Claforan (Cefotaxime)

CLAFORAN®

Hoechst Marion Roussel

Cefotaxime Sodium

Antibiotic

Action And Clinical Pharmacology: Animal studies demonstrate that cefotaxime has no significant effect on the CNS, cardiovascular and respiratory systems, kidneys, blood clotting mechanisms and blood glucose levels.

There is a dose-dependent increase in serum levels after i.v. administration of 500 mg, 1 and 2 g of cefotaxime (38.9, 101.7 and 214.4 g/mL respectively), without alteration in the elimination half-life.

The biological half-life was approximately 1 hour and the 24 hours urinary excretion of unchanged drug amounted to 62.6% of the administered dose (almost all of it in the first 6 hours).

In an in vitro study, approximately 51% (range 35 to 64%) of cefotaxime was bound to human serum proteins when concentrations ranged from 6.25 to 50 g/mL. The bound percentage of the desacetyl metabolite was 16 to 32% which is approximately half of the parent compound.

In vitro studies indicate that the bacterial action of cefotaxime, a semi-synthetic cephalosporin antibiotic, results from inhibition of cell wall synthesis.

Cefotaxime is partially metabolized in humans by non-specific esterases which desacetylate the acetoxymethylside chain to form the desacetyl cefotaxime (DACM). Desacetylation is followed by formation of the lactone and subsequent conversion to open b-lactam ring structures (UP1) and (UP2).

Approximately 20 to 36% of an i.v. dose of 4 cefotaxime is excreted by the kidney as unchanged drug and 15 to 25% as the DACM derivative, the major metabolite. Two other urinary metabolites (UP1 and UP2) account together for about 20 to 25%. Fecal recovery accounts for approximately 10% of the administered dose.

The DACM has been shown to contribute to 10 to 15% of the bactericidal activity of the parent compound. It has no activity against Pseudomonas. UP1 and UP2 lack antibacterial activity.

In a study conducted on 22 healthy volunteers administered cefotaxime and alcohol, there was no disulfiram-like reaction.

Indications And Clinical Uses: Cefotaxime may be indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the diseases listed below:

Lower respiratory tract infections: pneumonia and lung abscess caused by S. pneumoniae, other streptococci (excluding enterococci, e.g., S. faecalis), S. aureus (penicillinase and non-penicillinase producing), E. coli, H. influenzae, (including ampicillin resistant strains) and unspecified Klebsiella species.

Urinary tract infections: caused by E. coli, unspecified Klebsiella species (including K. pneumoniae), P. mirabilis, indole positive Proteus, S. marcescens and S. epidermidis. Also, uncomplicated gonorrhea caused by N. gonorrhoeae including penicillin resistant strains.

Bacteremia/Septicemia: caused by E. coli, unspecified Klebsiella strains and S. marcescens.

Skin infections: caused by S. aureus (penicillinase and non-penicillinase producing), S. epidermidis, Group A streptococci, E. coli, P. mirabilis and indole positive Proteus.

Intra-abdominal infections: caused by E. coli, and unspecified Klebsiella species.

Gynecological infections: including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by E. coli, Group A streptococci and S. epidermidis; anaerobic bacteria including unspecified Peptococcus and Peptostreptococcus strains and some strains of B. fragilis. In several cases, although clinical cures were achieved, bacteriological follow-up was not available.

CNS infections: meningitis and ventriculitis caused by H. influenzae, N. meningitidis, S. pneumoniae, K. pneumoniae and E. coli. Cefotaxime is not active against L. monocytogenes.

Clinical experience in anaerobic infections is limited. It has been used with some success in wound and intra-abdominal infections against some strains of unidentified Bacteroides and anaerobic cocci.

Cefotaxime has been shown to be active against some strains of Pseudomonas.

In the treatment of infections encountered in immunosuppressed and granulocytopenic patients, results of therapy with cefotaxime have not been impressive.

Cefotaxime should not be considered in the treatment of enterococcal infections, i.e., S. faecalis.

Specimens for bacteriologic culture should be obtained prior to therapy in order to isolate and identify the causative organisms and to determine their susceptibilities to cefotaxime. Therapy may be instituted before results of susceptibility studies are known; antibiotic treatment should be re-evaluated once these results become available.

Prophylactic use: The administration of cefotaxime perioperatively (preoperatively, intraoperatively and postoperatively) may reduce the incidence of certain infections in patients undergoing elective surgical procedures (e.g., abdominal or vaginal hysterectomy, gastrointestinal and genitourinary tract surgery) that may be classified as contaminated or potentially contaminated.

In patients undergoing caesarian section who are considered to be at increased risk of infection, intraoperative (after clamping the umbilical cord) and postoperative use of cefotaxime may also reduce the incidence of certain postoperative infections.

Effective use for elective surgery depends on the time of administration (see Dosage).

For patients undergoing gastrointestinal surgery, preoperative bowel preparation by mechanical cleansing as well as with a nonabsorbable antibiotic (e.g., neomycin) is recommended.

If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate therapy may be instituted.

Contra-Indications: In patients who have shown hypersensitivity to cefotaxime sodium, the cephalosporin or the penicillin groups of antibiotics.

Manufacturers’ Warnings In Clinical States: Before therapy is instituted, it must be carefully determined whether the patient has had previous hypersensitivity reactions to cefotaxime, cephalosporins, penicillins or other drugs. Cefotaxime should be given with caution to patients with Type 1 hypersensitivity reactions to penicillin. Antibiotics, including cefotaxime should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. If an allergic reaction to cefotaxime occurs, the drug should be discontinued and the patient treated with the usual agents (e.g., epinephrine, antihistamine, pressor-amines or corticosteroids).

Pseudomembranous colitis has been reported with the use of cephalosporins (and other broad-spectrum antibiotics); therefore, it is important to consider its diagnosis in patients who develop diarrhea during the administration of cefotaxime. This colitis can range from mild to life-threatening in severity.

Treatment with broad-spectrum antibiotics, such as cefotaxime, alters the normal flora of the colon and may permit overgrowth of C. difficile or other clostridia. It has been established that a toxin produced by C. difficile is one primary cause of antibiotic-associated colitis.

Mild cases of colitis may respond to discontinuation of cefotaxime and replacement with a suitable specific antibiotic. Moderate to severe cases should be managed with fluid, electrolyte and protein supplementation as indicated. When the colitis is not relieved by discontinuance of cefotaxime administration or when it is severe, an antibiotic specifically effective in antibiotic-associated pseudomembranous colitis (e.g., vancomycin) or other suitable therapy may be indicated. Other possible causes of colitis should also be considered (see Adverse Effects).

Precautions: Cefotaxime should be prescribed with caution in individuals with a history of lower gastrointestinal disease, particularly colitis.

Pregnancy: Safety of cefotaxime in pregnancy has not been established. Consequently, use of the drug in pregnant women requires that the likely benefit from the drug be weighed against the possible risk to the mother and fetus.

Use of cefotaxime in women of childbearing potential requires that the anticipated benefits be weighed against the possible risks.

Lactation: Cefotaxime is excreted in human milk in low concentrations. Caution should be exercised when the drug is administered to nursing mothers.

Prolonged use may result in the overgrowth of nonsusceptible organisms. Constant evaluation of the patient’s condition is essential. If superinfection occurs, therapy should be discontinued and appropriate measures taken.

Although cefotaxime rarely produces alterations in kidney function, evaluation of renal status is recommended, especially in severely ill patients receiving high doses.

Patients with markedly impaired renal function should be placed on the special dosage schedule recommended under Dosage, because normal dosage in these individuals is likely to produce excessive and prolonged serum antibiotic concentrations.

Positive direct Coombs’ test is known to develop in individuals during treatment with the cephalosporin group of antibiotics, including cefotaxime.

In laboratory tests a false-positive reaction to glucose may occur with reducing substances but not with the use of specific glucose oxidase methods.

As with other beta-lactam antibiotics, granulocytopenia and, more rarely, agranulocytosis may develop during treatment with cefotaxime, particularly if given over long periods. For courses of treatment lasting longer than 10 days, blood counts should therefore be monitored.

Adverse Reactions: The most frequent adverse reactions with frequency of occurrence are:

  • Hypersensitivity (1.8%): rash, pruritus, fever;
  • Local (5%): injection site inflammation with i.v. administration. Pain, induration and tenderness after i.m. injection;
  • Gastrointestinal (1.7%): colitis, diarrhea, nausea and vomiting. Symptoms of pseudomembranous colitis can appear during or after cefotaxime treatment;
  • Hematologic System;
  • Genitourinary System;
  • CNS (0.2%): headache;
  • Liver;
  • Kidney.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Since no case of overdosage has been reported to date with cefotaxime, no specific information on symptoms or treatment is available. Treatment of overdosage should be symptomatic.

Dosage And Administration: Cefotaxime may be administered i.v. or i.m. after reconstitution (see Table with recommended mode of reconstitution according to route of administration).

Adults: Dosage should be determined by susceptibility of the causative organisms, severity of the infection and condition of the patient.

To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are as follows: (a) 1 g i.m. or i.v. administered 1/2 to 1 1/2 hours prior to the initial surgical incision to ensure that adequate antibiotic levels are present in the serum and tissues at the start of surgery; (b) 1 g i.m. or i.v. administered 1 1/2 to 2 hours following the first dose; for lengthy operative procedures, additional intraoperative doses may be administered, if necessary, at appropriate intervals (1 1/2 to 2 hours) during surgery; (c) 1 g i.m. or i.v. administered within 2 hours following completion of surgery.

The total cumulative prophylactic dose should not exceed 6 g in a 12-hour period.

Caesarian Section Patients: The first dose of 1 g is administered i.v. as soon as the umbilical cord is clamped. The second and third doses should be given as 1 g i.m. or i.v. at 6 and 12 hours after the first dose.

Neonates, Infants, and Children: The following dosage schedule is recommended. Neonates: 0 to 1 week of age; 50 mg/kg i.v. every 12 hours, 1 to 4 weeks of age; 50 mg/kg i.v. every 8 hours. Infants and children (1 month to 12 years): For body weights less than 50 kg, the recommended daily dose is 50 to 100 mg/kg i.m. or i.v. of body weight divided into 4 to 6 equal doses, or up to 180 mg/kg/day for severe infections (including CNS infections).

For body weights 50 kg or more, the usual adult dosage should be used.

The maximum daily dosage should not exceed 12 g.

Administration of cefotaxime should be continued for a minimum of 48 to 72 hours after the patient defervesces or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended for 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 infections and may be required for several months after therapy has been completed; persistent infections may require prolonged treatment. Doses less than those recommended should not be employed.

Patients with Impaired Renal Function: In patients with estimated creatinine clearance of less than 20 mL/min/1.73 m the dose should be halved (see Precautions).

If serum creatinine values alone are available, the following formulas (based on sex, weight, and age of the patient) may be used to convert these values into creatinine clearance.

Males:

Creatinine clearance (mL/sec) = Weight (kg)x(140-age) 49xserum creatinine (mmol/L)

Creatinine clearance (mL/min) = Weight (kg)x(140-age) 72xserum creatinine (mg/dL)

Females: 0.85xabove value

Administration: I.M.: Cefotaxime should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into a blood vessel.

I.V.: The i.v. route is preferable for patients with bacteremia, bacterial septicemia, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending.

For bolus administration a solution containing 1 or 2 g of cefotaxime can be injected over a period of 3 to 5 minutes. Using an infusion system, it may also be given over a longer period of time through the tubing system by which the patient may be receiving other i.v. solutions. Butterfly or scalp vein type needles are preferred for this type of infusion. However, during infusion of the solution containing cefotaxime, it is advisable to discontinue temporarily the administration of other solutions at the same site.

Reconstitution: I.M.: Cefotaxime should be reconstituted with Sterile Water for Injection or Bacteriostatic Water for Injection in accordance with the volumes recommended in Table II.

For direct i.v. injection (bolus) and/or continuous i.v. infusion:

Conventional Flip-Top Vial: 500 mg, 1 and 2 g vials should be reconstituted with at least 10 mL of Sterile Water for Injection. Reconstituted solution may be further diluted with 50 to 1 000 mL of the fluids recommended for i.v. infusion.

A solution of 1 g of cefotaxime in 14 mL of Sterile Water for Injection is isotonic.

Solutions for i.v. Infusion: Cefotaxime is compatible with the following infusion fluids: 0.9% NaCl injection; 5% dextrose injection; 0.9% NaCl and 5% dextrose injection; 0.45% NaCl and 5% dextrose injection; 0.2% NaCl and 5% dextrose injection; Sodium Lactate injection; 5% dextrose and 0.15% KCl injection; Plasma-Lyte 56 Electrolyte Solution in 5% dextrose injection; Ringer’s injection; Lactated Ringer’s solution; Lactated Ringer’s with 5% dextrose injection. Cefotaxime is also compatible with 1% lignocaine.

Stability and Storage: Solutions of cefotaxime range from light yellow to amber, depending on concentration and the diluent used. The solutions tend to darken depending on storage conditions and should be protected from elevated temperatures and excessive light.

Cefotaxime reconstituted in the original vial as described under Reconstitution maintains satisfactory potency for 24 hours at room temperature (25°C) and for 48 hours under refrigeration (0 to 5°C). Only freshly prepared reconstituted solutions may be further diluted with 50 to 1 000 mL of the recommended infusion fluids in Viaflex i.v. bags. Such solutions maintain satisfactory potency for 24 hours at room temperature (25°C) and for 72 hours under refrigeration (0 to 5°C). Any unused solutions should be discarded.

Cefotaxime reconstituted with 1% lignocaine maintains satisfactory potency for up to 24 hours at room temperature and 48 hours under refrigeration (reference to lignocaine restrictions is advisable).

Cefotaxime solutions exhibit maximum stability in the pH 5 to 7 range.

Special Instructions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Solutions of cefotaxime range from light yellow to amber, depending on concentration and diluent used. The dry powder as well as solutions tend to darken, depending on storage condition.

Incompatibilities: Solutions of cefotaxime must not be admixed with aminoglycoside solutions. If cefotaxime and aminoglycosides are to be administered to the same patient, they must be administered separately and not as a mixed injection.

Solutions of cefotaxime should not be prepared with diluents having a pH above 7.5 such as Sodium Bicarbonate Injection.

ADD-Vantage Vial: When administering cefotaxime using the ADD-Vantage Drug Delivery system, cefotaxime powder is added directly to a single-dose flexible plastic ADD-Vantage diluent container. Cefotaxime 1 g may be reconstituted in 50 to 100 mL of 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP.

Stability: Solutions of cefotaxime reconstituted in 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP in the ADD-Vantage flexible containers maintain satisfactory potency for 12 hours at room temperature.

Instructions for use, ADD-Vantage: (see package insert for diagrams).

To Open: Peel overwrap at corner and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container (Use Aseptic Technique): Remove the protective covers from the top of the vial and the vial port on the diluent container as follows: To remove the breakaway vial cap swing the pull ring over the top of the vial and pull down far enough to start the opening, then pull straight up to remove the cap. Note: Once the breakaway cap has been removed, do not access vial with syringe. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover.

Screw the vial into the vial port until it will go no further. The vial must be screwed in tightly to assure a seal. This occurs approximately 1/2 turn after the first audible click. The clicking sound does not assure a seal, the vial must be turned as far as it will go. Note: Once vial is seated, do not attempt to remove.

Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.

Label appropriately.

To Reconstitute the Drug: Squeeze the bottom of the diluent container gently to initiate the portion of the container surrounding the end of the drug vial.

With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container.

Pull the inner cap from the drug vial. Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.

Mix container contents thoroughly and use within the specified time.

Immediately prior to administration, confirm that the contents of the vial have been dissolved by observing the inner cap/stopper in the flexible container.

Availability And Storage: A sterile, white to pale yellow powder, in vials containing cefotaxime sodium 500 mg, 1 and 2 g and in ADD-Vantage Vials containing cefotaxime sodium 1 g (expressed as acid on a dry basis). In the dry state store at room temperature. Protect from light and heat.

CLAFORAN® Hoechst Marion Roussel Cefotaxime Sodium Antibiotic

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