INFORMATION FOR HEALTH PROFESSIONALS
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
Injection: 0.5 g, 1 g and 2 g; a white powder which reconstitutes to form a light yellow to amber solution, depending on the concentration and diluent used. The pH of freshly reconstituted solutions usually ranges from 6.0 to 8.5. The total sodium content is approximately 77 mg (3.3mEq sodium ion)/g of cephamandole activity.
Cephamandole is a broad-spectrum cephalosporin antibiotic for parenteral administration. The bactericidal action of cephamandole results from inhibition of cell wall synthesis. Cephalosporins have in vitro activity against a wide range of Gram-positive and Gram-negative organisms. Cephamandole is usually active against the following organisms in vitro and in clinical infections, however, appropriate culture and susceptibility studies should be performed:
Note: Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea sp.), and most Serratia strains are resistant to cephalosporins. Cephamandole is resistant to degradation by beta-lactamases from certain members of the Enterobacteriaceae.
After intramuscular administration of a 500 mg dose of cefamandole to normal volunteers, the mean peak serum concentration was 13 µg/mL. After a 1 g dose, the mean peak concentration was 25 µg/mL. These peaks occurred at 30 to 120 minutes. Following intravenous doses of 1, 2 and 3 g, serum concentrations were 139, 240 and 533 µg/mL, respectively, at 10 minutes. These concentrations declined to 0.8, 2.2 and 2.9 µg/mL at 4 hours. Intravenous administration of 4 g doses every 6 hours produced no evidence of accumulation in the serum. The half-life after an intravenous dose is 32 minutes; after intramuscular administration, the half-life is 60 minutes.
Cephamandole nafate is partially hydrolysed to cephamandole upon dissolution. This conversion proceeds further in vivo. Both are microbiologically active in vivo. Approximately 85%-89% of the antibacterial activity in blood is due to cephamandole, only a small amount being present as cephamandole nafate. Approximately 70% of cephamandole is bound to plasma protein. Cephamandole appears to be rapidly dissociated from the serum proteins, as evidenced by its relatively short half-life and its rapid appearance in the urine.
Cephamandole is excreted unchanged in urine. About 75%-95% of a single IM dose and 60%-80% of a single IV dose of cephamandole is excreted within 6-8 hours in adults with normal renal function.
Cephamandole nafate is excreted by glomerular filtration as well as by active tubular secretion. Probenecid slows tubular excretion and doubles the peak serum level and duration of measurable serum concentrations.
The antibiotic reaches therapeutic levels in pleural and joint fluids and in bile and bone.
Cephamandole nafate is indicated for the treatment of serious infections of the lower respiratory tract, genitourinary tract, skin and soft tissue, bones and joints, septicaemia, gall bladder and peritoneum when due to susceptible strains of organisms.
Specimens for bacteriological cultures should be obtained in order to isolate and identify causative organisms and to determine their susceptibilities to cephamandole. Therapy may be instituted before results of susceptibility studies are known, however once these results become available, the antibiotic treatment should be adjusted accordingly.
In certain cases of confirmed or suspected Gram-positive or Gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, cephamandole may be given concomitantly with an aminoglycoside, eg: tobramycin (see Precautions). The recommended doses of both antibiotics may be given, depending on the severity of infection and the condition of the patient. The patient's renal function should be carefully monitored, especially if higher dosages of the antibiotics are to be administered.
Antibiotic therapy of beta-haemolytic streptococcal infections should continue for at least 10 days.
Preventative Therapy: The administration of cephamandole preoperatively, intraoperatively, and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures that are classified as contaminated or potentially contaminated (e.g. gastrointestinal surgery, caesarean section, vaginal hysterectomy, or cholecystectomy in high-risk patients such as those with acute cholecystitis, obstructive jaundice, or common bile-duct stones).
In major surgery in which the risk of postoperative infection is low but serious (cardiovascular surgery, neurosurgery, or prosthetic arthroplasty), cephamandole may be effective in preventing such an infection. Perioperative use of cephamandole should be discontinued after 48 hours, but in prosthetic arthroplasty, administration is recommended to be continued for 72 hours.
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.
The usual dosage range for cephamandole is 500 mg to 1 g every 4 to 8 hours depending on the severity of the infection and the susceptibility of the causative organism.
In mild skin and soft-tissue infections and in uncomplicated pneumonia, a dosage of 500 mg every 6 hours is adequate.
In mild, uncomplicated urinary tract infections, a dosage of 500 mg every 8 hours is sufficient. In more serious urinary tract infections, a dosage of 1 g every 8 hours may be needed.
In severe infections, 1 g doses may be given at 4 to 6 hour intervals.
In life-threatening infections or infections due to less susceptible organisms, doses up to 2 g every 4 hours (ie 12 g/day) may be needed.
Administration of 50 to 100 mg/kg/day in equally divided doses every 4 to 8 hours has been effective for most infections susceptible to cephamandole. This may be increased to a total daily dose of 150 mg/kg (not to exceed the maximum adult dose) for serious infections (see Warnings and Precautions for this age group).
Note:
As with antibiotic therapy in general, administration of cephamandole should be
continued for a minimum of 48 to 72 hours after the patient becomes asymptomatic
or after evidence of bacterial eradication has been obtained. A minimum of 10
days of treatment is recommended in infections caused by Group A β-haemolytic
streptococci in order to guard against the risk of rheumatic fever or
glomerulonephritis. Frequent bacteriological and clinical appraisal is necessary
during therapy of chronic urinary tract infection and may be required for
several months after therapy has been completed. Persistent infections may
require treatment for several weeks, and doses smaller than those indicated
above should not be used.
For perioperative use of cephamandole, the following dosages are recommended:
Adults: 1 or 2 g intravenously or intramuscularly one-half to 1 hour prior to the surgical incision followed by 1 g or 2 g every 6 hours for 24 hours.
Children (3 months of age and older): 50 to 100 mg/kg/day in equally divided doses by the routes and schedule designated above.
Note: In patients undergoing prosthetic arthroplasty, administration is recommended for as long as 72 hours.
In patients undergoing caesarean section, the initial dose may be administered just prior to surgery or immediately after the cord has been clamped.
When renal function is impaired, a reduced dosage must be employed and the serum levels closely monitored. After an initial dose of 1 g or 2 g (depending on the severity of infection), a maintenance dosage schedule should be followed (see below). Continued dosage should be determined by the degree of renal impairment, severity of the infection, and susceptibility of the causative organism.
When only serum creatinine is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.
| Males: | Weight (kg) x (140 - age) |
| 72 x serum creatinine | |
Females: |
0.9 x above value. |
| Creatinine clearance mL/min/1.732 |
Renal function | Life-threatening infections - maximum dosage |
Less severe infections |
|---|---|---|---|
| > 80 | Normal | 2 g q 4h | 1-2 g q 6h |
| 80-50 | Mild impairment | 1.5 g q 4h or 2 g q 6h | 0.75-1.5 g q 6h |
| 50-25 | Moderate impairment | 1.5 g q 6h or 2 g q 8h | 0.75-1.5 g q 8h |
| 25-10 | Severe impairment | 1 g q 6h or 1.25 g q 8h | 0.5-1 g q 8h |
| 10-2 | Marked impairment | 0.67 g q 8h or 1 g q 12h | 0.5-0.75 g q 12h |
| <2 | None | 0.5 g q 8h or 0.75 g q 12h | 0.25-0.5 g q 12h |
| q= every; h = hours. | |||
In patients undergoing haemodialysis the dose derived from the above table may
be given IV just after the dialysis. An additional dose of cephamandole is not
generally needed after haemodialysis if the patient has received an IV dose just
prior to the institution of dialysis.
Maintenance doses should be continued as indicated in the table. Monitoring of serum levels is advised.
Cephamandole 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.
Each gram of cephamandole should be diluted with 3 mL of one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride injection, Bacteriostatic Sodium Chloride Injection or 0.5% lignocaine injection. Shake well until dissolved.
The intravenous route may be preferable for patients with bacterial septicaemia, 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. In those with normal renal function, the intravenous dosage for such infections is 3 to 12 g of cephamandole daily. In conditions such as bacterial septicaemia, 6 to 12 g/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.
If combination therapy with cephamandole and an aminoglycoside is indicated, each of these antibiotics should be administered in different sites.
Do not mix an aminoglycoside with cephamandole in the same intravenous fluid container.
A solution of 1 g of cephamandole in 22 mL of Sterile Water for Injection is isotonic.
The choice of saline, dextrose, or electrolyte solution and the volume to be employed are dictated by fluid and electrolyte management.
Each gram of cephamandole should be reconstituted with 10 mL of Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection. Slowly inject directly into the vein over a period of 3 to 5 minutes, or give it 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, or Sodium Lactate Injection (M/6).
Can also be accomplished while any of the above-mentioned intravenous fluids are being infused. However, during infusion of the solution containing cephamandole, it is desirable to discontinue the other solution. When this technique is employed, careful attention should be paid to the volume of the solution containing cephamandole so that the calculated dose will be infused. When a Y-tube hook-up is used, 100mL of an appropriate diluent should be added to a 100ml piggyback vial containing 1g or 2g of cephamandole. If Sterile Water for Injection is used as the diluent, reconstitute with approximately 20 mL/g to avoid a hypotonic solution.
Each gram of cephamandole should be diluted with 10 mL of Sterile Water for Injection. An appropriate quantity of the resulting solution may be added to an IV bottle containing one of the following 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, or Sodium Lactate Injection (M/6).
Reconstituted cephamandole has been shown to be chemically and physically stable for 24 hours at room temperature (25°C) and for 96 hours if stored under refrigeration (5°C). During storage at room temperature, carbon dioxide develops inside the vial after reconstitution. This pressure may be dissipated prior to withdrawal of the vial contents, or it may be used to aid withdrawal if the vial is inverted over the syringe needle and the contents are allowed to flow into the syringe.
The colour of cephamandole solution will darken, especially at room temperature. Slight discolouration of the solution is permissible. Light protection is recommended during storage of the vials because the powder discolours upon prolonged exposure to light.
Sodium carbonate is present in the formulation to prevent turbidity or precipitation of cephamandole nafate and cephamandole free acids as the pH of the solution drops from aqueous ester hydrolysis.
Solutions of cephamandole in sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection that are frozen immediately after reconstitution in the original container are stable for 6 months when stored at -20°C. If the product is warmed (to a maximum of 37°C), care should be taken to avoid heating it after the thawing is complete. Once thawed, the solution should not be refrozen and should be used within 24 hours.
Cephamandole is contraindicated in patients with known allergy to the cephalosporin group of antibiotics and persons who have previously experienced a major allergy to penicillin.
Use in infants under the age of one month is contraindicated, since safety and efficacy of this drug has not been established in prematures and infants.
Lignocaine hydrochloride should not be used as a diluent for intramuscular injection in patients who are hypersensitive to lignocaine.
Before therapy with cephamandole is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins or other medicines. This product should be given cautiously to penicillin-sensitive patients. Serious acute hypersensitivity reactions may require adrenaline and other emergency measures.
There is evidence of partial cross allerginicity of the penicillins and the cephalosporins. Patients have been reported to have had severe reactions (including anaphylaxis) to both classes of drugs. Serious acute hypersensitivity reactions may require adrenaline and other emergency measures.
Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly to medicines.
As with other broad-spectrum antibiotics, hypoprothrombinaemia, with or without bleeding, has been reported rarely, but it has been promptly reversed by administration of Vitamin K. Such episodes usually have occurred in elderly, debilitated, or otherwise compromised patients with deficient stores of Vitamin K. Treatment of such individuals with antibiotics possessing significant Gram-negative and/or anaerobic activity is thought to alter the number and/or type of intestinal bacterial flora, with consequent reduction in synthesis of Vitamin K. Prophylactic administration of Vitamin K may be indicated in such patients, especially when intestinal sterilisation and surgical procedures are performed.
The use of cephamandole can lead to the development of severe colitis as a result of colonisation with C. difficile, a toxin producing organism. The colitis, which may or may not be accompanied by the formation of a pseudomembrane in the colon can be fatal. If significant diarrhoea occurs (this may begin up to several weeks after the cessation of antibiotic therapy) cephamandole should be discontinued. This may be sufficient treatment in the early stages, although cholestyramine orally may help by binding the toxin in the colonic lumen. In severe cases oral vancomycin in a dose of 250 mg 6 hourly for 5-10 days has proved effective. Vancomycin is not effective if given parenterally. Treatment with bacitracin has also been reported to be successful. Drugs which delay peristalsis eg: opiates and diphenoxylate with atropine, may prolong and/or worsen the condition and should not be used. Fluids, electrolytes and protein replacement therapy should be provided when indicated.
Although cephamandole rarely produces alteration in kidney function, evaluation of renal status is recommended, especially in seriously ill patients receiving maximum doses.
Prolonged use of cephamandole may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.
In a few patients receiving cephamandole, nausea, vomiting, and vasomotor instability with hypotension and peripheral vasodilatation occurred following the ingestion of ethanol. Cefamandole inhibits the enzyme acetaldehyde dehydrogenase in laboratory animals. This causes accumulation of acetaldehyde when ethanol is administered concomitantly.
A false-positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution or with CLINITEST Tablets, but not with TES-TAPE (urine sugar analysis paper, Lilly). There may be a false-positive test for proteinuria with acid and denaturisation precipitation tests.
Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
Repeated use of lignocaine hydrochloride as a diluent for intramuscular use should be avoided in patients with severe liver disease or decreased hepatic blood flow due to the possibility of lignocaine toxicity (resulting from deceased metabolism and accumulation).
Hypoprothrombinaemia has been reported, particularly in patients with poor dietary intake such as seriously ill patients receiving parenteral nutrition, in elderly, debilitated or otherwise compromised patients with deficient stores of Vitamin K. It has been promptly reversed by administration of Vitamin K. Prophylactic administration of Vitamin K may be indicated in such patients, especially when intestinal sterilization and surgical procedures are performed.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Certain beta-lactam antibiotics containing the N-methylthiotetrazole side chain have been reported to cause delayed maturity of the testicular germinal epithelium when given to neonatal rats during initial spermatogenic development (6 to 36 days of age). In animals that were treated from 6 to 36 days of age with 1000 mg/kg/day of cephamandole (approximately 5 times the maximum clinical dose), the delayed maturity was pronounced and was associated with decreased testicular weights and a reduced number of germinal cells in the leading waves of spermatogenic development. The effect was slight in rats given 50 or 100 mg/kg/day.
Some animals that were given 1000 mg/kg/day during days 6 to 36 were infertile after becoming sexually mature. No adverse effects have been reported in rats exposed in utero, in neonatal rats (4 days of age or younger) treated prior to the initiation of spermatogenesis or in older rats (more than 36 days of age) after exposure for up to 6 months. The significance to man of these findings in rats is unknown because of differences in the time of initiation of spermatogenesis, rate of spermatogenic development and duration of puberty.
Safety of this product for use during pregnancy has not been established. Reproduction studies have been performed in rats given doses of 500 or 1000 mg/kg/day (about 5 times the maximum clinical dose) and have revealed no evidence of impaired fertility or harm to the foetus due to cephamandole nafate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this medicine should be not used in women of child-bearing potential unless in the judgement of the treating clinician its use is considered essential to the welfare of the patient and the expected benefits outweigh the potential risks.
Cephamandole has been detected in breast milk. It is not advised for nursing mothers unless alternative arrangements for feeding the infant can be made.
Safety and efficacy of this product has not been established in premature babies and infants under 1 month of age. Safety for infants between one and six months of age has not been established. Cephamandole has been effectively used in this latter age group, but all laboratory parameters have not been extensively studied. Therefore, if cephamandole is administered to infants between one and six months of age, the physician should determine whether the potential benefits outweigh the possible risks involved. In newborn infants, accumulation of other cephalosporin class antibiotics (with resulting prolongation of drug half-life) have been reported.
Gastrointestinal: As with other broad spectrum antibiotics, colitis, including rare pseudomembranous colitis has been reported in conjunction with therapy with cephamandole. Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Nausea and vomiting have been reported rarely.
Hypersensitivity: Maculopapular rash, urticaria, eosinophilia, medicine fever and anaphylaxis have been reported. These reactions are more likely to occur in patients with a history of allergy, particularly to penicillin.
Blood: Thrombocytopenia, leucopenia and pancytopenia have been reported rarely. Neutropenia has been reported, especially in long courses of treatment. Some individuals have developed positive direct Coombs' tests during treatment with the cephalosporin antibiotics.
Hypoprothrombinaemia has been reported, particularly in patients with poor dietary intake such as seriously ill patients receiving parenteral nutrition. It has been proposed that the methythio-tetrazole group which is present in cephamandole inhibits the gamma carboxylation of glutamic acid which is necessary for the synthesis of prothrombin. Vitamin K is a cofactor in this reaction.
Erythropenia decreases in hematocrit values and haemoglobin concentrations have been observed.
Liver: Transient rises in AST, ALT, and alkaline phosphatase levels have been noted. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.
Kidney: Decreased creatinine clearance has been reported, particularly in patients with prior renal impairment. As with some other cephalosporins, transitory elevations of BUN have occasionally been observed; their frequency increases in patients over 50 years of age. In some of these cases, there was also a mild increase in serum creatinine. The role of cephamandole in renal changes is difficult to assess, because other factors predisposing to prerenal azotaemia or to acute renal failure usually have been present.
Local Reactions: Pain, induration, tenderness and elevation of temperature have been reported following repeated intramuscular injection. Thrombophlebitis occurs rarely.
Alcohol - Disulfiram-like reactions (eg. nausea, vomiting, headache, tachycardia, facial flushing) have occurred when alcohol was ingested within 48-72 hours of beta-lactam antibiotics that contain a methyltrathiozole side chain such as cephamandole. The reaction appears to result from accumulation of acetaldehyde in the blood. Patients should be advised to avoid alcoholic beverages and alcohol-containing medications while receiving cephamandole and for several days after discontinuing it.
A false-positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution, or with CLINITEST Tablets, but not with TES-TAPE (urine sugar analysis paper, Lilly). There may be a false-positive test for proteinuria with acid and denaturisation precipitation tests.
Symptoms: The administration of inappropriately large doses of parenteral cephalosporins may cause seizures, particularly in patients with renal impairment. Dosage reduction is necessary when renal function is impaired (see Dosage and Administration).
Treatment: If seizures occur, the medicine should be promptly discontinued. Anticonvulsant therapy may be administered if clinically indicated. General supportive care is recommended with monitoring of haematological, renal and hepatic functions, and coagulation status, until the patient is stable. Haemodialysis may be considered in cases of overwhelming overdosage.
Shelf life is 2 years for Cephamandole Nafate for Injection 500 mg and 2 g.
Shelf life is 3 years for Cephamandole Nafate for Injection 1 g.
Store below 25°C.
Do not mix an aminoglycoside with cephamandole in the same intravenous fluid container.
Cephamandole nafate should not be mixed with intravenous infusion fluids containing magnesium or calcium ions because of an incompatibility between these ions and sodium carbonate.
Reconstituted cephamandole has been shown to be chemically and physically stable for 24 hours at room temperature (25°C) and for 96 hours if stored under refrigeration (5°C). During storage at room temperature, carbon dioxide develops inside the vial after reconstitution. This pressure may be dissipated prior to withdrawal of the vial contents, or it may be used to aid withdrawal if the vial is inverted over the syringe needle and the contents are allowed to flow into the syringe.
Cephamandole nafate has been reported to be incompatible with aminoglycosides and cimetidine hydrochloride, calcium gluceptate and calcium gluconate.
Lignocaine hydrochloride 0.5%, 1.0% and 2.0% IM solutions were compatible with cephamandole nafate at concentrations greater than 100 mg/mL and lignocaine hydrochloride 0.1% and 0.2% IV solutions were compatible with cephamandole nafate concentrations less than 100 mg/mL; admixtures at concentrations other than these produced turbidity or precipitation immediately or during storage.
Cephamandole has been reported to be incompatible with acetated Ringer's injection, isolyte M with glucose 5%, Plasma-Lyte, Ringer's injection and lactated Ringer's injection.
Prescription Medicine.
Injection,
0.5 g 5 x 10 mL vials and 10 x 10mL vials
1 g 5 x 10 mL vials and 10 x 10mL vials
2 g 5 x 22 mL vials and 10 x 22mL vials
Hospira NZ Limited
23 Haining Street
Te Aro
Wellington
New Zealand
1 October 2007