Levetrax

Each vial contains: Ceftriaxone (as sodium) USP eq. to Ceftriaxone 1 g.
Ceftriaxone for injection USP is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate.
The chemical formula of ceftriaxone sodium is C₁₈H₁₆N₈Na₂O₇S₃·3.5H₂O. lt has a calculated molecular weight of 661.59.
Ceftriaxone for injection USP 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 for injection solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.
Each vial contains ceftriaxone sodium equivalent to 250 mg, 500 mg, 1 gram or 2 grams of ceftriaxone activity. Ceftriaxone for injection USP contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.

Pharmacology: Antibacterial (Third-Generation Cephalosporin).
The bacterial activity of ceftriaxone results from inhibition of bacterial cell wall synthesis. Ceftriaxone exerts in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ceftriaxone a highly stable to most β-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/Uses): Gram-Positive Aerobes: Staphylococcus aureus (methicillin-sensitive). Staphylococci coagulase-negative, Streptococcus pyogenes (β-hemolytic group A), Staphylococcus agalactiae (β-hemolytic, group B), β-hemolytic Streptococci (non-group A or B), Streptococcus viridans, Streptococcus pneumoniae. Note: Methicillin-resistant Staphylococcus spp. is resistant to cephalosporins, including ceftriaxone. In general, Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are resistant.
Pharmacokinetics: The pharmacokinetics of ceftriaxone are non-linear and all basic pharmacokinetic parameters, except the elimination half-life, are dose dependent if based on total drug concentrations, increasing less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone but not for free (unbound) ceftriaxone.
Absorption: The maximum plasma concentration after a single i.m dose of 1 g is about 81 mg/L and is reached in 2-3 hours after administration. The area under the plasma concentration-time curve after i.m. administration is equivalent to that after i.v. administration of an equivalent dose, indicating 100% bioavailability of intramuscularly administered ceftriaxone. After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/L respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/L respectively. Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose.
Distribution: The volume of distribution of ceftriaxone is 7-12 L. Ceftriaxone has shown excellent tissue and body fluid penetration after a dose of 1-2 g; concentrations well above the minimal inhibitory concentrations of most pathogens responsible for infection are detectable for more than 24 hours in over 60 tissues or body fluids including lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone as well as cerebrospinal, pleural, prostatic and synovial fluids. On intravenous administration, ceftriaxone diffuses rapidly into the interstitial fluid, where bactericidal concentrations against susceptible organisms are maintained for 24 hours (see figure).
Protein Binding: Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95% at plasma concentrations below 100 mg/L. Binding is saturable and the bound portion decreases with rising concentration (up to 85% at a plasma concentration of 300 mg/L). (See figure).

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Penetration into particular tissues: Ceftriaxone penetrates the meninges. Penetration is greatest when the meninges are inflamed. Mean peak ceftriaxone concentrations in CSF in patients with bacterial meningitis are reported to be up to 25% of plasma levels compared to 2% of plasma levels in patients with uninflamed meninges. Peak ceftriaxone concentrations in CSF are reached approximately 4-6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is excreted in the breast milk at low concentrations.
Metabolism: Ceftriaxone is not metabolized systemically; but is converted to inactive metabolites by the gut flora.
Elimination: Total plasma clearance is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of ceftriaxone is excreted unchanged in the urine, while 40-50% is excreted unchanged in the bile. The elimination half-life in adults is about 8 hours.
Pharmacokinetics in Special Populations: Patients with Renal or Hepatic Impairment: ln patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased, (less than two fold), even in patients with severely impaired renal function. The modest increase in half-life in renal impairment is explained by a compensatory increase in non-renal clearance, resulting from a decrease in protein binding and corresponding increase in non-renal clearance of total ceftriaxone. In patients with hepatic impairment, the elimination half-life of ceftriaxone is not increased, due to a compensatory increase in renal clearance. This is also due to an increase in plasma free fraction of ceftriaxone contributing to the observed paradoxical increase in total drug clearance, with an increase in volume of distribution paralleling that of total clearance.
Elderly: In elderly persons aged over 75 years the average elimination half-life is usually two to three times that of young adults.
Children: The half-life of ceftriaxone is prolonged in neonates. From birth to 14 days of age, the levels of free ceftriaxone may be further increased by factors such as reduced glomerular filtration and altered protein binding. During childhood, the half-life is lower than in neonates or adults. The plasma clearance and volume of distribution of total ceftriaxone are greater in neonates, infants and children than in adults.
Toxicology: Preclinical Safety: Teratogenicity: Reproductive studies in animals have shown no evidence of embryotoxicity, fetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal or postnatal development. In primates, no embryotoxicity or teratogenicity has been observed.

Resp & urinary tract, ENT, soft tissue, bone & joint, O & G infections, gonorrhea & other infections including septicemia, meningitis & peritonitis. Prophylaxis against infections in abdominal, pelvic orthopedic, cardiac, pulmonary, esophageal & vascular surgery where there is increased risk from infections.
Injection: Ceftriaxone (as sodium) is a bactericidal cephalosporin antibiotic which is resistant to most beta-lactamases and is active against a wide range of Gram-positive and Gram-negative organisms. It is indicated for the treatment of infections before the infecting organism has been identified or when caused by sensitive bacteria. Susceptibility to Ceftriaxone (as sodium) will vary with geography and time and local susceptibility data should be consulted where available.
Indications include: Respiratory tract infections for example acute and chronic bronchitis, infected bronchiectasis, bacterial pneumonia, lung abscess and post-operative chest infections. Ear, nose and throat infections for example, sinusitis, tonsillitis, pharyngitis and otitis media. Urinary tract infections for example, acute and chronic pyelonephritis, cystitis and asymptomatic bacteriuria. Soft-tissue infections for example, cellulitis, erysipelas and wound infections. Bone and joint infections for example, osteomyelitis and septic arthritis. Obstetric and gynecological infections, pelvic inflammatory diseases. Gonorrhea particularly when penicillin is unsuitable. Other infections including septicemia, meningitis and peritonitis. Prophylaxis against infection in abdominal, pelvic, orthopedic, cardiac, pulmonary, esophageal and vascular surgery where there is increased risk from infection. Usually Ceftriaxone (as sodium) will be effective alone, but when appropriate it may be used in combination with an aminoglycoside antibiotic, or in conjunction with metronidazole (orally or by suppository or injection), especially for prophylaxis in colonic or gynecological surgery. Where appropriate Ceftriaxone (as sodium) is effective when used prior to oral therapy with Ceftriaxone (as sodium) in the treatment of pneumonia and acute exacerbations of chronic bronchitis.

Adults and Children over 12 years: The usual dosage is 1-2 g of Ceftriaxone once daily (every 24 hours). In severe cases or in infections caused by moderately sensitive organisms, the dosage may be raised to 4 g, once daily.
Duration of Therapy: The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of Ceftriaxone should be continued for a minimum of 48-72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.
Combination Therapy: Synergy between Ceftriaxone and aminoglycosides has been demonstrated with many gram-negative bacteria 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. Due to chemical incompatibility between Ceftriaxone (Rocephin) and aminoglycosides, the two drugs must be administered separately at the recommended dosages.
Chemical incompatibility with Ceftriaxone has also been observed with IV administration of amsacrine, vancomycin and fluconazole.
Special Dosage Instructions: Patients with Hepatic impairment: In patients with liver damage, there is no need for the dosage to be reduced provided renal function is not impaired.
Patients with Renal Impairment: In patients with impaired renal function, there is no need to reduce the dosage of Ceftriaxone provided hepatic function is not impaired. Only in cases of preterminal renal failure (creatinine clearance <10 ml/min) should the Ceftriaxone dosage not exceed 2 g daily. Ceftriaxone is not removed by peritoneal- or hemodialysis. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis.
Patients with Severe Renal and Hepatic Impairment: In patients with both severe renal and hepatic dysfunction, clinical monitoring for safety and efficacy is advised.
Elderly: The dosages recommended for adults require no modification in elderly patients, provided there is no severe renal and hepatic impairment.
Children: Neonates, infants and children up to 12 years: The following dosage schedules are recommended for once daily administration: Neonates (up to 14 days): 20-50 mg/kg body weight once daily. The daily dose should not exceed 50 mg/kg. Ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks gestational age + chronological age.

In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic.

Hypersensitivity: Ceftriaxone is contraindicated in patients with known hypersensitivity to ceftriaxone, any of its excipients or to any other cephalosporin. Patients with previous hypersensitivity reactions to penicillin and other beta lactam agents may be at greater risk of hypersensitivity to ceftriaxone.
Premature Neonates: Ceftriaxone is contraindicated in premature neonates up to postmenstrual age of 41 weeks (gestational age + chronological age).
Hyperbilirubinemic newborns: Hyperbilirubinemic newborns should not be treated with ceftriaxone. 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.
Neonates and Calcium Containing IV Solutions: Ceftriaxone is contraindicated in neonates (≤28 days) 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 Ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Ceftriaxone 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 Ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates.

General: Hypersensitivity: As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftriaxone, to other cephalosporins, or to any other type of beta-lactam agent. Caution should be used if ceftriaxone is given to patients with a history of hypersensitivity to other beta-lactam agents.
Hemolytic Anemia: An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including Ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone discontinued until the etiology is determined.
Clostridium difficile Associated Diarrhea (CDAD): Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Ceftriaxone and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Toxin hyperproducing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Superinfections: Superinfections with non-susceptible microorganisms may occur as with other antibacterial agent.
Calcium-Ceftriaxone Precipitates: Calcium ceftriaxone precipitates in the gallbladder have been observed on ultrasound scan in patients receiving ceftriaxone, particularly at doses of 1 g per day and above. The probability of such precipitates appears to be greatest in pediatric patients. Precipitates disappear after discontinuation of ceftriaxone therapy and are rarely symptomatic. In symptomatic cases, conservative nonsurgical management is recommended, and discontinuation of ceftriaxone treatment should be considered by the physician based on an individual benefit-risk assessment. In the available scientific data, there are no reports of intravascular precipitations in patients, other than newborns, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. However, ceftriaxone should not be mixed or administered to any patient simultaneously with calcium-containing solutions, even via different infusion lines (see Contraindications, Interactions, and Post Marketing under Adverse Reactions).
Pancreatitis: Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with Ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of Ceftriaxone-related biliary precipitation cannot be ruled out.

Pregnancy: Ceftriaxone crosses the placental barrier. Safety in human pregnancy has not been established. Reproductive studies in animals have shown no evidence of embryotoxicity, fetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed.
Nursing Mothers: Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone is administered to a nursing woman.

Clinical Trials: The most frequently reported adverse reactions for ceftriaxone are eosinophilia, leucopenia, thrombocytopenia, diarrhea, rash, and hepatic enzymes increased. Data to determine the frequency of ceftriaxone ADRs was derived from clinical trials. The following convention has been used for the classification of frequency: Very common (>1/10); Common (>1/100-<1/100); Uncommon (>1/1000-<1/100); Rare (>1/10000-<1/1000). (See Table 1.)

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Post Marketing: The following adverse reactions have been identified during post-marketing use of ceftriaxone. These reactions are reported from a population of uncertain size, therefore, it is not always possible to reliably estimate their frequency and/or establish a causal relationship to drug exposure.
Systemic Side Effects: Gastrointestinal Complaints: Pancreatitis, stomatitis and glossitis.
Hematological Changes: Isolated cases of agranulocytosis (<500/mm³) have been reported, most of them after 10 days of treatment and following total doses of 20 g or more.
Skin Reactions: Acute generalized exanthematous pustulosis (AGEP) and isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's Syndrome/toxic epidermal necrolysis) have been reported.
Nervous System Disorders: Convulsion.
Infections and Infestations: Superinfection.
Other, Rare Side Effects: Symptomatic precipitation of ceftriaxone calcium salt in the gallbladder, kernicterus, oliguria, and anaphylactic or anaphylactoid reactions.
Interaction with Calcium: Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 grams ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone calcium precipitation. 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 Ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Ceftriaxone 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 Ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates. Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g. ≥80 mg/kg/day or total doses exceeding 10 grams) and who have other risk factors (e.g. dehydration, confinement to bed). This event may be asymptomatic or symptomatic, and may lead to ureteric obstruction and postrenal acute renal failure, but is usually reversible upon discontinuation of Ceftriaxone.
Local Side Effects: In rare cases, phlebitis reactions occurred after i.v. administration. These may be minimized by slow (2-4 minutes) injection.
Investigations: Coombs test false positive, galactosemia test false positive, non-enzymatic methods for glucose determination false positive.

Special Instructions for Use, Handling and Disposal: Disposal of Syringes/Sharps: The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps: Needles and syringes should never be reused. Place all used needles and syringes into a sharps containers (puncture-proof disposable container). Keep this container out of the reach of children. Placing used sharps containers in the household waste should be avoided. Dispose of the full container according to local requirements or as instructed by your healthcare provider.
Disposal of Unused/Expired Medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater, and disposal through household waste should be avoided. Use established 'collection systems' if available in location.
Preparation of Solution: Ceftriaxone for injection, USP shall be reconstituted as per table as follows for lM/IV injection: See Table 2.

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Diluted with reconstituted Levetrax powder with the appropriate diluent (IV=9.6 mL; IM=3.6 mL). Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose. After reconstitution, the solution should be used immediately. Any unused portion must be discarded.

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.

Rx