Xtenda

Each vial contains ceftriaxone (as sodium), USP 1g.
Ceftriaxone is a white to yellowish-orange crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The pH of a 1% aqueous solution is approximately 6.7.
The color of Ceftriaxone solution ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.
Packaging: BP Type 1 Colorless Glass Vial x 1's + LDPE Ampoule x 10 mL (Diluent) [box of 1's].
Chemically, Ceftriaxone sodium USP is a 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3- yl)thio]methyl]-, disodium salt, [6R-[6a,7b(2)]]-, hydrate, (2:7). Its empirical formula is C₁₈H₁₆N₈Na₂O₇S₃3.5H₂O with molecular weight of 662.00.

Pharmacology: Pharmacodynamics: Mechanism of Action: Ceftriaxone like other cephalosporin and penicillins, kills bacteria by inhibiting mucopeptide synthesis and hence interfere with the synthesis of the bacterial cell wall. Ceftriaxone binds with high affinity to penicillin binding proteins in the bacterial cell wall, thus interfering with peptidoglycan synthesis. Peptidoglycan is a hetropolymeric structure that provides a cell with mechanical stability. The final stage in the synthesis of peptidoglycan involves a completion of the cross linking and the terminal glycine residue of the pentaglycine bridge is linked to the fourth residue of the penta-peptide(D-alanine). The transpeptidase enzyme that performs this step is inhibited by cephalosporins and penicillins. As a result the bacterial cell wall is weakened and the cell swell and then ruptures.
Ceftriaxone is bactericidal against a broad spectrum of bacteria at easily achievable plasma concentrations.
Ceftriaxone is a third generation cephalosporin which has a broad spectrum of activity against aerobic Gram Positive and Gram Negative organisms. Sensitive organisms are generally killed by a concentration of Ceftriaxone of 8 mg/L or less white resistant organisms can survive concentrations of 64 mg/L.
Pharmacokinetics: Ceftriaxone is administered as intravenous and intramuscular injection. The mean elimination half-life in healthy adults is about 6-9 hours and is thus much longer than any other Cephalosporins or cephamycins. The half life does not alter with changes in the route of administration and was only slightly to moderately affected in patients with decreased renal function and relatively normal non renal elimination, but was increased in neonates and in patients over 75 years of age.
Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post dosing. Multiple IV or IM doses ranging from 0.5 to 2 gm at 12- to 24- hour intervals resulted in 15% to 36% accumulation of ceftriaxone above single dose values.
33% to 67% of a ceftriaxone was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 gm IV dose, average concentrations of ceftriaxone, determined from 1 to 3 hours after dosing, were 581 mcg/mL in the gall bladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/gm in the gall bladder wall and 62.1 mcg/mL in the concurrent plasma.
The drug is highly protein bound (95%), demonstrating distinctly nonlinear concentration-dependent binding, with 5% free drug at levels <70 mg/L with this fraction increased to 16% at 300 mg/L, 26.5% at 500 mg/L and 42% at 600 mg/L. This however has little clinical reference.
30 minutes after infusions of 0.5, 1.0 and 2.0 gm, mean peak plasma concentrations were 82,151 and 257 mg/L respectively. 2 hours after intramuscular injection, mean peak plasma concentrations were around half of those after intravenous administration of an equivalent dose.

Lower respiratory tract infections; acute bacterial otitis media; skin and skin structure infections; urinary tract infections; uncomplicated gonorrhea; pelvic inflammatory disease; bacterial septicemia; bone and joint infections; intra-abdominal infections; meningitis; surgical prophylaxis.

Ceftriaxone is administered as a sodium salt by intravenous infusion or as deep intramuscular injections in the treatment of various susceptible infections that include chancroid, gastro-enteritis (invasive salmonellosis, shigellosis) gonorrhea, lyme disease, meningitis, septicaemia, surgical infection (prophylaxis), syphilis, typhoid fever and Whipple's disease among others.
Adults: The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. The total daily dose should not exceed 4 grams. For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously ½ to 2 hours before surgery is recommended.
A single intramuscular dose of 250 mg is recommended for the treatment of gonorrhea in adults. For surgical infection prophylaxis in adults, a single dose of 1 gm is administered 0.5 to 2 hours prior to surgery. A reduction in dosage may be necessary in patients with severe renal failure and in both with renal and hepatic function; plasma concentrations should be monitored in such patients.
Pediatric Patients: For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily doses should not exceed 2 grams. For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended. For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.
In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.
Generally, Ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.
In the elderly the dosage does not require modification provided that renal and hepatic functions are satisfactory. If creatinine clearance is less than 10 mL/min, the daily dose must not exceed 2 gm. In patients with liver damage dose reductions is not required if renal functions are required. In severe renal impairment with hepatic insufficiency the plasma concentration of ceftriaxone should be measured regularly it is in excess of the MIC of the causative organism, and the dosage of ceftriaxone adjusted to prevent accumulation.
Directions for Use: Intramuscular Administration: Reconstitute Ceftriaxone powder with the appropriate diluent (Sterile water for injection) (See Table 1.)

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After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to the amount of diluent indicated as follows. If required, more dilute solutions could be utilized.
A 350 mg/mL concentration is not recommended for the 250 mg vial since it may not be possible to withdraw the entire contents. As with all intramuscular preparations, Ceftriaxone should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel.
Intravenous Administration: Ceftriaxone should be administered intravenously by infusion over a period of 30 minutes. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials with an appropriate IV diluents. (See Table 2.)

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After reconstitution, each 1 mL solution contains approximately 100 mg equivalent of ceftriaxone. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.
Compatibility of Reconstituted Solution: Ceftriaxone sterile powder should be stored at temperatures not exceeding 30°C and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluents used.
Ceftriaxone solutions remain stable (loss of potency less than 10%) for the following time periods: (See Table 3.)

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Frozen solutions should be thawed at room temperature before use. After thawing, unused portions should be discarded. Do not refreeze.

Report to the physician an overdose. No antidote reported.

Ceftriaxone is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.
Carcinogenicity: Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with ceftriaxone in animals have not been performed.
Mutagenicity: Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.
Use in children: Safety and effectiveness of ceftriaxone in neonates, infants and children have been established for the dosages described in the dosage and administration section. In vitro studies have shown that ceftriaxone like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone should not be administered to hyperbilirubinemic neonates, especially prematures.
Use in elderly: Due to high protein binding the dosage should be adjusted based upon the creatinine clearance.
Use in pregnancy: 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.
Reproduction: Ceftriaxone produced no impairment of fertility when given intravenously to rats at a daily dose up to 586 mg/kg per day, approximately 20 times the recommended clinical dose of 2 gm/day.
Use in lactation: Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone is administered to a nursing woman.

Before therapy with Ceftriaxone 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 the use of subcutaneous epinephrine and other emergency measures.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftriaxone and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents 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.
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis.

General: Ceftriaxone is excreted via both biliary and renal excretion. Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of Ceftriaxone are administered but concentrations of drug in the serum should be monitored periodically. If evidence of accumulation exists, dosage should be decreased accordingly.
Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and significant renal disease, Ceftriaxone dosage should not exceed 2 gm daily without close monitoring of serum concentrations.
Prolonged use of Ceftriaxone result in an overgrowth of non-susceptible organism. Careful observation of the patient is essential. If super infection occurs during therapy appropriate measures should be taken.
Ceftriaxone should be prescribed with caution in individuals with a history of gastrointestinal disease, especially colitis.
Carcinogenicity: Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with ceftriaxone in animals have not been performed.
Mutagenicity: Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.
Use in pregnancy: 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.
Reproduction: Ceftriaxone produced no impairment of fertility when given intravenously to rats at a daily dose up to 586 mg/kg per day, approximately 20 times the recommended clinical dose of 2 gm/day.
Use in lactation: Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone is administered to a nursing woman.
Use in children: Safety and effectiveness of ceftriaxone in neonates, infants and children have been established for the dosages described in the dosage and administration section. In vitro studies have shown that ceftriaxone like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone should not be administered to hyperbilirubinemic neonates, especially prematures.
Use in elderly: Due to high protein binding the dosage should be adjusted based upon the creatinine clearance.
Effects on ability to drive and use machines: Since this drug does not cause somnolence it is not contraindicated in drivers or people who use machines.

Pregnancy: 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.
Reproduction: Ceftriaxone produced no impairment of fertility when given intravenously to rats at a daily dose up to 586 mg/kg per day, approximately 20 times the recommended clinical dose of 2 gm/day.
Lactation: Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone is administered to a nursing woman.

Ceftriaxone is generally well tolerated. However the following adverse reactions, which were considered to be related to Ceftriaxone therapy or of uncertain etiology, were observed: Local Reactions: Pain, induration and tenderness. Phlebitis was reported after I.V. administration. The incidence of injection site reaction after I.M. administration was reported.
Hypersensitivity: Rash, less frequently reported were pruritus, fever or chills.
Hematologic: Thrombocytosis and leukopenia, Less frequently reported were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.
Gastrointestinal: Diarrhea, less frequently reported were nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment.
Hepatic: Elevations of SGOT or SGPT. Less frequently reported were elevations of alkaline phosphatase and bilirubin.
Renal: Elevations of the BUN. Less frequently reported were elevations of creatinine and the presence of casts in the urine.
Central Nervous System: Headache or dizziness were reported occasionally.
Genitourinary: Moniliasis or vaginitis were reported occasionally.
Miscellaneous: Diaphoresis and flushing were reported occasionally.
Other rarely observed reactions include leukocytosis, lymphocytosis, monocytosis, basophilia, a decrease in the prothrombin time, jaundice, gall bladder sludge, glycosuria, hematuria, anaphylactic shock, palpitations and epistaxis.

Probenecid: Concomitant administration of oral Probenecid (500 mg daily) does not appear to effect the pharmacokinetics of ceftriaxone, presumably because ceftriaxone is excreted principally by glomerular filtration and non renal mechanism. However higher dosage of oral probenecid (1 or 2 gm daily) administered concomitantly reported may partially block biliary secretion of ceftriaxone as well as displace the drug from plasma proteins. As a result, serum clearance of ceftriaxone may be decreased by about 20%.
Aminoglycosides: In vitro studies indicate that the antibacterial activity of ceftriaxone and aminoglycosides (amikacin, gentamicin, tobramycin) may be additive or synergistic against some strains of Enterobacteriaceae and some strains of Pseudomonas aeruginosa. Although the clinical importance has not been determined to date.
Antagonism has also occurred rarely in vitro when ceftriaxone was used in combination with an aminoglycoside. Organisms with high level resistance to both the aminoglycoside and the beta-lactam antibiotic alone are unlikely to be synergistically inhibited by concomitant use of drugs.
Quinolones: Although the clinical importance is unclear, results of an in vitro study indicate that the combination of ceftriaxone and trovafloxacin is synergistic against both penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae, including some strains that also were resistant to ceftriaxone alone. There was no evidence of antagonism with the combination of ceftriaxone and trovafloxacin.
Alcohol: A disulfiram like reaction reportedly occurred in one patient who ingested alcohol while receiving ceftriaxone; however this effect generally has been reported only with beta-lactam antibiotics that contain an N-methylthiotetrazole (NMTT) side chain (e.g. cefamandole, cefoperazone, cefotetan).
Laboratory Value Alterations: Although transient elevations of BUN and serum creatinine have been observed, at the recommended dosages the nephrotoxic potential of Ceftriaxone is similar to that of other cephalosporins.
Alternations in prothrombin times have occurred rarely in patients treated with Ceftriaxone. Patients with impaired vitamin K synthesis or low vitamin K stores (eg. Chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during Ceftriaxone treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.
There have been reports of sonographic abnormalities in the gall bladder of patients treated with Ceftriaxone; some of these patients also had symptoms of gall bladder disease. These abnormalities appear on sonography as an echo without acoustical shadowing suggesting sluge 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 previously.

Store at temperatures not exceeding 30°C.

Cephalosporins

J01DD04 - ceftriaxone ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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