Sunday, February 12, 2017


Ceftriaxone for Injection USP
Composition: Trlaxone 500 mg I.M.: The vial contains: Sterile Ceftriaxone Sodium USP equivalent to 500 mg Ceftriaxone. The ampoule contains 5 ml 011% w/v Lidocaine Hydrochloride Injection USP. Triaxone 1 g I.M.: The vial contains: Sterile Ceftriaxone Sodium USP equivalent to 1 g Ceftriaxone. The ampoule contains 5 ml of 1% w/v Lidocaine Hydrochloride injection USP. Triaxone 1 g I.V.: The vial contains: Sterile Ceftriaxone Sodium USP equivalent to 1 g Ceftriaxone. The ampoule contains 10 ml Sterile Water for Injection USP.
Properties, Effects, Microbiology: The bactericidal activity of Ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone exerts in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ceftriaxone is highly stable to most B-lactamases, both penicillinases and cephalosporinases, of gram-positive and gram-negative bacteria. Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections (see Indications): Gram-positive aerobes: Staphylococcus aureus (including penicillinase-producing strains) Staphylococcus epiderrnidis Streptococcus pneumoniae Streptococcus group A (Str. Pyogenes) Streptococcus group B (Str. Agalactiae) Streptococcus viridans Streptococcus bovis Note: Methicillin-resistant Staphylbeoccus spp. are resistant to cephalosporins, including Ceftriaxone. Most strains of Enterococci (e.g. Streptococcus faecalis) are resistant. Gram-negative aerobes: Aeromonas spp. Alcaligenes spp. Branhamella catarrhalis (13-lactamase negative and positive) Citrobacter spp. Enterobacter spp. (some strains are resistant) Escherichia coil Haemophilus ducreyi Haemophilus influenzae (including penicillinase-producing strains) Haemophilus parainfluenzae Klebsiella spp. (including KI. pneumoniae) Moraxella spp. Morganella morganii Neisseria gonorrhoeae (including penicillinase-producing strains) Neisseria meningitidis Plesiomonas shigelloides Proteus mirabilis Proteus vulgaris Providencia spp. Pseudomonas aeruginosa (some strains are resistant) Salmonella spp. (including S. typhi) Serratia spp. (including S. marcescens) Shigella spp. Vibrio spp. (including V. cholerae) Yersinia spp. (including Y. enterocolifica) Note: Many strains of the above microorganisms that are multiply resistant to other antibiotics, e.g. penicillins, older cephalosporins and aminoglycosides, are susceptible to Ceftriaxone. Treponema pallidum is sensitive in vitro and in animal experiments. Clinical investigations indicate that primary and secondary syphilis respond well to Ceftriaxone therapy. Anaerobic organisms: Bacteroides spp. (including some strains of B. fragilis) Clostridium spp. (except Cl. difficile) Fusobacterium spp. (except F. mortiterum and F. varium) Peptococcus spp. Peptostreptococcus spp. Note: Many strains of 8-lactamase-producing Bacteroides spp. (notably B. fragilis) are resistant. Susceptibility to Ceftriaxone can be determined by the disk diffusion test or by the agar or broth dilution test using standardized techniques for susceptibility testing such as those recommended by the National Committee for Clinical • Laboratory Standards (NCCLS). The (NCCLS) issued the following interpretative breakpoints for Ceftriaxone:
Susceptible 5 8 Moderately • susceptible 16-32 Resistant o 84 Dilution test, inhibitory concentrations in mg/1 Diffusion test (disk with 30 pg Ceftriaxone), inhibition zone diameter in mm o 21 14-20 5 13
Microorganisms should be tested with the Ceftriaxone disk Once it has been shown by in vitro tests to be active against certain strains resistant to cephalosporin class disks. Where (NCCLS) recommendations are no in daily use, altemative, well standardized, susceptibility interpretative guidelines such as those issued by DIN, ICS and others may be substituted. Pharmacokinetics: Ceftriaxone is characterized by an unusually long elimination half-life of approximately eight hours in healthy adults. The area under the plasma concentration time curves after 1.V: and I.M. administration is identical. This means Mat the bloavailatAfity of Ceftriaxone administered -1.1ok is 100%. On intravenous administration, Ceftriaxone diffuses rapidly into the interstitial fluid, where bactericidal concentrations against susceptible organisms are maintained for 24 hours. Elimination: The elimination half-life in healthy adults is about eight hours. In infants aged less than eight days and in persons over 75 years of age the average elimination half-life is about twice as long. In adults, 50-60% of Ceftriaxone is excreted unchanged by the kidneys. while 40-50% is excreted unchanged in the bile. The intestinal flora transforms Ceftriaxone into inactive metabolites. In neonates, renal elimination accounts for about 70% of the dose. In patients with renal impairment or hepatic dysfunction, the pharmacokinetics of Ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of Ceftriaxone is increased; if liver function alone is impaired, renal elimination Is increased. — Protein binding: Ceftriaxone is reversibly bound to albumin, and the binding decreases with the increase in the concentration, e.g. from 95% binding at plasma concentrations of <100 mg/I to 85% binding at 300 mgA. Owing to the lower albumin content, the proportion of free Ceftriaxone in interstitial fluid is correspondingly higher than in plasma. Penetration into the cerebrospinal fluid: Ceftriaxone penetrates the inflamed meninges of infants and children: The average extent of diffusion in the cerebrospinal fluid in bacterial meningitis is 17% of the plasma concentration, i.e. approximately four times that in aseptic meningitis. Ceftriaxone concentrations of >1.4 mg/ have been found in the CSF 24 hours after I.V. injection of Triaxone in doses of 50-100 mg/kg. In adult meningitis patients, administration of 50 mg/kg leads within 2-24 hours to CSF concentrations several times higher than the minimum inhibitory concentrations required for the most common causative organisms of meningitis.
Combination therapy: Synergy between Triaxone and aminoglycosides has been demonstrated with many gram-negative bacilli under experimental conditions. Although enhanced activity of such combinations is not always predictable, it should be considered in severe, life-threatening infections due to microorganisms such as Pseudomonas aeruginosa. Because of physical incompatibility the two drugs must be administered separately at the recommended dosages.
Special dosage instructions: Meningitis: In bacterial meningitis in infants and children, treatment begins with doses of 100 mg/kg (not to exceed 4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dosage can be reduced accordingly. The best results have been found with the following duration of therapy:
Neisseria meningitidis 4 days Streptococcus pneumoniae 7 days Haemophilus influenzae 6 days Susceptible Enterobacteriaceae 10-14 days
Gonorrhea: for the treatment of gonorrhea (penicillinase-producing and nonpenicillinase-producing strains), a single I.M. dose of 250 mg Triaxone is recommended. Perioperative prophylaxis: To prevent postoperative infections in contaminated or potentially contaminated surgery, the recommended approach - depending on the risk of infection - is a single dose of 1-2 g Triaxone administered 30-90 minutes prior to surgery. In colorectal surgery, concurrent (but separate) administration of Triaxone and a 5-nitroimidazole, e.g. ornidazole, has proven effective. Impaired renal and hepatic function: In patients with impaired renal function, there is no need to reduce the dosage of Trlaxone provided hepatic function is intact. Only in cases of preterminal renal failure (creatinine clearance <10 ml/min) should the Triaxone dosage not exceed 2 g daily. In patients with liver damage, there is no need for the dosage to be reduced provided renal function is intact. • In cases of concomitant severe renal and hepatic dysfunction, the plasma concentrations of Ceftriaxone should be determined at regular intervals. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.
Reconstitution: For Triaxone 500 mg I.M. injection: Dissolve the contents of one vial using 2 ml from the Lidocaine Hydrochloride ampoule. For Trlaxone 1 g I.M. Injection: Dissolve the contents of one vial using 3.5 ml from the Lidocaine Hydrochloride ampoule. For Triaxone 1 g I.V. Injection: Dissolve the contents of one vial using 10 ml of Sterile Water for Injection. The lidocaine solution must never be administered intravenously. The reconstituted solution colour is pale yellow to amber depending on concentration and storage duration. For I.V. infusion, use a calcium free infusion solution such as: Sodium chloride 0.9%, sodium chloride 0.45% + dextrose 2.5%, dextrose 5%, dextrose 10%, levulose 5%, dextran 6% in dextrose, sterile water for injections. Triaxone solutions should not be mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, owing to possible incompatibility. Triaxone intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods:
Sto age Diluent Concentration Room Temp(25°C) Refrigerated (4°C) mg/ml Sterile Water for 100 2 days 10 days Injection 250, 350 24 hours 3 days 0.9% Sodium 100 2 days 10 days Chloride Solution 250, 350 24 hours 3 days 5% Dextrose 100 2 days 10 days Solution 250, 350 24 hours 3 days Bacteriostatic 100 24 hours 10 days Water + 0.9% 250, 350 24 hours 3 days Benzyl Alcohol 1% Lidocaine Solution 100 24 hours 10 days (without epinephrine) 250, 350 24 hours 3 days
Triaxone intravenous solutiona, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss o potency less than 10%) for the following time periods stored in glass or PVC containers:
Storage Diluent Room Temp. (25°C) Refrigerated (4°C) Sterile Water 2 days 10 days 0.9% Sodium Chloride Solution 2 days 10 days 5% Dextrose Solution 2 days 10 days 10% Dextrose Solution 2 days 10 days 5% Dextrose + 0.9% Sodium Chloride Solution' 2 days Incompatible 5% Dextrose + 0.45% Sodium Chloride Solution 2 days Incompatible
Data available for 10 to 40 mg/m1 concentrations in this diluent in PVC containers only. Restrictions on use: Triaxone is contraindicated in patients with known allergy to the cephalosponn class of antibiotics. Neonates (a 28 days) Hyperbilirubinaemic neonates. especially prerrnatures. should not be treated with Triaxone. In vitro studies have shown that Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a possible risk of bilirubin encephalopathy in these patients. Triaxone Is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of Ceftriaxone-calcium. A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Trlaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Triaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom Trlaxone and calcium-containing fluids were administered at different time points via different intravenous fines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates.
Precautions: As with other cephalosporins, anaphylactic shock cannot be ruled out even it a thorough patient history is taken. Anaphylactic shock requires immediate countermeasures such as intravenous epinephrine followed by a glucocorticoid. In rare cases, shadows suggesting sludge have been detected by sonograms of the gallbladder. This condition was reversible on discontinuation or completion of Trlaxone therapy. Even if such findings are associated with pain, conservative, nonsurgical management is recommended. In vitro studies have shown that Ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Caution should be exercised when considering Trlaxone for hyperbilirubinemic neonates, especially prematures.

Indications: Infections caused by pathogens sensitive to Triaxone, e.g: - Sepsis. - Meningitis. - Abdominal infections (peritonitis, infections of the biliary and gastrointestinal tracts). - Infections of the bones, joints, soft tissue, skin and of wounds. - Infections in patients with impaired defence mechanisms. - Renal and urinary tract infections. - Respiratory tract infections, particularly pneumonia, and ear, nose and throat infections. - Genital infections, including gonorrhea. Perioperative prophylaxis of infections Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic Effects: In rats, in the Segment I (fertility and general reproduction) and Segment III (perinatal and postnatal) studies. with intravenously administered Ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less. Nursing Mothers: Low concentrations of Ceftriaxone are excreted in human milk. Caution should be exercised when Trlaxone is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Trlaxone in neonates, infants and pediatric patients have been established for the dosages described in the STANDARD DOSAGE section. In vitro studies have shown that Ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Triaxone should not be administered to hyperbilirubinemic neonates, especially prematures (see RESTRICTIONS ON USE) Geriatric Use: Of the total number of subjects in clinical studies of Ceftriaxone, 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patents, but greater sensitivity of some or individuals cannot be ruled out. The pharmacokinetics of Ceftriaxone were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with Ceftriaxone dosages up to 2 grams per day. Standard dosage: Adults and children over twelve years: The usual dosage is 1-2 g of Triaxone administered once daily (every 24 hours). In severe cases or in infections caused by moderately sensitive organisms, the dosage may be raised to 4 g, administered once daily. Neonates, infants and children up to twelve years: The following dosage schedules are recommended for once daily administration.* Neonates (up to two weeks): A daily dose of 20-50 mg/kg bodyweight, not to exceed 50 mg/kg, on account of the immaturity of the infant's enzyme systems. It is not necessary to differentiate between premature and infants born at term. Infants and children (three weeks to twelve years): A daily dose of 20-80 mg/kg. For children with bodyweights of 50 kg or more, the usual adult dosage should be used. Intravenous doses of 50 mg or more per kg should be given by infusion over at least 30 minutes. Elderly patients: The dosages recommended for adults require no modification in the case of geriatric patients. Duration of therapy: The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of Triaxone should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.
During prolonged treatment the blood picture should be checked at regular intervals. Ceftriaxone must not be mixed or administered simultaneously with calcium containing solution or products, even via separate infusion lines furthermore, calcium containing solution product, must not be administered within 48 hours of the last Ceftriaxone administration. Undesirable effects: Trlaxone is generally well tolerated. During the use of Triaxone, the following side effects, which were reversible either spontaneously or after withdrawal of the drug, have been observed: Systemic side effects: Gastrointestinal complaints (about 2% of cases): Loose stools or diarrhea, nausea, vomiting, stomatitis and glossitis. Hematological changes (about 2%): Eosinophilia, leukopenia, granulocytope-nia, hemolytic anemia, thrombocylopenia. Skin reactions (about 1%): Exanthema, allergic dermatitis, pruritus, urticaria, edema, erythema multiforme. Other rare, side-effects: Headache and dizziness, increase in liver enzymes, gallbladder sludge, olicina, increase in serum creatmine, mycosis of the genital tract, fever, shivering and anaphylactic or anaphylactoid reactions. Pseudomembranous enterocolitis and coagulation disorders have been reported as very rare side effects. Local side effects: In rare cases, phlebitic reactions occurred after I.V. administration. These may be prevented by slow (two to four minutes) injection of the substance. Intramuscular injection without lidocaine solution is painful. Consult your Pharmacist or Physician if any side effect is observed. Interactions: No impairment of renal function has so far been observed after concurrent administration of large doses of Trlaxone and potent diuretics (e.g. furosemide). There is no evidence that Triaxone increases renal toxicity of aminoglycosides. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Triaxone. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of Triaxone is not altered by probenecid. Pharmaceutical Precautions: Keep at room temperature (15-30T). Keep the vial in the carton until content is consumed. Do not use beyond the expiry date or if the product shows any sign of deterioration.
Presentations: Trlaxone 500 mg I.M.: A carton containing one vial and one 5 ml ampoule of Lidocaine Hydrochloride solution. Trlaxone 1 g I.M.: A carton containing one vial and one 5 ml ampoule of Lidocaine Hydrochloride solution. Trlaxone 1 g I.V.: A carton containing one vial and one 10 ml ampoule of Sterile Water for Injection.
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