INFORMATION FOR HEALTH PROFESSIONALS
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MANDOL 500 mg vial contains a white powder, which reconstitutes to form a light-yellow to amber solution, depending
on the concentration and diluent used. Each vial contains cephamandole nafate equivalent to 500 mg cephamandole.
MANDOL 1 g vial contains a white powder, which reconstitutes to form a light-yellow to amber solution, depending on the
concentration and diluent used. Each vial contains cephamandole nafate equivalent to 1 g cephamandole.
MANDOL is a semi-synthetic 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. MANDOL is usually active against the following organisms in vitro and in clinical infections:
Staphylococcus aureus
, including penicillinase- and non-penicillinase-producing strains; Staphylococcus epidermidis; β-haemolytic and other streptococci (Most strains of enterococci e.g. Enterococcus faecalis [formerly Streptococcus faecalis ], are resistant.); Streptococcus pneumoniae (formerly Diplococcus pneumoniae ).Escherichia coli
; Klebsiella sp; Enterobacter sp (Initially susceptible organisms occasionally may become resistant during therapy.); Haemophilus influenzae; Proteus mirabilis; Providencia rettgeri (formerly Proteus rettgeri ); Morganella morganii (formerly Proteus morganii ); Proteus vulgaris (Some strains of P. vulgaris have been shown by in vitro tests to be resistant to cephamandole and certain other cephalosporins).Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus sp);
gram-positive bacilli (including Clostridium sp); gram-negative bacilli (including Bacteroides and
Fusobacterium sp); most strains of Bacteroides fragilis are resistant.
Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea sp), and most
Serratia strains are resistant to cephamandole and certain other cephalosporins. Cephamandole is resistant to
degradation by β-lactamases from certain members of the Enterobacteriaceae.
Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic
susceptibility. One such procedure 1 has been recommended for use with discs to test
susceptibility to cephamandole. Interpretation involves correlation of the diameters obtained in the disc test with
minimal inhibitory concentration (MIC) values for cephamandole.
Reports from the laboratory giving results of the standardised single-disc susceptibility criteria:
Susceptible organisms produce zones of 18 mm or greater, indicating that the tested organism is likely to respond to
therapy.
Organisms of intermediate susceptibility produce zones of 15 to 17 mm, indicating that the tested organism would be
susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g. urine), in which high
antibiotic levels are attained.
Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected.
For gram-positive isolates, the test may be performed with either the cephalosporin-class disc (30 mcg cephalothin) or
the cephamandole disc (30 mcg cephamandole), and a zone of 18 mm is indicative of a cephamandole susceptible organism.
Gram-negative organisms should be tested with the cephamandole disc (using the above criteria), since cephamandole has
been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found
resistant when tested with the cephalosporin-class disc. Gram-negative organisms having zones of less than 18 mm around
the cephalothin disc are not necessarily of intermediate susceptibility or resistant to cephamandole.
The cephamandole disc should not be used for testing susceptibility to other cephalosporins.
A bacterial isolate may be considered susceptible if the MIC value for cephamandole 2 is not
more than 16 mg/L. Organisms are considered resistant if the MIC is greater than 32 mg/L.
1 Bauer A W Kirby WMM, et al: Antibiotic susceptibility testing by a standardised single disk method. Am J Clin Pathol 1966;45:493. Standardised disk susceptibility test. Federal Register 1974;39:19182-19184. National Committee for Clinical Laboratory Standards. Approved Standard: M2-A3 Performance standards for antimicrobial disk susceptibility tests--Third Edition, December, 1984.
2 Determined by the ICS agar-dilution method (Ericsson HM, and Sherris JC: Acta Pathol Microbiol Scand 1971; [suppl 217]:B, or any other method that has been shown to give equivalent results.
After intramuscular administration of a 500-mg dose of cephamandole to normal volunteers, the mean peak serum
concentration was 13 mg/L. After a 1-g dose, the mean peak concentration was 25 mg/L. These peaks occurred at 30 to 120
minutes. Following intravenous doses of 1, 2, and 3 g, serum concentrations were 139, 240, and 533 mg/L, respectively,
at 10 minutes. These concentrations declined to 0.8, 2.2, and 2.9 mg/L at four 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.
Sixty-five to 85% of cephamandole is excreted by the kidneys over an 8-hour period, resulting in high urinary
concentrations. Following intramuscular doses of 500 mg and 1 g, urinary concentrations averaged 254 and 1357 mg/L
respectively. Intravenous doses of 1 and 2 g produced urinary levels averaging 750 and 1380 mg/L respectively.
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.
MANDOL is indicated for the treatment of serious infections caused by susceptible strains of the designated
microorganisms in the diseases listed below:
Lower respiratory infections, including pneumonia, caused by S. pneumoniae (D. pneumoniae), H. influenzae,
Klebsiella sp., S. aureus (penicillinase- and non-penicillinase-producing), β-haemolytic streptococci, and
P. mirabilis;
Urinary tract infections caused by E. coli, Proteus sp (both indole-negative and indole-positive),
Enterobacter sp, Klebsiella sp, group D streptococci (Note: most enterococci, eg, E. faecalis,
are resistant), and S epidermidis;
Peritonitis caused by E. coli and Enterobacter sp;
Septicaemia caused by E. coli, S. aureus (penicillinase- and non-penicillinase-producing), S.
pneumoniae, S. pyogenes (group A β-haemolytic streptococci), H. influenzae, and Klebsiella sp;
Skin and skin structure infections caused by S. aureus (penicillinase- and non-penicillinase-producing), S.
pyogenes (group A β -haemolytic streptococci), H. influenzae, E. coli, Enterobacter sp, and P.
mirabilis;
Bone and joint infections caused by S. aureus (penicillinase- and non-penicillinase-producing).
Clinical microbiologic studies in nongonococcal pelvic inflammatory disease in females, lower respiratory infections,
and skin infections frequently reveal the growth of susceptible strains of both aerobic and anaerobic organisms. MANDOL
has been used successfully in those infections in which several organisms have been isolated. Most strains of B.
fragilis are resistant in vitro; however, infections caused by susceptible strains have been treated
successfully.
Specimens for bacteriologic cultures should be obtained in order to isolate and identify causative organisms and to
determine their susceptibilities to MANDOL. Therapy may be instituted before results of susceptibility studies are
known; however, once these results become available, the antibiotic 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, MANDOL may be given concomitantly with an
aminoglycoside ( 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 β-haemolytic streptococcal infections should continue for at least 10 days.
The administration of MANDOL 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, caesarian 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), MANDOL may be effective in preventing such an infection.
The perioperative use of MANDOL should be discontinued after 48 hours; however, in prosthetic arthroplasty, it is
recommended that administration 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 MANDOL is 500 mg to 1 g every 4 to 8 hours.
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 (i.e. 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 MANDOL. This may be increased to a total daily dose of 150 mg/kg (not to exceed the maximum
adult dose) for severe infections (see Warnings and Precautions).
Note: As with antibiotic therapy in general, administration of MANDOL 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 bacteriologic 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 MANDOL, 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 or 2 g every 6 hours for 24 to 48 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 caesarian 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 to 2 g (depending on the severity of the infection), a maintenance dosage schedule should be followed (see below).
| Creatinine Clearance mL/min/1.73 m² |
Renal Function | Life-Threatening Infections, Maximum Dosage |
Less Severe Infections |
|---|---|---|---|
| > 80 | Normal | 2 g q4h | 1-2 g q6h |
| 80-50 | Mild Impairment |
1.5 g q4h OR 2 g q6h |
0.75-1.5 g q6h |
| 50-25 | Moderate Impairment |
1.5 g q6h OR 2 g q8h |
0.75-1.5 g q8h |
| 25-10 | Severe Impairment |
1 g q6h OR 1.25 g q8h |
0.5-1 g q8h |
| 10-2 | Marked Impairment |
0.67 g q8h OR 1 g q12h |
0.5-0.75 g q12h |
| <2 | None | 0.5 g q8h OR 0.75 g q12h |
0.25-0.5 g q12h |
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 rate of renal
function.
| Males: | Weight (kg) x (140 -age) 72 x serum creatinine |
Females: |
0.9 x above value |
MANDOL 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 MANDOL 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, or Bacteriostatic Sodium Chloride Injection. Shake well until dissolved.
The intravenous route may be preferable for patients with bacterial septicaemia, localised parenchymal abscesses
(such as intra-abdominal abcess), 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 MANDOL 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 MANDOL and an aminoglycoside is indicated, each of these antibiotics should be administered
in different sites. Do not mix an aminoglycoside with MANDOL in the same intravenous fluid container.
A solution of 1 g of MANDOL 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 MANDOL 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).
Intermittent intravenous infusion with a Y-type administration set or volume control set can also be accomplished while any of the above-mentioned intravenous fluids are being infused. However, during infusion of the solution containing MANDOL, 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 MANDOL so that the calculated dose will be infused. When a Y-tube hookup is used, 100 mL of an appropriate diluent should be added to the 1- or 2-g piggyback (100 mL) vial. If Sterile Water for Injection is used as the diluent, reconstitute with approximately 20 mL/g to avoid a hypotonic solution.
For continuous intravenous infusion, each gram of MANDOL 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).
MANDOL is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
Before therapy with MANDOL 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.
Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly
to medicines.
Serious acute hypersensitivity reactions may require adrenaline and other emergency measures.
In newborn infants, accumulation of other cephalosporin-class antibiotics (with resulting prolongation of medicine
half-life) has been reported.
Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics (including macrolides,
semisynthetic penicillins, and cephalosporins); therefore, it is important to consider its diagnosis in patients who
develop diarrhoea in association with the use of antibiotics. Such colitis may range in severity from mild to
life-threatening.
Treatment with broad-spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of clostridia.
Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated
colitis.
Mild cases of pseudomembranous colitis usually respond to medicine discontinuance alone. In moderate to severe cases,
management should include sigmoidoscopy, appropriate bacteriologic studies, and fluid, electrolyte, and protein
supplementation. When the colitis does not improve after the medicine has been discontinued, or when it is severe, oral
vancomycin is the medicine of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile.
Other causes of colitis should be ruled out.
Although MANDOL rarely produces alteration in kidney function, evaluation of renal status is recommended, especially
in seriously ill patients receiving maximum doses.
Prolonged use of MANDOL 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.
A false-positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution or with Clinitest®
tablets. There may be a false-positive test for proteinuria with acid and denaturisation-precipitation tests.
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.
In a few patients receiving MANDOL, nausea, vomiting, and vasomotor instability with hypotension and peripheral
vasodilatation occurred following the ingestion of ethanol.
Cephamandole inhibits the enzyme acetaldehyde dehydrogenase in laboratory animals. This causes accumulation of
acetaldehyde when ethanol is administered concomitantly.
Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease,
particularly colitis.
Certain β-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 observed 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.
Reproduction studies have been performed in rats given doses of 500 or 1000 mg/kg/day and have revealed no evidence of impaired fertility or harm to the foetus due to MANDOL. 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 used during pregnancy only if clearly needed.
Caution should be exercised when MANDOL is administered to a nursing woman.
MANDOL has been effectively used in this age group, but all laboratory parameters have not been extensively studied in infants between 1 and 6 months of age; safety of this product has not been established in prematures and infants under 1 month of age. Therefore, if MANDOL is administered to infants, the physician should determine whether the potential benefits outweigh the possible risks involved.
Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Nausea and vomiting have been reported rarely. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.
Maculopapular rash, urticaria, eosinophilia, drug fever, and anaphylaxis have been reported. These reactions are more likely to occur in patients with a history of allergy, particularly to penicillin.
Thrombocytopenia has 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.
Transient increases in SGOT, SGPT, and alkaline phosphatase levels have been noted.
Decreased creatinine clearance has been reported in patients with prior renal impairment. As with some other cephalosporins, transitory elevations of BUN have occasionally been observed with MANDOL; their frequency increases in patients over 50 years of age. In some of these cases, there was also a mild increase in serum creatinine.
Pain on intramuscular injection is infrequent. Thrombophlebitis occurs rarely.
When ethanol is taken concomitantly, accumulation of acetaldehyde may occur (see Precautions).
A false-positive reaction for glucose in the urine may occur with Benedict's or Fehlings's solution or with Clinitest®
tablets. There may be a false-positive test for proteinuria with acid and denaturisation-precipitation tests.
Probenecid slows tubular excretion and doubles the peak serum level and duration of measurable serum concentrations.
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). If seizures occur, the medicine should be promptly discontinued.
Anticonvulsant therapy may be administered if clinically indicated. Haemodialysis may be considered in cases of overwhelming overdosage.
Shelf-life is 3 years. Store below 25°C.
Reconstituted MANDOL has been shown to be chemically and physically stable for 24 hours under refrigerated conditions
(2-8°C). To reduce microbiological hazard, use as soon as practicable after reconstitution. Contains no
antimicrobial agent. Product is for single use in one patient only. Discard any residue. After addition of
diluent, cephamandole nafate rapidly hydrolyses to cephamandole, and both compounds have microbiologic activity in
vivo depending on concentration and diluent used.
Solutions of cephamandole nafate in Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride
Injection that are frozen immediately after reconstitution in the conventional vials in which the medicines are supplied
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.
Prior to administration, parenteral medicine products should be inspected visually for particulate matter and
discolouration whenever solution and container permit.
If combination therapy with MANDOL and an aminoglycoside is indicated, each of the antibiotics should be administered in different sites. Do not mix an aminoglycoside with MANDOL in the same intravenous fluid.
Prescription Medicine.
MANDOL 500 mg and 1 g vials are available in boxes of 10.
Cephamandole nafate is the sodium salt of 7-D-Mandelamido-3-[[1-methyl-1 H
-tetrazol-5-yl)-thio]methyl]-3cephem-4-carboxylic acid, formate (ester).
The pH of freshly reconstituted solutions of MANDOL usually ranges from 6.0 to 8.5. The total sodium content is
approximately 77 mg (3.3 mEq sodium ion)/g of cephamandole activity.
Cephamandole nafate also contains 63 mg sodium carbonate/g of cephamandole activity.
Eli Lilly & Company (NZ) Limited
9 Gladding Place, Manukau City
P O Box 97-046
South Auckland Mail Centre, Wiri
Auckland, New Zealand
Telephone: (09) 261-1000
27 March 2003