriate in patients with impaired renal function (See DOSAGE AND DIRECTIONS FOR USE).
Prolonged use of cefazolin may cause overgrowth of nonsusceptible organisms in which case appropriate measures should be taken.
CEFACIDAL should be used with caution in patients with a history of gastrointestinal disease, especially colitis.
Probenecid may cause prolonged cephalosporin blood levels.
False-positive reactions for glucose in the urine may occur if copper reduction test methods are used. Glucose tests should therefore be based on enzymatic glucose oxidase reactions.
Concomitant administration of cephalosporins and aminoglycoside antibiotics has been associated with increased nephrotoxicity.
Positive direct and indirect antiglobulin (Coombs') test have occurred; those may also occur in neonates whose mothers received cephalosporins before delivery. Safety of cefazolin during pregnancy has not been established. Cefazolin has been found to readily cross the placental barrier into the cord blood and amniotic fluid.
Safety in lactation has no been established.
Cefazolin is present in very low concentrations in the milk of nursing women
Safety and effectiveness for use in premature infants and infants under one month of age have not been established. See DOSAGE AND DIRECTIONS FOR USE for recommended dosage in children over one month.
As experience in premature infants and neonates is limited the use of CEFACIDAL in these patients should only be undertaken with caution.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Inappropriately large doses of parenteral cephalosporins may cause dizziness, paresthesias and headache. Seizures may occur following overdosage with some cephalosporins, particularly in patients with renal impairment in whom accumulation is likely to occur.
Dosage reduction is necessary when renal function is impaired. (See DOSAGE AND DIRECTIONS FOR USE). If seizures occur, the drug should be promptly discontinued; anticonvulsant therapy may be administered if clinically indicated. Haemodialysis may be considered in cases of overwhelming overdosage.
Laboratory abnormalities that may occur after an overdose include elevations in creatinine, BUN, liver enzymes and bilirubin, a positive Coombs' tests, thrombocytosis, thrombocytopenia, eosinophilia, leukopenia and prolongation of the prothrombin time.
Treatment of overdosage should be symptomatic and supportive.

IDENTIFICATION
White to off-white crystalline powder.

PRESENTATION
CEFACIDAL is available in sterile vials containing 500 mg and 1 g of cefazolin activity as the sodium salt. Cartons contain 5 vials.

STORAGE INSTRUCTIONS:
Store in a cool dry place. Temperature should not exceed 25°C.
Constituted solutions should be used within 24 hours.
Keep out of reach of children.

REGISTRATION NUMBER
F/20.1.1/148
F/20.1.1/149

NAME AND BUSINESS ADDRESS OF APPLICANT
Bristol-Myers Squibb (Pty) Ltd*
47 Van Buuren Road
BEDFORDVIEW. 2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
January 1996

*Authorised user of the TM CEFACIDAL
03/93        025B98

Updated on this site: July 2005
Source: Pharmaceutical Industry
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