Prescription Drugs

CLINICAL PHARMACOLOGY After intramuscular administration of a 500-mg dose of cefamandol (cefamandole) e 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 mcg/mL respectively at 10 minutes. These concentrations declined to 0.8, 2.2, and 2.9 mcg/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. Sixty-five percent to 85% of cefamandol (cefamandole) e 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 1,357 mcg/mL respectively. Intravenous doses of 1 and 2 g produced urinary levels averaging 750 and 1,380 mcg/mL respectively. Probenecid slows tubular excretion and doubles the peak serum level and the duration of measurable serum concentrations. The antibiotic reaches therapeutic levels in pleural and joint fluids and in bile and bone. Microbiology The bactericidal action of cefamandol (cefamandole) e results from inhibition of cell-wall synthesis. Cephalosporins have in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefamandol (cefamandole) e is usually active against the following organisms in vitro and in clinical infections: Gram-positive Staphylococcus aureus, including penicillinase- and non-penicillinase-producing strains Staphylococcus epidermidis (beta)-hemolytic and other streptococci (Most strains of enterococci, eg, Enterococcus faecalis [formerly Streptococcus faecalis ], are resistant.) Streptococcus pneumoniae Gram-negative Escherichia coli Klebsiella spp. Enterobacter spp. (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 cefamandol (cefamandole) e and certain other cephalosporins.) Anaerobic organisms Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus spp.) Gram-positive bacilli (including Clostridium spp.) Gram-negative bacilli (including Bacteroides and Fusobacterium spp.). Most strains of Bacteroides fragilis are resistant. Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea spp.), and most Serratia strains are resistant to cefamandole and certain other cephalosporins. Cefamandol (cefamandole) e is resistant to degradation by (beta)-lactamases from certain members of the Enterobacteriaceae. Susceptibility Tests 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 disks to test susceptibility to cefamandol (cefamandole) e. Interpretation involves correlation of the diameters obtained in the disk test with minimal inhibitory concentration (MIC) values for cefamandol (cefamandole) e. Reports from the laboratory giving results of the standardized single-disk susceptibility test 1 using a 30-mcg cefamandol (cefamandole) e disk should be interpreted according to the following 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 (eg, 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 disk (30 mcg cephalothin) or the cefamandole disk (30 mcg cefamandole), and a zone of 18 mm is indicative of a cefamandol (cefamandole) e-susceptible organism. Gram-negative organisms should be tested with the cefamandole disk (using the above criteria), since cefamandol (cefamandole) e has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalosporin-class disk. Gram-negative organisms having zones of less than 18 mm around the cephalothin disk are not necessarily of intermediate susceptibility or resistant to cefamandole. The cefamandol (cefamandole) e disk should not be used for testing susceptibility to other cephalosporins. A bacterial isolate may be considered susceptible if the MIC value for cefamandol (cefamandole) e 2 is not more than 16 mcg/mL. Organisms are considered resistant if the MIC is greater than 32 mcg/mL.

DESCRIPTION Mandol® (Cefamandol (cefamandole) e Nafate for Injection, USP) is a semisynthetic broad-spectrum cephalosporin antibiotic for parenteral administration. It is 5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(formyloxy)phenylacetyl]amino]-3-[[(1-methyl-1 H -tetrazol-5-yl)thio]methyl]-8-oxo-, monosodium salt, [6 R- [6(alpha),7(beta)( R *)]]. Cefamandol (cefamandole) e has the empirical formula C 19 H 17 N 6 NaO 6 S 2 representing a molecular weight of 512.49. Mandol (cefamandole) also contains 63 mg sodium carbonate/g of cefamandol (cefamandole) e activity. The total sodium content is approximately 77 mg (3.3 mEq sodium ion) per g of cefamandole activity. After addition of diluent, cefamandole nafate rapidly hydrolyzes to cefamandol (cefamandole) e, and both compounds have microbiologic activity in vivo. Solutions of Mandol (cefamandole) range from light-yellow to amber, depending on concentration and diluent used. The pH of freshly reconstituted solutions usually ranges from 6.0 to 8.5.

INDICATIONS Mandol (cefamandole) 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, H. influenzae, Klebsiella spp., S. aureus (penicillinase- and non-penicillinase-producing), (beta)-hemolytic streptococci, and P. mirabilis Urinary tract infections caused by E. coli, Proteus spp. (both indole-negative and indole-positive), Enterobacter spp., Klebsiella spp., group D streptococci (Note: Most enterococci, eg, E. faecalis, are resistant), and S. epidermidis Peritonitis caused by E. coli and Enterobacter spp. Septicemia caused by E. coli, S. aureus (penicillinase- and non-penicillinase-producing), S. pneumoniae, S. pyogenes (group A (beta)-hemolytic streptococci), H. influenzae, and Klebsiella spp. Skin and skin structure infections caused by S. aureus (penicillinase- and non-penicillinase-producing), S. pyogenes (group A (beta)-hemolytic streptococci), H. influenzae, E. coli, Enterobacter spp., 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 (cefamandole) 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 cefamandol (cefamandole) e. 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, Mandol (cefamandole) may be used concomitantly with an aminoglycoside ( see Precautions ). The recommended doses of both antibiotics may be given, depending on the severity of the infection and the patient's condition. The renal function of the patient should be carefully monitored, especially if higher dosages of the antibiotics are to be administered. Antibiotic therapy of (beta)-hemolytic streptococcal infections should continue for at least 10 days. Preventive Therapy The administration of Mandol (cefamandole) 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 (eg, gastrointestinal surgery, cesarean 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 (cefamandole) may be effective in preventing such infections. 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. DOSAGE AND ADMINISTRATION Dosage Adults: The usual dosage range for cefamandol (cefamandole) e is 500 mg to 1 g every 4 to 8 hours. In infections of skin structures and in uncomplicated pneumonia, a dosage of 500 mg every 6 hours is adequate. In 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. Infants and Children: 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 (cefamandole) . This may be increased to a total daily dose of 150 mg/kg (not to exceed the maximum adult dose) for severe infections. ( See recommendations regarding this age group in WARNINGS and Precautions.) Note: As with antibiotic therapy in general, administration of Mandol (cefamandole) 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 (beta)-hemolytic 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 (cefamandole) , the following dosages are recommended: Adults 1 or 2 g intravenously or intramuscularly 1 / 2 to 1 hour prior to the surgical incision followed by 1 or 2 g every 6 hours for 24 to 48 hours. Pediatric Patients (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 cesarean section, the initial dose may be administered just prior to surgery or immediately after the cord has been clamped. Impaired Renal Function 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 infection), a maintenance dosage schedule should be followed (see chart). Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organism. MAINTENANCE DOSAGE GUIDE FOR PATIENTS WITH RENAL IMPAIRMENT Creatinine Clearance (mL/min/1.73 m 2 ) 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

PATIENT INFORMATION No Information Provided

OVERDOSE 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 drug should be promptly discontinued; anticonvulsant therapy may be administered if clinically indicated. Hemodialysis may be considered in cases of overwhelming overdosage. CONTRAINDICATIONS Mandol (cefamandole) is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

SIDE EFFECTS Gastrointestinal 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. Hypersensitivity Anaphylaxis, maculopapular rash, urticaria, eosinophilia, and drug fever have been reported. These reactions are more likely to occur in patients with a history of allergy, particularly to penicillin. Blood 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. Liver Transient rise in SGOT, SGPT, and alkaline phosphatase levels has been noted. Kidney 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 (cefamandole) ; their frequency increases in patients over 50 years of age. In some of these cases, there was also a mild increase in serum creatinine. Local Reactions Pain on intramuscular injection is infrequent. Thrombophlebitis occurs rarely. DRUG INTERACTIONS No Information Provided

WARNINGS BEFORE THERAPY WITH MANDOL (cefamandole) IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. 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 DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES. In neonates, accumulation of other cephalosporin-class antibiotics (with resulting prolongation of drug 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 diarrhea 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 a primary cause of antibiotic-associated colitis. Mild cases of pseudomembranous colitis usually respond to drug 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 drug has been discontinued, or when it is severe, oral vancomycin is the drug of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile. Other causes of colitis should be ruled out. PRECAUTIONS General Although Mandol (cefamandole) rarely produces alteration in kidney function, evaluation of renal status is recommended, especially in seriously ill patients receiving maximum doses. Prolonged use of Mandol (cefamandole) 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 denaturization-precipitation tests. As with other broad-spectrum antibiotics, hypoprothrombinemia, 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 sterilization and surgical procedures are performed. In a few patients receiving Mandol (cefamandole) , nausea, vomiting, and vasomotor instability with hypotension and peripheral vasodilatation occurred following the ingestion of ethanol. Cefamandol (cefamandole) e 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. 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 1,000 mg/kg/day of cefamandol (cefamandole) e (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 1,000 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 humans 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. Usage in Pregnancy Pregnancy Category B Reproduction studies have been performed in rats given doses of 500 or 1,000 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to Mandol (cefamandole) . There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Caution should be exercised when Mandol (cefamandole) is administered to a nursing woman. Usage in Infants Mandol (cefamandole) 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 premature infants and term neonates under 1 month of age. Therefore, if Mandol (cefamandole) is administered to infants, the physician should determine whether the potential benefits outweigh the possible risks involved.