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Logo KEFDOLE 750
KEFDOLE 1000

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

KEFDOLE 750
KEFDOLE 1000
Powder for reconstitution for injection

COMPOSITION:
Each KEFOLE 750 mg or 1000 mg vial contains
cefamandole nafate equivalent to 750 mg or 1000 mg of cefamandole as well as 47.25 mg or 63 mg sodium carbonate respectively. The total sodium content is approximately 77 mg (3,3 mEq sodium ion) per gram of cefamandole.

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1. Broad and medium spectrum antibiotics.

PHARMACOLOGICAL ACTION:
Cefamandole nafate, is a semi-synthetic, broad spectrum cephalosporin antibiotic for parenteral administration. It is the sodium salt of 7-D-mandelamido-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-3-cephem-4-carboxylic acid, formate (ester). Cefamandole nafate rapidly hydrolyzes to cefamandole and both compounds are microbiologically active in vivo.
Human Pharmacology:
The mean peak serum concentrations that were attained in normal volunteers after an intramuscular injection of 500 mg or 1g were 12,2 micrograms/mL (SD 5,5) and 20,6 micrograms/mL (SD 12,5) respectively. Maximum serum concentrations occurred within approximately 1 hour of injection.
Intramuscular administration of multiple 1g doses every six hours produced two-hour serum concentrations of 18 micrograms/mL to 30 micrograms/mL at two hours after the third to fifth dose. Following intravenous administration of a single 1g dose of cefamandole, serum concentrations were approximately 139 micrograms/mL at ten minutes and declined to about 0,8 micrograms/mL at four hours. With intravenous doses of 2g and 3g, serum concentrations determined similarly were about 240 micrograms/mL and 533 micrograms/mL respectively at 10 minutes declining approximately 2,2 micrograms/mL and 2,9 micrograms/mL respectively, at four hours.
Intravenous administration of 4g doses every 6 hours produced no evidence of accumulation in the serum of normal volunteers with normal renal function. The mean half-life after an intravenous dose is about 30 minutes and after intra-muscular administration, the half-life is about 60 minutes. 65% to 85% of an intra-muscular or intravenous dose is excreted by the kidneys over an eight-hour period, resulting in high urinary concentrations. Following intra-muscular doses of 500 mg and 1g, urinary concentrations averaged 254 micrograms/mL and 1 357 micrograms/mL respectively.
Intravenous doses of 1g and 2g produced urinary levels averaging 750 micrograms/mL and 1 380 micrograms/mL respectively. Probenecid slows the tubular excretion and nearly doubles the peak serum levels of cefamandole after intra-muscular administration.
The antibiotic reaches therapeutic levels in pleural and joint fluids and in bile and bone.
Microbiology:
The in vitro bactericidal action of cefamandole results from inhibition of cell-wall synthesis.
Cefamandole is usually active against the following organisms in vitro.
Beta-haemolytic and other streptococci (many strains of enterococci, e.g. Streptococcus faecalis, are relatively resistant) Staphylococci, including coagulase-positive, coagulase-negative (e.g. staphylococcus epidermidis), penicillinase-producing and most methicillin-resistant strains.
Streptococcus pneumoniae
Haemophilus influenza (including ampicillin-resistant strains)
Escherichia coli and other coliform bacteria.
Klebsiella sp.
Proteus mirabilis
Proteus sp. (Indole-positive, including P. morganii, P. rettgeri and P. vulgaris)
Enterobacter sp.
Salmonella sp., including S. typhi
Many strains of Serratia sp.
Cefamandole has in vitro activity against the following anaerobic bacteria:
Gram-positive and Gram-negative cocci, including Peptococcus and Peptostreptococcus sp:
Gram-positive rods, including Clostridium sp.
Gram-negative rods, Bacteroides and Fusobacterium sp.
Of the organisms listed above, the following require high concentrations of cefamandole:
Proteus sp. (Indole-positive)
Enterobacter
Serratia sp. and anaerobic bacteria such as Bacteroides (including B. Fragilis)
Pseudomonas are resistant to cefamandole.
In vitro sensitivity does not necessarily imply in vivo efficacy.
Beta-lactamase stability:
Cefamandole is resistant to degradation by penicillinases from S. aureus and by beta-lactamases from certain members of the Enterobacteriaceae.

INDICATIONS:
KEFDOLE
is indicated for the treatment of the following infections due to susceptible strains of the above mentioned organisms:
Respiratory tract infections, bone and joint infections, bacteremia, skin and soft-tissue infections, gallbladder and peritoneum infections as well as pelvic infection in women.
KEFDOLE is not indicated in the treatment of meningitis as satisfactory therapeutic concentrations are not attained in cerebrospinal fluid even in the presence of inflamed meninges.
Specimens for bacteriologic cultures should be obtained in order to isolate and identify causative organisms and to determine their susceptibility to cefamandole.
Preventive therapy: The administration of KEFDOLE pre-operatively, intra-operatively and post-operatively may reduce the incidence of certain post-operative infections caused by susceptible organisms in patients undergoing surgical procedures that are classified as contaminated or potentially contaminating (eg. gastro-intestinal surgery, Caesarean section, vaginal hysterectomy or holecystectomy in high risk patients such as those with acute cholecystitis, obstructive jaundice, or common duct gallstones).
If signs of infection occur, specimens for culture should be obtained for identification of the causative organism so that appropriate antibiotic therapy may be instituted.

CONTRA-INDICATIONS:
KEFDOLE
is contra-indicated in patients with known hypersensitivity to the cephalosporins.
Usage in pregnancy: Safety of KEFDOLE for use during pregnancy has not been established.
Use in infancy: Safety of KEFDOLE has not been adequately established in prematures and infants under 6 months of age.
Porphyria. KEFDOLE 750 or 1000 should not be prescribed to patients with porphyria.

WARNINGS:
Before KEFDOLE therapy is instituted, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins or other medicines. Cefamandole should be given cautiously to penicillin-sensitive patients. There is some evidence of partial cross-allergenicity between the penicillins and the cephalosporins. Patients have been reported to have had severe reactions to both classes of medicines. Serious acute hypersensitivity reactions may require adrenaline and other emergency measures.
Clinical efficacy is not adequately demonstrated for severe Bacteroides fragilis and indole-positive proteus. In the treatment of Bacteroides fragilis requiring higher doses than normal, increased possible side-effects could occur.
The diagnosis of pseudomembranous colitis must be considered 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 KEFDOLE.

DOSAGE AND DIRECTIONS FOR USE:
In the treatment of beta-haemolytic streptococcal infections a therapeutic dose must be administered for at least 10 days.
Usual adult and adolescent dose:
Intramuscular or intravenous -
Pneumonia ( uncomplicated ) and skin and soft tissue infections:
500 mg Cefamandole every six hours.

Urinary tract infections:
500 mg to 1 gram Cefamandole every eight hours.

Other infections:
500 mg to 2 grams Cefamandole every four to six hours.

Perioperative prophylaxis - Intramuscular or intravenous:
1 to 2 grams Cefamandole one-half to one hour prior to the start of surgery; and 1 to 2 grams every six hours following surgery for up to twenty-four hours.
After an initial loading dose of 1 to 2 grams Cefamandole, adults with impaired renal function may require a reduction in dose as follows:

DOSE OF KEFDOLE
Creatinine Clearance (mL/min)/(mL/sec)         Less Severe Infections Life-threatening Infections (maximum)
        >80 / ( 1.33 ) 1 - 2 grams every 6 hours 2 grams every 4 hours
50 - 80 / ( 0.83 - 1.33 ) 750 mg - 1.5 grams every
6 hours
1.5 grams every 4 hours;
or 2 grams every 6 hours
25 - 50 / (0.42 - 0.83 ) 750 mg - 1.5 grams
every 8 hours
1.5 grams every 6 hours;
or 2 grams every 8 hours
10 - 25 / ( 0.17 - 0.42 ) 500 mg - 1 gram
every 8 hours
1 gram every 6 hours; or
1.25 grams every 8 hours
2 - 10 / ( 0.03 - 0.17 ) 500 - 750 mg every 12 hours 670 mg every 8 hours; or
1 gram every 12 hours
< 2 / ( 0.03 ) 250 - 500 mg every 12 hours 500 mg every 8 hours; or
750 mg every 12 hours
Usual adult prescribing limits: Up to 12 grams Cefamandole daily.
Continued dosage in patients with impaired renal function should be determined by the degree of renal impairment, severity of infection and susceptibility of the causative organism.
Paediatric dose:
50 - 100 mg/kg/day in equally divided doses. In serious infections this may be increased to a total daily dosage of 150 mg/kg not to exceed the maximum adult dosage

Modes of administration:
KEFDOLE
may be given intravenously or by deep intramuscular injection into a large muscle mass, such as the gluteus or lateral part of the thigh, to minimise pain and induration.

Intramuscular administration:
Each gram of KEFDOLE should be diluted with 3 mL of one of the following diluents:
Sterile water for injection
Bacteriostatic water for injection
0,9% Sodium chloride injection
Bacteriostatic sodium chloride injection
0,5% Lignocaine injection
Shake well until dissolved.

Intravenous administration:
The intravenous route may be preferred for patients with bacteraemia, localised parenchymal abscesses (such as intra-abdominal abscess), peritonitis or other severe or life-threatening infections when they may be poor risks because of lowered resistance. For these infections in patients with normal renal function, the intravenous dosage is 3g to 12g of KEFDOLE daily.
In conditions such as bacteraemia, 6g to 12g per day may be given initially by the intravenous route for several days and dosage may then be gradually reduced according to clinical response and laboratory findings.
A solution of 1g or 750 mg of KEFDOLE in 22 mL or 17 mL of sterile water for injection is isotonic.

For direct intermittent intravenous administration:
Add 10 mL of sterile water for injection, 5% dextrose injection or 0,9% sodium chloride injection per gram of KEFDOLE. Slowly inject directly into the vein over a period of three to five minutes or give through the tubing of an administration set while the patient is also receiving one of the following intravenous fluids:
0,9% Sodium chloride injection
5% Dextrose injection
10% Dextrose injection
5% Dextrose and 0,9% sodium chloride injection
5% Dextrose and 0,45% sodium chloride injection
5% Dextrose and 0,2% sodium chloride injection
If combination therapy of KEFDOLE and an aminoglycoside is indicated, each of these antibiotics should be given by separate routes of administration.
Do not mix an aminoglycoside with KEFDOLE in the same intravenous container.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The most common side-effects are hypersensitivity reactions, including skin rashes, urticaria, eosinophilia, fever, reactions resembling serum sickness, and anaphylaxis.
There may be a positive response to the Coombs test although haemolytic anaemia occurs less frequently. Neutropenia and thrombocytopenia have been reported less frequently. Agranulocytosis has occured less frequently. Bleeding complications related to hypoprothrombinaemia and/or platelet dysfunction have occurred. Acute renal tubular necrosis has followed excessive dosage and has also been associated with its use in older patients or those with pre-existing renal impairment, or with the concomitant administration of nephrotoxic medicines such as amino-glycoside antibiotics. Acute interstitial nephritis is also a possibility as a manifestation of hypersensitivity.
Transient increases in liver enzyme values have been reported. Hepatitis and cholestatic jaundice have occurred less frequently.
Convulsions and other Central Nervous System toxicity have been associated with high doses, especially in patients with renal failure.
Gastro-intestinal adverse effects such as nausea, vomiting, and diarrhoea may occur. A sore mouth or tongue or a black hairy tongue have been reported less frequently. Prolonged use may result in overgrowth of non-susceptible organisms and pseudomembranous colitis may develop.
There may be pain at the injection site following intramuscular administration and thrombophlebitis has occurred following intravenous infusion, usually of more than 6g daily for more than 3 days.
KEFDOLE 750 or 1000 should not be given to patients who are hypersensitive to it or to other cephalosporins. About 10% of penicillin-sensitive patients may also be allergic to cephalosporins although the true incidence is uncertain; great care should be taken if Cefamandole nafate is to be given to such patients.
Care is also necessary in patients with known history of allergy. KEFDOLE 750 or 1000 should be given with caution to patients with renal impairment; a dosage reduction may be necessary. Renal and haematological status should be monitored especially during prolonged and high-dose therapy.
Some patients with syphilis may experience a Jarish-Hexheimer reaction shortly after starting treatment with KEFDOLE.Symptoms include fever, chill headache and reactions at the site of the lesions. The reaction can be dangerous in cardiovascular syphilis or where there is a serious risk of increased local damage such as with optic atrophy.
Cefamandole nafate may interfere with the Jaffe method of measuring creatinine concentrations and may produce falsely high values; this should be borne in mind when measuring renal function. Positive results to the direct Coombs test have been found during treatment and these can interfere with blood cross-matching. The urine of patients may give false-positive reactions for glucose using copper-reduction reactions.
The concomitant use of a nephrotoxic agent such as the aminoglycoside antibiotic, gentamicin may increase the risk of kidney damage with Cefamandole nafate. There is also some evidence for enhanced nephrotoxicity with a loop diuretic like furosemide, similarly to the penicillins, the renal excretion of Cefamandole nafate is inhibited by Probenecid.
There may be antagonism between Cefamandole nafate and bacteriostatic antibacterial agents.
Cefamandole nafate has an N-methylthiotetrazole side-chain and may cause bleeding as a result of hypoprothrombinemia which is usually reversible with administration of vitamin K. Care should be taken in patients receiving anti-coagulants.
Patients receiving KEFDOLE 750 or 1000 should avoid alcohol and preparations containing significant amounts of alcohol during treatment and several days after treatment. A disulfiram-like interaction with alcohol may occur and is attributed to the methylthiotetrazole side-chain.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See “Side Effects and Special Precautions”
Treatment: Treatment is symptomatic and supportive.

IDENTIFICATION:
KEFDOLE
750 or 1000 (Powder for reconstitution for Injection) vial is a 8 mL size glass vial with a grey rubber stopper, an aluminium cap. It contains white to almost white sterile powder for injection. The reconstituted solution is a clear colourless solution

PRESENTATION:
KEFDOLE
750 mg, 1g,(Powder for injection) vials are supplied in cartons containing 1, 5, 10, 30 & 50 vials.

STORAGE INSTRUCTIONS:
Before reconstitution: Store at 25°C.
After reconstitution: Reconstituted KEFDOLE is stable for 24 hours when stored at 25°C and for 96 hours when stored in a refrigerator (2-8°C).
During storage at 25°C, carbon dioxide from sodium carbonate in the product formulation develops inside the vial after reconstitution. The resulting pressure may be dissipated prior to withdrawing the contents of the vial or it may be used to aid withdrawal if the vial is inverted slowly over the syringe needle and the contents allowed to flow into the syringe. Proper aseptic technique should be employed at all times.
The colour of concentrated solution will darken, especially at 25°C. Slight discoloration of the solution
is permissible. Solutions of KEFDOLE in sterile water for injection, 5% dextrose injection or 0,9% sodium chloride injection which are frozen immediately after reconstitution in the original container are stable for 1 month when stored at -20°C. If the product is warmed (maximum 37°C), care should be taken to avoid heating it after the thawing is complete. Once thawed, the solution should not be frozen again.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS:
KEFDOLE 1000
        –        31/20.1.1/0373
KEFDOLE 750        –        31/20.1.1/0372

NAME AND BUSINESS ADDRESS OF APPLICANT:
CompuPharm (Pty) Ltd
Kings Highway 476
Lynnwood
Pretoria

DATE OF PUBLICATION OF THIS PACKAGE INSERT:

Updated on this site: February 2001

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