INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
CEFRIL-A 250 mg Injection
CEFRIL-A 500 mg Injection
CEFRIL-A 1 g Injection
CEFRIL-A 2 g Injection

SCHEDULING STATUS
S4

PROPRIETARY NAME
(and dosage form)

CEFRIL-A 250 mg Injection
CEFRIL-A 500 mg Injection
CEFRIL-A 1 g Injection
CEFRIL-A 2 g Injection

COMPOSITION
CEFRIL-A is a sterile powder blend of cephradine and arginine base which is intended for intramuscular or intravenous administration after reconstitution. Each vial contains 250 mg, 500 mg, 1 g or 2 g cephradine. Cephradine is a semisynthetic cephalosporin chemically designated as 7-[D-2-amino-2-(1,4-cyclo hexadien-1-yl) acetamidol]-3-methyl-8-oxo-5-thia-1-azobicyclo (4,2,0)oct-2-ene- 2-carboxylic acid.

PHARMACOLOGICAL CLASSIFICATION
Category A 20.1.1 Broad Spectrum Antibiotics

PHARMACOLOGICAL ACTION
Cephradine is a broad spectrum, bactericidal antibiotic active against both gram positive and gram negative bacteria. This antibiotic demonstrates high activity against most strains of penicillinase producing staphylococci and E.coli.
Microbiology: The following organisms have shown sensitivity to cephradine in vitro:
Gram positive: Staphylococci (both penicillin sensitive and resistant strains); Group A beta-hemolytic streptococci, and Streptococcus pneumoniae.
Gram negative: Escherichia coli, Klebsiella species, Proteus mirabilis, Haemophilus influenzae,
Cephradine is not active against most strains of Enterobacter species, Morganella morganii,andProteus vulgaris. Most strains of enterococci (Enterococcus faecalis)are resistant to cephradine. It has no activity against Pseudomonas or Herellea species.
Because cephradine is unaffected by penicillinase, strains of E.Coli and Staphylococcus aureus that produce this enzyme may be susceptible to cephradine.
When tested by in vitro methods, staphylococci exhibit cross resistance between cephradine and methicillin-type antibiotics.
Human Pharmacology: Following intramuscular administration of a single 0,5 gram dose of cephradine to normal volunteers, the average peak serum concentration was 8,41 microgram/mL with the time to peak concentration being 0,93 hours. The serum half-life averaged 1,25 hours. A single 1 gram intravenous dose resulted in serum concentrations of 86 micrograms/mL at 5 minutes and 12 micrograms/mL at 1 hour; these concentrations declined to 1 microgram/mL at 4 hours. Continuous infusion of 500 mg per hour into a 70 kg man maintained a concentration of about 21,4 micrograms/mL cephradine activity; this study showed that a serum concentration of approximately 3 micrograms/mL can be obtained for each milligram of cephradine administered per kg of body mass per hour of infusion.
Cephradine is excreted unchanged in the urine. The kidneys excrete 57% to 80% of an intramuscular dose in the first 6 hours; this results in a high urine concentration, e.g. 880 micrograms/mL of urine after a 500 mg intramuscular dose. Probenecid slows tubular excretion and almost doubles peak serum concentration.
Assays of bone obtained at surgery have shown that cephradine penetrates bone tissue.
Cephradine is only slightly bound to serum proteins (less than 10% on average).
Cephradine readily passes into other body fluids, e.g. joints and aqueous and vitreous humours of the eye.
Cephradine does not pass across the blood brain barrier to any appreciable extent.

INDICATIONS
CEFRIL-A is indicated for use primarily in the treatment of infections of the respiratory tract, genitourinary tract, soft tissue and skin, blood stream, and bones, caused by susceptible organisms as listed below:
Staphylococcus aureus (penicillin sensitive and penicillinase producing strains); Group-A Beta-haemolytic streptococci; Pneumococci; Haemophilus influenzae; Escherichia coli and other coliform bacteria; Klebsiella species; Proteus mirabilis.
CEFRIL-A is also effective in cases of peritonitis.
Bacteriology studies to determine the causative organisms and their sensitivity to cephradine should be performed. Therapy may be instituted prior to receiving the results of the sensitivity test.
CEFRIL-A is effective prophylactically, to avoid infections due to susceptible organisms in patients about to undergo caesarian section or vaginal hysterectomy.
CEFRIL-A is primarily indicated for those patients unable to tolerate oral medication. It is also indicated for intravenous use either by direct intravenous injection or by intravenous infusion for the treatment of serious and life threatening infections.

CONTRA-INDICATIONS
CEFRIL-A is contra-indicated in patients with known sensitivity to the cephalosporin family of antibiotics or to any component of the formulation.
Pregnacy and Lactation
Safety in pregnancy and lactation has not been established. Cephradine is secreted in breast milk.

DOSAGE AND DIRECTIONS FOR USE
Adults: The usual daily dose of CEFRIL-A for Injection is 2 to 4 g daily in four equally divided doses intramuscularly or intravenously (e.g. 500 mg to 1 g four times a day). A dosage of 500 mg four times a day is adequate in uncomplicated pneumonia, furunculosis with cellulitis, and most urinary tract infections. In severe infections, the dose may be increased by giving injections every four hours or by increasing the dose.
The maximum dose should not exceed 8 g per day.
The recommended dose for surgical prophylaxis is either a single 2 g dose given 1 hour before surgery or a regimen of 1 g given one hour before surgery followed by a second dose 4 hours later. Additional doses of 1 g may be given every 4 hours until vital signs are stabilized.
Infants and Children: The usual dose range is 50 to 100 mg/kg/day in equally divided doses four times a day and should be regulated by age, mass of the patient, and severity of the infection being treated.
All Patients, irrespective of Age and Mass: Therapy should be continued for a minimum of 48 to 72 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. In the treatment of beta-haemolytic streptococcal infections a therapeutic dose must be administered for at least 10 days. In the treatment of chronic urinary tract infections, frequent bacteriological and clinical appraisal is necessary during therapy and may be necessary for several months afterwards. Stubborn infections may require treatment for several weeks. Smaller doses than those indicated above should not be used.
Parenteral therapy may be followed by oral cephradine either as capsules or as oral suspension.
CEFRIL-A may be given intravenously or by deep intramuscular injection. Intramuscular injections should be made into a large muscle mass, such as the gluteus or lateral aspect of the thigh.
(Reference is made to the use of local anaesthetics in the section on reconstitution).
Renal Impairment Dosage: The following dosage schedule is suggested as a guideline based on a dosage of 500 mg every six hours and on creatinine clearance. Further modification in the dosage schedule may be required because of the dosage selected and individual variation.

Creatinine Clearance	Dose	Time Interval
>20 mL/min 5-20 mL/min <5 mL/min	500 mg         250 mg         250 mg	6 hours         6 hours         12 hours

On Chronic, Intermittent Hemodialysis:	250 mg Start
	250 mg at 12 hours
	250 mg 36-48 hours (after start)

Children may require dosage modification proportional to their weight and severity of infection.

Reconstitution
For intramuscular use: Aseptically add sterile water for injection, bacteriostatic water, or 0,9% sodium chloride injection according to the following table:

Single Dose*         Vial Size	Volume of Diluent         to be added
250 mg         500 mg         1g        1 g	1,2 mL         2,0 mL         4,0 mL

*The preparation contains no bactericide and is not intended for multiple dose use.
Shake to effect solution and withdraw the entire contents. Intramuscular solutions should be used within 2 hours at room temperature. If stored in the refrigerator at 5°C solutions retain full potency for 12 hours. Reconstituted solutions may vary in colour from light to straw yellow; however, this does not affect the potency.
If local anaesthetic is considered desirable for intramuscular use, only 0,5% lignocaine hydrochloride solution is recommended as the solvent in place of the above mentioned volumes of water for injection. Other diluents also suitable for I.M. use are lignocaine HCl 1% or procaine HCl 1% or 2% solutions.
Intravenous use
CEFRIL-A may also be administered by direct intravenous injection or by intravenous infusion. A 3 microgram/mL serum concentration can be maintained for each mg of cephradine per kg body mass per hour of infusion.
Suitable IV infusions are 5% dextrose solutions, isotonic solution of sodium chloride or M/6 sodium lactate solution.
For Direct Intravenous Injection
Suitable intravenous injection solutions are sterile water for injection, 5% dextrose injection, or 0,9% sodium chloride injection.
Aseptically add 5 mL of diluent to the 250 mg or 500 mg vial, or 10 mL to the 1 g vial or 20 mL to the 2 g vial. Shake to effect solution and withdraw the entire contents. The solution may be slowly injected directly into a vein over a three to five minute period or may be given through the injection site of an administration set where the infusion solution is compatible with cephradine. The solutions should be used within 2 hours when kept at room temperature; if stored at 5°C solutions retain full potency for 12 hours.
For Continuous or Intermittent IV Infusion
Suitable intravenous infusion solutions are sterile water for injection (50 mg/mL cephradine solutions are approximately isotonic); 5% or 10% dextrose injection, 0,9% sodium chloride injection, sodium lactate injection (M/6 sodium lactate); dextrose and sodium chloride injection (5% : 0,9%) or (5% : 0,45%); 10% invert sugar in water for injection; lactated Ringer's injection; Ringer's injection; 5% dextrose in lactated Ringer's injection; 5% dextrose in Ringer's injection; Normosol^R-M with 5% dextrose; Ionosol^R-B with 5% dextrose; Ionosol^R-G with 10% dextrose; Plasma-Lyte^R-M with 5% dextrose; Isolyte^R-M with 5% dextrose and Normosol^R-R.
Aseptically add 10 mL of sterile water for injection to the 1 g vial or 20 mL to the 2 g vial, and shake to effect solution. Aseptically transfer the entire contents to the IV diluent.
Intravenous infusions prepared with the above infusion solutions remain potent for 24 hours at room temperature or 1 week at 5°C at concentrations up to 10 mg of cephradine activity per mL (1%), and for 10 hours at room temperature or 48 hours at 5°C at concentrations up to 50 mg of cephradine activity per mL (5%). For prolonged infusions, replace 5% infusions every 10 hours and 1% infusions every 24 hours with freshly prepared solutions.
Protect solutions of cephradine from concentrated light or direct sunlight.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The following adverse reactions have been reported following the use of cephradine:
Gastrointestinal: Glossitis, nausea, vomiting, diarrhoea or loose stools, tenesmus, abdominal pain , colitis and pseudomembranous colitis.
Hypersensitivity Reactions: Urticaria or skin rash, oedema, erythema, pruritus, joint pain, drug fever and anaphylaxis. Less frequently erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Hematologic: Eosinophilia, leukopenia and neutropenia.
Liver: Elevated SGOT, SGPT, total bilirubin, alkaline phosphatase, and LDH have been observed.
Renal: Elevations of blood urea and occasionally serum creatinine have been reported. In most cases, however, the values tended to return to normal. In adults for whom serum creatinine determinations were performed, the raise in blood urea was not accompanied by a rise in serum creatinine, which would suggest an extrarenal mechanism for the elevation of blood urea.
Other adverse reactions have included headache, dizziness, dyspnoea, paraesthesia, monilial overgrowth, vaginitis, and isolated instances of hepatomegaly, and thrombophlebitis at the site of injection.
Pain at the injection site on intramuscular injection may be experienced by some patients. Since sterile abscesses have been reported following accidental subcutaneous injection, the preparation should be administered by deep intramuscular injection.
There is evidence of partial cross-allergenicity between the penicillins and the cephalosporins. Therefore, cephradine should be used with caution in those patients with known hypersensitivity to penicillins. Anaphylaxis may occur.
Pseudomembranous colitis has been reported with the use of cephalosporins including cephradine; therefore,it is important to consider this diagnosis in patients who develop diarrhoea in asssociation with CEFRIL-A use.
Patients with known or suspected renal impairment should receive careful clinical observation and appropriate laboratory studies since cephradine accumulates in the serum and tissues unless dosage is suitably reduced. (See Dosage and Directions for Use).
Increased nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibiotics and/or potent diuretics.
Prolonged use may result in overgrowth of nonsusceptible organisms.
After treatment with cephradine a false positive reaction for glucose may occur with Benedict's solution, Fehling's solution, or with Clinistix^R tablets, but not with enzyme based tests such as Clinistix^R, and Test-Tape^R.
Positive direct Coombs' tests have been reported.
Cefril-A contains arginine. Studies in low birth weight infants have demonstrated that arginine administration may result in increases in serum arginine, insulin and indirect bilirubin. The consequences of exposure to this amino acid during treatment of neonates have not been fully ascertained.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Treatment of overdosage should be symptomatic and supportive.

IDENTIFICATION
A white to off-white powder contained in round, glass vials for injection. When reconstituted in water a light to straw yellow coloured solution is formed.

PRESENTATION
Sterile CEFRIL-A is available in vials containing 250 mg, 500 mg and 1 g and 2 g cephradine activity. Sterile CEFRIL-A does not contain sodium carbonate.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBERS

CEFRIL-A 250 mg	N/20.1.1/61
CEFRIL-A 500 mg	N/20.1.1/62
CEFRIL-A 1 g	N/20.1.1/63
CEFRIL-A 2 g	N/20.1.1/64

NAME AND BUSINESS ADDRESS OF APPLICANT
BRISTOL-MYERS SQUIBB (PTY) LTD^*
47 Van Buuren Road,
Bedfordview.

DATE OF PUBLICATION OF THIS PACKAGE INSERT
April 2000

* Authorised user of the TM CEFRIL-A

Updated on this site: July 2005
Source: Pharmaceutical Industry
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