g, 1 g, 2 g, 10g ceftriaxone per vial (ceftriaxone as ceftriaxone sodium)

Sterile Antibiotic Sandoz Canada Inc. Date of Preparation: February 22, 2007 145 Jules-Leger Date of Revision: February 22, 2007 Boucherville, QC J4B 7K8 Submission Control No: 100987

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3

INDICATIONS AND CLINICAL USE 3

CONTRAINDICATIONS 4

WARNINGS AND PRECAUTIONS 4

ADVERSE REACTIONS 7

DRUG INTERACTIONS 8

DOSAGE AND ADMINISTRATION 9

OVERDOSAGE 13

ACTION AND CLINICAL PHARMACOLOGY 13

STORAGE AND STABILITY 13

SPECIAL HANDLING INSTRUCTIONS 15

DOSAGE FORMS, COMPOSITION AND PACKAGING 15

PART II: SCIENTIFIC INFORMATION 16

PHARMACEUTICAL INFORMATION 16

DETAILED PHARMACOLOGY 17

MICROBIOLOGY 35

TOXICOLOGY 47

REFERENCES 56

PART III: CONSUMER INFORMATION 59

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Ceftriaxone for Injection USP (Sterile)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Ceftriaxone is contraindicated in patients with known allergy to ceftriaxone, other cephalosporins or penicillins. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

WARNINGS AND PRECAUTIONS

General

Hypoprothrombinemia and alterations in prothrombin time have occurred rarely in patients treated with ceftriaxone (see ADVERSE REACTIONS). Patients with impaired vitamin K synthesis or low vitamin K stores (e.g. chronic hepatic disease and malnutrition) may require monitoring of hematology and coagulation parameters during ceftriaxone treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during treatment. Prolonged treatment with ceftriaxone may result in overgrowth of non-susceptible organisms and organisms initially sensitive to the drug. Development of resistant organisms during the administration of ceftriaxone in clinical trials has been observed in 6% of the 94 patients infected with P. aeruginosa, in 33% of 3 patients infected with Citrobacter species and in 10% of the 10 patients infected with Enterobacter species. If superinfection occurs, appropriate measures should be taken. Ceftriaxone should be administered with caution to individuals with a history of gastrointestinal disease, particularly colitis. Pseudomembranous colitis has been reported with the use of ceftriaxone, (and with broad- spectrum and other antibiotics). Therefore, it is important to consider its diagnosis in patients administered ceftriaxone who develop diarrhea. Treatment with broad-spectrum antibiotics, including ceftriaxone, 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 colitis may respond to drug discontinuation alone. Moderate to severe cases should be managed with fluid, electrolyte, and protein supplementation as indicated. When the colitis is not relieved by discontinuation of ceftriaxone administration or when it is severe, consideration should be given to the administration of vancomycin or other suitable therapy. Other possible causes of the colitis should also be considered.

Hepatic/Biliary/Pancreatic

There have been reports of sonographic abnormalities in the gallbladder of patients treated with ceftriaxone; some of these patients also had symptoms of gallbladder disease. These abnormalities appear on sonography as an echo without acoustical shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. The chemical nature of the sonographically-detected material has been determined to be predominantly a ceftriaxone-calcium salt. The condition appears to be transient and reversible upon discontinuation of ceftriaxone and institution of conservative management. Therefore, ceftriaxone should be discontinued in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above. The effect of preexisting gallbladder disease is not known. Although transient elevations of BUN and serum creatinine have been observed in clinical studies, there is no other evidence that ceftriaxone, when administered alone, is nephrotoxic.

Renal

Very rare cases of nephrolithiasis (renal precipitation) have been reported, mostly in children older than 3 years and who have been treated with either high daily doses (e.g. $80 mg/kg/day) or total doses exceeding 10 grams and presenting other risk factors (e.g. fluid restrictions, confinement to bed, etc. ). This event may be symptomatic, may lead to renal insufficiency, and appears to be reversible upon discontinuation of ceftriaxone. In severe renal impairment (creatinine clearance of less than 10 mL/min), periodic monitoring of serum ceftriaxone concentrations is recommended. The maximum daily dose should not exceed 2 g. In severe renal impairment associated with clinically significant hepatic impairment, close monitoring of serum ceftriaxone concentrations, at regular intervals, is recommended. If there is evidence of accumulation, dosage should be decreased accordingly.

Sensitivity/Resistance

Before therapy with ceftriaxone is instituted, careful inquiry should be made concerning previous hypersensitivity reactions to ceftriaxone, other cephalosporins, penicillins or other allergens. Ceftriaxone should only be administered with caution to any patient who has demonstrated any form of allergy particularly to drugs. Serious, and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients receiving cephalosporins. The reactions are more likely to occur in persons with a history of sensitivity to multiple allergens. Ceftriaxone should be administered with caution to patients with type I hypersensitivity reaction to penicillin. If an allergic reaction occurs, the administration of ceftriaxone should be discontinued and appropriate therapy instituted.

Special Populations

Pregnant Women:

The safety of ceftriaxone in the treatment of infections during pregnancy has not been established. Ceftriaxone should only be used during pregnancy if the likely benefit outweighs the potential risk to the fetus and/or the mother. Ceftriaxone has been detected in the umbilical cord blood, amniotic fluid and placenta. At parturition, 1 hour after a 2 g IV dose of ceftriaxone, average ceftriaxone concentrations in maternal serum, umbilical cord serum, amniotic fluid, and placenta were 106 +- 40 mcg/mL, 19.5 +- 11.5 mcg/mL, 3.8 +- 3.2 mcg/mL and

20.9 +- 4.4 mcg/g.

Nursing Women:

Ceftriaxone is excreted in human milk at low concentrations, (e.g. the peak concentration of total drug in milk ranged between 0.45 to 0.65 mcg/mL, approximately five hours after the administration of 1 g IV or IM). The clinical significance of this is unknown, therefore, caution should be exercised when ceftriaxone is administered to a nursing mother.

Pediatrics (neonates): The safety of ceftriaxone in neonates (birth to one month of age) has not been established (see HUMAN PHARMACOLOGY). In vitro studies have shown that ceftriaxone can displace bilirubin from serum albumin. Caution should be exercised when considering ceftriaxone treatment for hyperbilirubinemic neonates especially if premature.

Geriatrics: HUMAN PHARMACOLOGY

The elimination of ceftriaxone may be reduced in elderly patients possibly due to impairment of both renal and hepatic function (see

).

Monitoring and Laboratory Tests

Ceftriaxone may interfere with urine glucose determinations utilizing the copper-reduction test (Clinitest), but not utilizing the glucose-oxidase test (Diastix or Tes Tape). In patients treated with ceftriaxone the Coombs' test may rarely become false-positive; and ceftriaxone, like other antibiotics, may result in false-positive tests for galactosemia.

DRUG INTERACTIONS

Drug-Drug Interactions

Interactions between ceftriaxone and other drugs have not been fully evaluated.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Ceftriaxone may be administered intravenously or intramuscularly after reconstitution. Dosage and route of administration should be determined by the severity of infection, susceptibility of the causative organisms, and condition of the patient. The intravenous route is preferable for patients with septicemia or other severe or life-threatening infections.

Adults

Infants and Children (One Month to 12 Years of Age)

With the exception of gonorrhea, which is treated with a single dose, the administration of ceftriaxone should be continued for a minimum of 48 to 72 hours after defervescence or after evidence of bacterial eradication has been obtained, usually 4 to 14 days. In bone and joint infections the average duration of treatment during clinical trials was 6 weeks, with a range of 1 to 13 weeks, depending on the severity of the infection. When treating infections caused by beta-hemolytic streptococcus, it is recommended that therapy be continued for at least 10 days. The average duration of therapy for infections associated with beta-hemolytic streptococcus during clinical trials was 2 weeks, with a range of 1 to 5 weeks, depending on the site and severity of the infection.

Prophylaxis (Vaginal or Abdominal Hysterectomy, Coronary Artery Bypass Surgery, Biliary Tract Surgery)

: For preoperative use as prophylaxis before vaginal or abdominal hysterectomy, coronary artery bypass surgery, or biliary tract surgery in patients at risk of infection, a single dose of 1 g administered 1/2 to 2 hours before surgery is recommended.

Impairment of Renal and/or Hepatic Functionprovided liver function is intactprovided renal function is intact.

: In patients with mild to moderate renal impairment, changes in the dosage regimen are not required,

. In cases of preterminal renal failure (creatinine clearance less than 10 mL/min), periodic monitoring of serum ceftriaxone concentrations is recommended. The daily dosage should be limited to 2 g or less. In patients with liver damage, there is no need for the dosage to be reduced

In cases of coexistent renal and clinically significant hepatic insufficiency, close monitoring of serum ceftriaxone concentrations, at regular intervals, is recommended. If there is evidence of accumulation, dosage should be decreased accordingly.

Administration

Intramuscular

: The reconstituted solution of ceftriaxone should be administered by deep intragluteal injection. It is recommended that not more than 1 g be injected at a single site. Pain on intramuscular injection is usually mild and less frequent when ceftriaxone is administered in sterile 1% Lidocaine solution.

Intravenous (bolus) Injection

: The reconstituted solution should be administered over approximately 5 minutes. If the distal port of an intravenous administration set is used, stop the primary flow, inject the reconstituted ceftriaxone solution and then restart the primary flow. This will prevent mixing with the primary fluid and possible incompatibilities.

Short Intravenous Infusion

: The further diluted intravenous solution should be given over a period of 10 to 15 minutes in infants and children and 20 to 30 minutes in adults.

Note

: Ceftriaxone solution should not be physically mixed with aminoglycoside antibiotics nor administered at the same site because of possible chemical incompatibility. There have

also been literature reports of physical incompatabilities between ceftriaxone and vancomycin, amsacrine, or fluconazole.

Reconstitution Parenteral Products: For Intramuscular Use

Reconstitute ceftriaxone powder with the appropriate diluent:

C

Sterile Water for Injection

C

0.9% Sodium Chloride Injection

C

5% Dextrose Injection

C

Bacteriostatic Water for Injection

C

1% Lidocaine Solution

Reconstitute as follows:

Regular Volume Reconstitution Table (IM)

Shake well until dissolved

Low Volume Reconstitution Table (IM)

Shake well until dissolved.

Note: Solutions prepared for intramuscular use or any solution containing lidocaine or bacteriostatic water for injection should never be administered intravenously.

For Intravenous Use

Reconstitute only with Sterile Water for Injection. Reconstitute as follows:

Reconstitution Table (IV)

Shake well until dissolved. The prepared solution may be further diluted to the desired volume with any of the Solutions for IV Infusion listed below.

Solutions for IV Infusion

C

0.9% Sodium Chloride Injection

C

5% Dextrose Injection

C

Dextrose and Sodium Chloride Injection

Pharmacy Bulk Vial Reconstitution for Preparation of Intravenous Infusion Solutions

The closure of the pharmacy bulk vial shall be penetrated only one time after reconstitution, using a suitable sterile transfer device or dispensing set which allows measured dispensing for the contents.

Reconstitution Table for Bulk Pharmacy Vial

Shake well until dissolved. Withdraw the required amount and dilute with one of the solutions for IV infusion. Any unused solution remaining within a period of 8 hours should be discarded.

OVERDOSAGE

Ultrasonographic shadows suggesting precipitations in the kidneys accompanied by calcium ceftriaxone precipitate in the urine was observed in one patient dosed with ceftriaxone sodium at 10 g/day (2.5 times the maximum recommended dose). No other case of overdosage has been reported to date with ceftriaxone sodium. No specific information on symptoms or treatment is available. Excessive serum concentration of ceftriaxone cannot be reduced by hemodialysis or peritoneal dialysis. Treatment should be symptomatic.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

In vitro studies indicate that the bactericidal action of ceftriaxone results from the inhibition of cell-wall synthesis. In E. coli, ceftriaxone showed a high affinity for penicillin binding proteins (PBP) 1a and 3 and a moderate affinity for 1b and 2. In H. influenzae, the highest affinity was shown for PBP 4 and PBP 5. The binding affinity to PBP 4 was 35-fold that of PBP 3, 10-fold that of PBP 2 and approximately 100-fold that of PBP 1. The morphological changes resulting from the PBP binding include filament formation or cell-wall and septal thickening, and then cell lysis.

STORAGE AND STABILITY

Ceftriaxone sterile powder should be stored between 15 and 30degC and protected from light.

Reconstituted Solutions - Stability and Storage Recommendations

For Intramuscular Use

Solutions should be reconstituted immediately before use. If storage is required, these solutions may be stored under refrigeration and should be used within 48 hours.

For IV Bolus Injection (without further dilution)

Reconstituted solutions should be administered within 24 hours when stored at room temperature and within 72 hours when refrigerated between 2 and 8degC.

For IV Infusion

Further diluted reconstituted solutions should be administered within 24 hours when stored at room temperature.

• Solutions further diluted with 0.9% Sodium Chloride Injection, or with 5% Dextrose Injection should be administered within 72 hours when refrigerated between 2 and 8degC.

• Solutions further diluted with Dextrose and Sodium Chloride Injection as diluent should not be refrigerated. These solutions are not physically compatible when refrigerated.

Extended Use of Intravenous Admixtures

Although intravenous admixtures may often be physically and chemically stable for longer periods, due to microbiological considerations, they are usually recommended for use

within a maximum of 24 hours at room temperature or 72 hours when refrigerated between 2 and 8degC

. Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of intravenous solutions may extend the storage times for ceftriaxone admixtures with 0.9% Sodium Chloride Injection or 5% Dextrose Injection in polyvinylchloride infusion containers, in concentrations of 3-40 mg/mL, to seven days when

refrigerated between 2 and 8degC.

Warning

: As with all parenteral drug products, intravenous admixtures should be visually inspected prior to administration, whenever solution and container permit. Solutions showing any evidence of haziness or cloudiness, particulate matter, precipitation, discolouration or leakage should not be used.

Frozen IV Infusion Solutions

Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of intravenous solutions may freeze and store ceftriaxone IV infusion solutions when prepared in accordance with the following instructions. IV infusion solutions prepared from reconstituted ceftriaxone further diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection, in flexible polyvinylchloride infusion containers, in concentrations up to 40 mg ceftriaxone per mL, may be stored at -10 to -20degC for periods up to three months. The frozen solutions should be thawed in a refrigerator between 2 and 8degC overnight and should subsequently be used within 24 hours when stored at room temperature or seven days when refrigerated between 2 and 8degC. After thawing, check for leaks by squeezing the bag firmly. If leaks are found, discard the container as sterility may be impaired. Do not use unless the solution is clear and seals/outlet ports are intact. Ceftriaxone solutions range from light yellow to amber in colour. Parenteral drug products should be inspected visually for clarity, particulate matter, precipitation, discolouration and leakage prior to administration whenever the solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

Do not refreeze

the previously frozen ceftriaxone IV infusion solutions.

SPECIAL HANDLING INSTRUCTIONS

Incompatibility

Ceftriaxone should not be physically mixed with other antimicrobial agents, vancomycin, amsacrine, or fluconazole. Ceftriaxone should not be added to blood products, protein hydrolysates or amino acids. Ceftriaxone should not be added to solutions containing calcium.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Ceftriaxone for Injection USP contains: sterile powder equivalent to 0.25 g, 1 g, 2 g and 10 g of ceftriaxone, respectively. Ceftriaxone for Injection USP is available in vials of 0.25 g, boxes of 10; vials of 1 g, boxes of 10; vials of 2 g, boxes of 10; and vials of 10 g, boxes of 1.