Rocephin (Ceftriaxone)

ROCEPHIN®

Roche

Ceftriaxone Sodium

Antibiotic

Action And Clinical Pharmacology: 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, ten 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. tag_IndicationsIndications

Indications And Clinical Uses: The treatment of the following infections when caused by susceptible strains of the designated microorganisms:

Lower Respiratory Tract Infections: caused by E. coli, H. influenzae, K. pneumoniae and species, S. aureus, S. pneumoniae and species (excluding enterococci).

Urinary tract Infections (complicated and uncomplicated): caused by E. coli, Klebsiella species, P. mirabilis and P. vulgaris.

Bacterial Septicemia: caused by E. coli, H. influenzae, K. pneumoniae, S. aureus and S. pneumoniae, (excluding enterococci).

Skin and Skin Structure Infections: caused by K. pneumoniae and species, P. mirabilis, S. aureus, S. epidermidis and Streptococcus species (excluding enterococci).

Bone and Joint Infections: caused by S. aureus, S. pneumoniae and Streptococcus species (excluding enterococci).

Intra-Abdominal Infections: caused by E. coli and K. pneumoniae.

Meningitis: caused by H. influenzae, N. meningitidis, and S. pneumoniae. Ceftriaxone should not be used for the treatment of meningitis caused by L. monocytogenes.

Uncomplicated Gonorrhea (cervical/urethral, pharyngeal and rectal): caused by N. gonorrhoeae (penicillinase and nonpenicillinase producing strains).

Susceptibility Testing: Specimens for bacteriologic culture should be obtained prior to therapy in order to identify the causative organisms and to determine their susceptibilities to ceftriaxone. Therapy may be instituted before results of susceptibility testing are known. However, modification of the treatment may be required once these results become available.

Prophylaxis: The preoperative administration of a single 1 g dose of ceftriaxone may reduce the incidence of postoperative infections in patients undergoing vaginal or abdominal hysterectomy, coronary artery bypass surgery, or in patients at risk of infection undergoing biliary tract surgery. If signs of post surgical infection should appear, specimens for culture should be obtained for identification of the causitive organism(s) so that the appropriate therapy may be instituted.

Contra-Indications: Known allergy to ceftriaxone, other cephalosporins or penicillins.

Manufacturers’ Warnings In Clinical States: Before therapy 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.

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 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 C. 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.

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 or as an echo with acoustical shadowing suggesting sludge 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 sonographic findings described above. The effect of pre-existing gallbladder disease is not known.

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., ³80 mg/kg/day) or total doses exceeding 10 g 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.

Precautions: General: Hypoprothrombinemia and alterations in prothrombin time have occurred rarely (see Adverse Effects). 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 treatment.

Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during treatment.

Prolonged treatment 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.

Renal and Hepatic Impairment: 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.

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.

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

Pregnancy: Safety 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 i.v. dose, average ceftriaxone concentrations in maternal serum, umbilical cord serum, amniotic fluid, and placenta were 106±40 g/mL, 19.5±11.5 g/mL, 3.8±3.2 g/mL and 20.9±4.4 g/g.

Lactation: 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 g/mL, approximately 5 hours after the administration of 1 g i.v. or i.m.). The clinical significance of this is unknown, therefore, caution should be exercised.

Neonates: Safety in neonates (birth to 1 month of age) has not been established. 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: The elimination of ceftriaxone may be reduced in elderly patients possibly due to impairment of both renal and hepatic function.

Drug-Laboratory Test Interactions : 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.

Adverse Reactions: During clinical trials in postmarketing experience the following adverse reactions have been observed: Clinical Adverse Experiences: Dermatological: rash (1.3%); exanthema, allergic dermatitis and pruritus (0.1 to 1.0%); urticaria (postmarketing reports). Isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens Johnson syndrome, or Lyell’s syndrome/toxic epidermal necrolysis) have also been reported.

Hematological: anemia (0.1 to 1.0%); auto-immune hemolytic anemia and serum sickness (
Hepatic: jaundice, reports (in asymptomatic and symptomatic patients) of ultrasonographic shadows suggesting precipitations in the gallbladder and reports of gallbladder sludge;
Urogenital: moniliasis and vaginitis (0.1 to 1.0%); oliguria and nephrolithiasis (postmarketing reports).

Gastrointestinal: diarrhea (3.3%); nausea, vomiting, dysgeusia and gastric pain (0.1 to 1.0%); abdominal pain, colitis, flatulence, dyspepsia, pseudomembranous colitis and stomatitis;
Neurological: dizziness and headache (0.1 to 1.0%); ataxia and paresthesia;
Miscellaneous: fever, chills, diaphoresis, malaise, burning tongue, flushing, edema and anaphylactic shock (0.1 to 1.0%); bronchospasm, palpitations and epistaxis;
Local Reactions at Injection Site: pain (9.4%) induration and tenderness (1 to 2%); phlebitic reactions (0.1 to 1.0%); thrombophlebitis;
aPain on i.m. injection is usually mild and less frequent when the drug is administered in sterile 1% lidocaine solution.

Laboratory: Hematologic: eosinophilia (4.6%), thrombocytosis (5.1%), leukopenia (2.0%); neutropenia, lymphopenia, thrombocytopenia, increase or decrease in hematocrit, prolongation of prothrombin time and decrease in hemoglobin (0.1 to 1.0%); leukocytosis, lymphocytosis, monocytosis, basophilia and decrease in prothrombin time;
Hepatic: increase in AST (4.0%) ALT (4.8%) increase in alkaline phosphatase (1.0%); increase in bilirubin (0.1 to 1.0%).

Urinary: increase in BUN (1.1%) increase in creatinine, erythrocyturia, proteinuria and presence of casts in urine (0.1 to 1.0%); glycosuria;
bIncidence is more frequent in patients less than 1 year old.

Incidence is more frequent in patients less than 1 year old and over 50 years old.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Ultrasonographic shadows suggesting precipitations in the kidneys accompanied by calcium ceftriaxone precipitate in the urine was observed in 1 patient dosed at 10 g/day (2.5 times the maximum recommended dose). No other case of overdosage has been reported to date. 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.

Dosage And Administration: Ceftriaxone may be administered i.v. or i.m. 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 i.v. route is preferable for patients with septicemia or other severe or life-threatening infections.

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 the patient defervesces 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 Function: In patients with mild to moderate renal impairment, changes in the dosage regimen are not required, provided liver function is intact. 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 provided renal function is intact. 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.

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

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

Short I.V. Infusion: The further diluted i.v. 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 incompatibilities between ceftriaxone and vancomycin, amsacrine, or fluconazole.

Reconstitution: I.M. Reconstitute the powder with the appropriate diluent: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Bacteriostatic Water for Injection, 1% lidocaine solution. Shake well until dissolved.

Note: Solutions prepared for i.m. use or any solution containing lidocaine or bacteriostatic water for injection should never be administered i.v.

I.V.: Reconstitute only with Sterile Water for Injection. Shake well until dissolved. The prepared solution may be further diluted to the desired volume with any of the following: 0.9% Sodium Chloride Injection, 0.9% Sodium Chloride Injection in ADD-Vantage flexible diluent container, 50 mL and 100 mL, 5% Dextrose Injection, 5% Dextrose Injection in ADD-Vantage flexible diluent container, 50 mL and 100 mL, Dextrose and Sodium Chloride Injection.

ADD-Vantage System Reconstitution for Preparation of I.V. Infusion Solutions: To open diluent container: Peel overwrap from the corner and remove 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: a) 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. Do not access vial with syringe. b) To remove the vial port cover, grasp the tab on the pull ring, pull up to break the 3 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 (180°) 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 sealed, 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 inflate 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.

Preparation for administration (use aseptic technique): Confirm the activation and admixture of vial contents. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired. Close flow control clamp of administration set. Remove cover from outlet port at bottom of container. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. Note: See full directions on administration set carton. Lift the free end of the hanger loop on the bottom of the vial, breaking the 2 tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger. Squeeze and release drip chamber to establish proper fluid level in chamber. Open flow control clamp and clear air from set. Close clamp. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. Regulate rate of administration with flow control clamp.

Warning: Do not use flexible container in series connections.

Stability: The ADD-Vantage system is designed to minimize drug waste by allowing the drug and diluent to be mixed at bedside just prior to administration. However, in those rare instances where the admixed unit cannot be administered within the specified time, it may be stored as specified under Stability and Storage. Reconstituted ADD-Vantage units should not be stored in a frozen state (-20°C).

Pharmacy Bulk Vial: Reconstitution for Preparation of I.V. 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. Shake well until dissolved. Withdraw the required amount and dilute with one of the solutions for I.V. Infusion. Any unused solution remaining within a period of 8 hours should be discarded.

Stability and Storage: I.M.: 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.

I.V. Bolus Injections (without further dilution): Reconstituted solutions should be administered within 24 hours when stored at room temperature and within 72 hours when refrigerated (2 to 8°C).

I.V. 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 stored under refrigeration (2 to 8°C).

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 I.V. Admixtures: Although i.v. 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 (2 to 8°C). Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of i.v. solutions may extend the storage times for Rocephin admixtures with 0.9% Sodium Chloride Injection or 5% Dextrose Injection in glass or polyvinyl chloride infusion containers, in concentrations of 3 to 40 mg/mL, to 7 days when stored under refrigeration (2 to 8°C).

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

Frozen I.V. Infusion Solutions: Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of i.v. solutions may freeze and store ceftriaxone i.v. infusion solutions when prepared in accordance with the following instructions.

I.V. 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 -20°C for periods up to 3 months.

The frozen solutions should be thawed in a refrigerator (2 to 8°C) overnight and should subsequently be used within 24 hours when stored at room temperature or 7 days when stored under refrigeration (2 to 8°C).

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 color. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.

Do not refreeze the previously frozen ceftriaxone i.v. infusion solutions. Do not freeze Rocephin in ADD-Vantage flexible diluent containers.

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.

Availability And Storage: Each vial of sterile white to pale yellow crystalline powder contains: ceftriaxone sodium (expressed as anhydrous free acid), equivalent to ceftriaxone 0.25 g, 1 g or 2 g; and vials for use only with Abbott Laboratories Limited ADD-Vantage 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP in 50 mL and 100 mL containers equivalent to 1 g of ceftriaxone; and as a pharmacy bulk vial containing the equivalent of ceftriaxone 10 g (not for direct administration). The availability of the pharmacy bulk vial is restricted to hospitals with a recognized i.v. admixture program. No added excipients. Sodium: 3.6 mmol (83 mg)/g of ceftriaxone activity. pH 6 to 8. Solutions are yellowish in color.

Sterile powder should be stored at a controlled room temperature (between 15 and 30°C) and protected from light.

ROCEPHIN® Roche Ceftriaxone Sodium Antibiotic

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