Ceftriaxone-ACOS, 1 g

Pharmacotherapeutic group

Cephalosporin antibiotic

ATX code: J01DD04

Pharmacodynamics

Ceftriaxone is a broad-spectrum III generation cephalosporin antibiotic for parenteral administration. Bactericidal activity is due to inhibition of cell wall synthesis. In vitro it has a broad spectrum of action against Gram-negative and Gram-positive microorganisms. It is characterized by high resistance to action of most beta-lactamases (both penicillinases and cephalosporinases) produced by Gram-positive and Gram-negative bacteria.

Ceftriaxone is generally active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (methicillin-sensitive), coagulase-negative staphylococci, Streptococcus pyogenes (beta-hemolytic, group A), Streptococcus agalactiae (beta-hemolytic, group B), beta-hemolytic streptococci (neither group A nor B), Streptococcus viridans, Streptococcus pneumoniae.

Note: Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are also generally resistant.

Gram-negative aerobes: Acinetobacter lwoffii, Acinetobacter anitratus (mainly A. baumannii)*; Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, alkaligenes-like bacteria, Borrelia burgdorferi, Capnocytophaga spp, Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Enterobacter aerogenes*, Enterobacter cloacae*, Enterobacter spp. (other)*, Escherichia coli, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarrhalis (previously called Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris*, Pseudomonas fluorescens*, Pseudomonas spp. (other), Providencia rettgeri*, Providencia spp. (other), Salmonella typhi, Salmonella spp. (nontyphoid), Serratia spp. (other)*, Serratia marcescens*, Shigella spp, Vibrio spp., Yersinia enterocolitica, Yersinia spp. (other).

* – Some isolates of these species are resistant to ceftriaxone, mainly due to the formation of beta-lactamases encoded by chromosomes.

** – Some isolates of these species are resistant due to the formation of a variety of plasmid-mediated beta-lactamases.

Note: Many strains of the above microorganisms that are multiresistant to other antibacterial drugs, such as aminopenicillins and ureidopenicillins, first and second generation cephalosporins, aminoglycosides, are sensitive to ceftriaxone. Treponema pallidum is sensitive to ceftriaxone in vitro and in animal experiments. Clinical studies have shown that ceftriaxone has good efficacy against primary and secondary syphilis. With very few exceptions, clinical isolates of Pseudomonas aeruginosa are resistant to ceftriaxone.

Anaerobes: Bacteroides spp. (biliary sensitive)*, Clostridium spp. (except Clostridium difficile), Fusobacterium nucleatum, Fusobacterium spp. (other), Gaffkya anaerobica (previously called Peptococcus), Peptostreptococcus spp.

* – Some isolates of these species are resistant to ceftriaxone because of betalactamase formation‑.

Note: Many strains of beta-lactamase-producing Bacteroides spp. (particularly B. fragilis) are resistant. Clostridium difficile is also resistant.

Ceftriaxone discs should be taken for determination because in vitro studies have shown that ceftriaxone is active against individual strains that show resistance when discs designed for the entire group of cephalosporins are used.

In lieu of ICLS standards, other well-standardized standards such as those of the German Institute for Standardization DIN (Deutsches Institut fur Normung) and the International Collaborative Study (ICS) recommendations ‑can be used to adequately interpret the sus‑ceptibility status of ‑microorganisms.

Pharmacokinetics

The pharmacokinetics of ceftriaxone is nonlinear. All major pharmacokinetic parameters based on total drug concentrations, with the exception of the elimination half-life, are dose-dependent and increase in less than proportional proportion to its increase. Non-linearity is typical for pharmacokinetic parameters that depend on the total concentration of ceftriaxone in blood plasma (not only free ceftriaxone), and is explained by saturation of the drug binding to blood plasma proteins. After intravenous infusion of 500 mg, 1 g, and 2 g of ceftriaxone, plasma concentrations of the drug were approximately 80, 150, and 250 mg/L, respectively.

Distribution

The volume of distribution of ceftriaxone is 7-12 liters. After administration in a dose of 1-2 g ceftriaxone penetrates well into tissues and body fluids. For more than 24 hours, its concentrations far exceed the minimum suppressive concentrations for most infectious agents in more than 60 tissues and fluids (including the lungs, heart, biliary tract, liver, tonsils, middle ear and nasal mucosa, bones, as well as cerebrospinal, pleural and synovial fluid and prostate secretion). After intravenous administration ceftriaxone quickly penetrates into the cerebrospinal fluid, where bactericidal concentrations against sensitive microorganisms persist for 24 hours.

Protein binding

Ceftriaxone binds reversibly to albumin. The degree of binding is approximately 95% when values of ceftriaxone concentration in blood plasma are less than 100 mg/l. The proportion of ceftriaxone bound to plasma protein decreases with increasing concentration, as the binding is saturable and is about 85% at values of 300 mg/l.

Perfusion to selected tissues

Ceftriaxone penetrates through the cerebral membranes, but to the greatest extent in their inflammation. The average maximum concentration of ceftriaxone in the cerebrospinal fluid reaches 25% of the plasma ceftriaxone concentration in patients with bacterial meningitis, and only 2% of the plasma ceftriaxone concentration in patients with non-inflamed cerebral membranes. The maximum concentration of ceftriaxone in the cerebrospinal fluid is reached 4-6 hours after its intravenous administration. Ceftriaxone passes through the placental barrier and passes in low concentrations into breast milk.

Metabolism

Ceftriaxone does not undergo systemic metabolism but is converted into inactive metabolites by the intestinal microflora.

The total plasma clearance of ceftriaxone is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of ceftriaxone is excreted unchanged by the kidneys, and 40-50% – unchanged by the intestine. The half-life of ceftriaxone in adults is about 8 hours.

Pharmacokinetics in special clinical cases

In newborns, infants and children younger than 12 years

In newborn children the half-life of ceftriaxone is longer compared to other age groups. During the first 14 days of life, the plasma concentration of free ceftriaxone may be further increased due to low glomerular filtration and the features of the drug binding to blood plasma proteins. In pediatric patients the half-life is shorter than in newborns and adults.

The values of plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants and children younger than 12 years compared to those in adults.

Hepatic or renal impairment

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone do not change significantly, with only a slight increase in half-life (less than 2-fold) even in patients with severe renal impairment. Slight increase of ceftriaxone half-life in renal failure can be explained by compensatory increase of nonrenal clearance as a result of decrease of plasma protein binding degree and corresponding increase of nonrenal clearance of total ceftriaxone.

In patients with hepatic insufficiency the half-life is not increased. In these patients there is a compensatory increase in renal clearance. This is also due to an increase in the plasma concentration of free ceftriaxone, which contributes to a paradoxical increase in total drug clearance against an increase in the volume of distribution.

Patients of advanced age

In patients over 75 years of age, the half-life is, on average, two to three times longer than in adult patients.

Indications

Infections caused by pathogens sensitive to ceftriaxone: Sepsis; meningitis; disseminated Lyme disease (stage II and III disease); abdominal organ infections (peritonitis, biliary tract and gastrointestinal tract infections); bone, joint, soft tissue, skin, and wound infections; infections in immunocompromised patients; kidney and urinary tract infections; respiratory infections, especially pneumonia, and ENT organ infections; genital infections.

Perioperative prophylaxis of infections.

Active ingredient

Composition

One bottle of powder for preparation of solution for intravenous and intramuscular administration contains:

The active substance: ceftriaxone sodium – 1.071 g (in terms of ceftriaxone – 1 g).

How to take, the dosage

Intravenously, infusion.

Do not use calcium-containing solutions to dilute the drug!

If a single dose of more than 1 g is necessary and for the treatment of severe infections, intravenous administration is preferable. When administering intravenous doses of 50 mg/kg and above, an intravenous infusion should be used for at least 30 minutes.

Adults and children over 12 years of age with body weight ≥50 kg: initial daily dose depending on the type and severity of infection is 1-2 g once a day (every 24 hours). In severe cases or in infections whose pathogens have only moderate sensitivity to ceftriaxone the total daily dose may be increased to 4 g.

The duration of treatment depends on the course of the disease. As always with antibiotic therapy, treatment with ceftriaxone should continue for at least 48-72 hours after normalization of temperature and confirmation of eradication of the pathogen. The course of treatment is 4-14 days; for complicated infections a longer administration may be necessary. The course of treatment of infections caused by Streptococcus pyogenes should be at least 10 days.

Dosage in special cases

Patients with impaired hepatic function: There is no need to reduce the dose if there is no renal impairment.

Patients with impaired renal function: there is no need to reduce the dose provided there is no impairment of liver function. In chronic renal failure (creatinine clearance less than 10 ml/min) the daily dose of ceftriaxone should not exceed 2 g. Patients on hemodialysis or peritoneal dialysis do not require administration of an additional dose after a dialysis session since ceftriaxone is not excreted during hemodialysis or peritoneal dialysis.

When severe renal and hepatic impairment are combined, it is recommended that the efficacy and safety of the drug be closely monitored.

Patients in the elderly and elderly: Normal doses for adults without adjustment for age provided there is no severe renal or hepatic impairment.

Children (newborns, infants and children younger than 12 years of age): The following dosing regimens are recommended when prescribing once daily:

– newborns (up to 14 days): 20-50 mg/kg body weight once daily. The daily dose should not exceed 50 mg/kg of body weight;

– newborns, infants and young children (from 15 days to 12 years): 20-80 mg/kg body weight once daily;

In children with a body weight of 50 kg or more, adult doses are used.

In premature children under 41 weeks of age inclusive (cumulative gestational and chronological age) the use of ceftriaxone is contraindicated.

Ceftriaxone is contraindicated in newborns (≤28 days) who are already receiving or anticipate intravenous treatment with calcium-containing solutions, including prolonged calcium-containing infusions such as parenteral nutrition due to the risk of precipitation of calcium salts of ceftriaxone (see section “Contraindications”).

Infants and children less than 12 years of age should be given intravenous doses of 50 mg/kg or more by drip for at least 30 minutes. Newborns should be given intravenously for 60 minutes to reduce the potential risk of bilirubin encephalopathy.

Bacterial meningitis: in bacterial meningitis in infants and young children, treatment begins with a dose of 100 mg/kg (but no more than 4 g) once daily. After identifying the pathogen and determining its sensitivity, the dose can be reduced accordingly. The best results in treatment of meningitis caused by Neisseria meningitidis were achieved with a treatment duration of 4 days; in meningitis caused by Haemophilus influenzae – 6 days; Streptococcus pneumoniae – 7 days.

Lyme disease: adults and children – 50 mg/kg (highest daily dose – 2 g) once a day for 14 days.

Prevention of postoperative complications: depending on the degree of infection risk, 1-2 g ceftriaxone is administered once 30-90 minutes before surgery. For operations on the colon and rectum, simultaneous (but separate, see section “Dosage and administration”) administration of ceftriaxone and a drug from the 5-nitroimidazole group, such as metronidazole, is recommended.

Preparation and administration of solutions

Must only use freshly prepared solutions.

The solutions of Ceftriaxone prepared with water for injection, sodium chloride 0.9% solution, dextrose 5% and 10% solution, sodium chloride 0.45% solution + dextrose 2.5% solution are stable for 48 hours at room temperature (25 °C) or for 72 hours if stored in refrigerator (2 to 8 °C). Changing color of the drug solution from yellow to light brown does not affect its activity and tolerability. The drug solutions prepared using 6% dextran solution in 5% dextrose solution, 6% and 10% hydroxyethyl starch solutions should be used only freshly prepared.

Intravenous infusion: Dissolve 2 g of the drug in 40 ml of one of the following calcium ion-free infusion solutions (sodium chloride solution 0.9%, dextrose solution 5% or 10%, sodium chloride solution 0.45% + dextrose solution 2.5%, dextran solution 6% in dextrose solution 5%, hydroxyethyl starch solution 6-10%, water for injection), infusion should last at least 30 minutes. Ceftriaxone solutions should not be mixed or added to solutions containing other antimicrobials or other solvents, except as listed above, because of possible incompatibility.

Calcium-containing solvents such as Ringer’s or Hartmann’s solution should not be used to prepare Ceftriaxone infusion solution due to the possibility of precipitate formation. Precipitate formation can also occur when ceftriaxone and calcium-containing solutions are mixed when using the same venous access. Ceftriaxone should not be used simultaneously with calcium-containing solutions for intravenous administration, including prolonged infusions of calcium-containing solutions, for example, during parenteral nutrition using a Ò® connector. For all groups of patients, except infants, sequential administration of ceftriaxone and calcium-containing solutions is possible with careful flushing of the infusion systems between infusions with compatible fluid (see section “Interaction with other medicinal products”).

No interactions between ceftriaxone and oral calcium-containing drugs have been reported.

Interaction

When concomitant use of high doses of ceftriaxone and “loop” diuretics (e.g., furosemide) no renal dysfunction has been observed. There are conflicting data on the likelihood of increased nephrotoxicity of aminoglycosides when used with cephalosporins, so it is necessary to monitor renal function and blood concentrations of aminoglycosides.

It does not contain N-methylthiotetrazole group, which could cause ethanol intolerance and bleeding. Therefore, when interacting with ethanol it does not lead to disulfiram-like reactions inherent in some cephalosporins.

Probenecid does not affect the excretion of ceftriaxone.

Bacteriostatic antibiotics reduce the bactericidal effect of ceftriaxone.

In vitro antagonism has been found between chloramphenicol and ceftriaxone.

Pharmaceutically incompatible with solutions containing calcium ions (including Hartmann’s and Ringer’s solutions) when preparing solutions for intravenous administration and their subsequent dilution due to possible precipitate formation. Formation of precipitates of calcium salts of ceftriaxone may also occur when mixing the drug and calcium-containing solutions when using the same venous access. Ceftriaxone should not be used simultaneously with calcium-containing solutions for intravenous administration, including prolonged infusions of calcium-containing solutions, such as parenteral nutrition using a Ò® connector. For all groups of patients, except infants, sequential administration of the drug and calcium-containing solutions is possible with careful flushing of infusion systems between infusions with compatible fluid.

Two in vitro studies have been conducted to evaluate the interaction of ceftriaxone and calcium: one using adult blood plasma and the other using neonatal cord blood plasma. Various combinations of ceftriaxone with an initial concentration of up to 1 mM (the maximum concentration that ceftriaxone reaches in vivo when infused with 2 g of the drug for at least 30 minutes) and calcium with an initial concentration of up to 12 mM (48 mg/dL) were analyzed. A decrease in plasma ceftriaxone concentration was observed when calcium was used at a concentration of 6 mM (24 mg/dL) or higher for adult plasma and at a concentration of 4 mM (16 mg/dL) or higher for neonatal plasma, indicating an increased risk of calcium salts of ceftriaxone in neonates (see “Administration and Doses” and “Contraindications” sections).

Ceftriaxone is pharmaceutically incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

The use of vitamin K antagonists during ceftriaxone therapy increases the risk of bleeding. Blood clotting parameters should be constantly monitored and, if necessary, the dose of vitamin K antagonists should be adjusted both during and after ceftriaxone therapy.

Synergism between ceftriaxone and aminoglycosides has been shown against many Gram-negative bacteria. Although the increased efficacy of such combinations is not always predictable, it should be kept in mind in severe, life-threatening infections such as those caused by Pseudomonas aeruginosa.

Special Instructions

Ceftriaxone is used only in a hospital setting.

Hypersensitivity reactions: As with the use of other beta-lactam antibiotics, severe hypersensitivity reactions, including death, have been reported. In case of severe hypersensitivity reactions, ceftriaxone therapy should be immediately discontinued and appropriate emergency treatment measures should be taken. Before starting therapy with ceftriaxone it is necessary to establish whether the patient has had hypersensitivity reactions to ceftriaxone, cephalosporins or severe hypersensitivity reactions to other beta-lactam antibiotics (penicillins, monobactams and carbapenems). Caution should be exercised when using ceftriaxone in patients with a history of non-serious hypersensitivity reactions to other beta-lactam antibiotics (penicillins, monobactams and carbapenems).

The sodium content: 2 g of ceftriaxone contains 7.2 mmol of sodium, which should be taken into account by patients on a diet that restricts its intake.

Hemolytic anemia: As with other cephalosporins, autoimmune hemolytic anemia may develop during treatment with ceftriaxone. Cases of severe hemolytic anemia in adults and children have been recorded, including cases with fatal outcome. If a patient treated with ceftriaxone develops anemia, the diagnosis of cephalosporin-associated anemia cannot be excluded, and treatment should be withdrawn until the cause is determined.

Diarrhea caused by Clostridium difficile: As with most other antibacterials, cases of Clostridium difficile-induced diarrhea of varying severity have been reported with ceftriaxone treatment, from mild diarrhea to fatal colitis. Treatment with antibiotics suppresses the normal microflora of the large intestine and induces the growth of Clostridium difficile. In turn, this pathogen produces toxins A and B, which are factors in the pathogenesis of diarrhea caused by Clostridium difficile. Its toxin-producing strains are infectious agents with a high risk of complications and mortality due to their possible resistance to antimicrobial therapy, and treatment may require colectomy.

It is important to remember the possibility of Clostridium difficile-induced diarrhea in all patients with diarrhea after antibiotic therapy. A careful history must be taken, as there are cases of Clostridium difficile-induced diarrhea more than 2 months after antibiotic therapy. If diarrhea caused by Clostridium difficile is suspected or confirmed, current antibiotic therapy not directed at Clostridium difficile may need to be stopped. Appropriate treatment with administration of fluids and electrolytes, proteins, antibiotic therapy against Clostridium difficile, and surgical treatment should be prescribed according to clinical indications. Drugs that inhibit intestinal peristalsis should not be used.

Superinfections: as with treatment with other antibacterial drugs, superinfections may develop.

Protrombin time changes: rare cases of changes in prothrombin time have been described in patients treated with ceftriaxone. Patients with vitamin K deficiency (impaired synthesis, malnutrition) may require control of prothrombin time and administration of vitamin K (10 mg/week) if prothrombin time increases before or during therapy.

The formation of calcium salt precipitates of ceftriaxone: cases of fatal reactions due to the deposition of calcium salt precipitates of ceftriaxone in the lungs and kidneys of newborns have been described. Theoretically there is a possibility of interaction of ceftriaxone with calcium-containing solutions for intravenous administration and in other age groups of patients, so ceftriaxone should not be mixed with calcium-containing solutions (including those for parenteral nutrition), and also administered simultaneously, including through separate accesses for infusion at different sites. Theoretically, based on the calculation of 5 half-lives of ceftriaxone, the interval between the administration of ceftriaxone and calcium-containing solutions should be at least 48 hours.

There are no data on possible interaction of ceftriaxone with oral calcium-containing drugs, as well as ceftriaxone for intramuscular administration with calcium-containing drugs (intravenous or for oral administration). After administration of ceftriaxone, usually in doses exceeding the standard recommended ones (1 g per day or more), an ultrasound examination of the gallbladder revealed precipitates of the calcium salt of ceftriaxone, the formation of which is most likely in pediatric patients.

The precipitates rarely produce any symptomatology and disappear after discontinuation or completion of ceftriaxone treatment. If these phenomena are accompanied by clinical symptoms, conservative nonsurgical treatment is recommended, and the decision to discontinue the drug is left to the discretion of the treating physician and should be based on an individual benefit-risk assessment.

While there is evidence of intravascular precipitate formation only in neonates when using ceftriaxone and calcium-containing infusion solutions or any other calcium-containing drugs, ceftriaxone should not be mixed or administered simultaneously to children and adult patients with calcium-containing infusion solutions, even using different venous accesses (see See “Contraindications” and “Interaction with other medicinal products”, subsection “Post-registration monitoring”).

Pancreatitis: Rare cases of pancreatitis have been described when using the drug, possibly due to biliary tract obstruction. Most of these patients already had risk factors for biliary obstruction before ceftriaxone administration, such as previous therapy, severe illness, and complete parenteral nutrition. However, a trigger role in the development of pancreatitis cannot be excluded for precipitates formed in the biliary tract under the influence of ceftriaxone.

Paediatric use: The safety and efficacy of ceftriaxone in infants, infants and young children have been determined for the dosages described under “Administration and Dosages”. Studies have shown that, like other cephalosporins, ceftriaxone can displace bilirubin from binding to serum albumin. Ceftriaxone should not be used in newborns, especially in premature infants who have a risk of bilirubin encephalopathy (see section “Contraindications”).

Long-term treatment: with long-term treatment it is necessary to monitor the peripheral blood count, liver and kidney function parameters regularly.

Blood test monitoring: In long-term treatment, regular complete blood counts should be performed.

Serologic studies: during treatment with ceftriaxone there may be false positive results of Coombs test, galactosemia test, in determination of glucose in urine (glucosuria is recommended to be determined by enzymatic method only).

Impact on the ability to drive vehicles, mechanisms

There are no data on the effect of the drug on driving vehicles and operating machines and mechanisms. However, during treatment with ceftriaxone caution should be exercised while driving vehicles and operating machinery due to possibility of dizziness and other adverse reactions which may affect the ability to drive vehicles, operate machinery and perform other potentially dangerous activities requiring increased attention and quick psychomotor reactions.

Contraindications

Hypersensitivity. Hypersensitivity to ceftriaxone and any other component of the drug. Hypersensitivity to other cephalosporins. Severe hypersensitivity reactions (e.g., anaphylactic reactions) to other beta-lactam antibiotics (penicillins, monobactams and carbapenems) in the history.

Intermature infants. Premature infants up to and including 41 weeks (gestational and chronological age combined).

Preterm newborns (≤28 days of age)

. – Hyperbilirubinemia, jaundice or acidosis, and hypoalbuminemia in preterm infants (in vitro studies have shown that ceftriaxone can displace bilirubin from binding to serum albumin, increasing the risk of bilirubin encephalopathy in such patients).

Intravenous administration of calcium-containing solutions to newborns.

Preterm infants (≤28 days) who are already prescribed or expected to receive intravenous calcium-containing solutions, including prolonged calcium-containing infusions such as parenteral nutrition, because of the risk of precipitate formation of calcium salts of ceftriaxone (see sections “Administration and Doses” and “Interaction with Other Medicinal Products”).

In isolated fatal cases of precipitate formation in the lungs and kidneys in neonates receiving ceftriaxone and calcium-containing solutions have been described. In these individual cases, a single venous access has been used, and precipitate formation has been observed directly in the intravenous system. At least one case has also been described with a fatal outcome with different venous accesses and at different times of administration of ceftriaxone and calcium-containing solutions. Such cases were observed only in neonates (see subsection “Post-registration follow-up”).

With caution

The period of breastfeeding. No history of severe hypersensitivity reactions to other betalactam antibiotics (penicillins, monobactams and carbapenems).

Side effects

The most frequent adverse reactions reported with ceftriaxone therapy in clinical trials are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash and increased liver enzyme activity.

The following classification is used to describe the frequency of adverse reactions: very frequent (≥1/10), frequent (≥1/100 and < 1/10), infrequent (≥1/1000 and < 1/100), rare (≥1/10000 and < 1/1000) and very rare (< 1/10000) including single cases.

The adverse reactions are grouped according to the classes of medical dictionary organ systems for MedDRA regulatory activity.

Infectious and parasitic diseases:

Infrequently, genital mycoses; rarely, pseudomembranous colitis.

Disorders of the blood and lymphatic system:

Often – eosinophilia, leukopenia, thrombocytopenia; infrequent – granulocytopenia, anemia, coagulopathy.

Nervous system disorders:

Infrequent – headache and dizziness.

Respiratory system, chest and mediastinum disorders:

Rarely – bronchospasm.

Gastrointestinal disorders:

Often – diarrhea, loose stools; infrequently – nausea, vomiting.

Hepatic and biliary tract disorders:

Often – increased activity of liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase).

Skin and subcutaneous tissue disorders:

Often – rash; infrequently – itching; rarely – urticaria.

Rarely – hematuria, glucosuria.

General disorders and disorders at the site of administration:

Infrequent – phlebitis, pain at the injection site, increased body temperature; rarely – edema, chills.

Impact on the results of laboratory and instrumental studies:

Infrequent – increase in blood creatinine concentration.

Post-registration observation: adverse events observed when using ceftriaxone are described below. It is not always possible to determine their frequency of occurrence and whether they are associated specifically with ceftriaxone administration because the exact size of the patient population cannot be determined.

Gastrointestinal disorders:

Pancreatitis, stomatitis, glossitis, taste disorders.

Disorders of the blood and lymphatic system:

Thrombocytosis, increased thromboplastin and prothrombin time, decreased prothrombin time, hemolytic anemia. Individual cases of agranulocytosis (< 500 cells/μL) have been described, with most developing after 10 days of treatment and using a cumulative dose of 20 g or more.

Disorders of the immune system:

Anaphylactic shock, hypersensitivity.

Skin and subcutaneous tissue disorders:

Acute generalized exanthematous pustulosis, individual cases of severe adverse reactions (erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome)).

Nervous system disorders:

Convulsions.

Hearing and labyrinth disorders:

Vertigo.

Infectious and parasitic diseases:

Superinfections.

The following adverse reactions are also known:

The formation of precipitates of calcium salts of ceftriaxone in the gallbladder with associated symptoms, bilirubin encephalopathy, hyperbilirubinemia, oliguria, vaginitis, increased sweating, “flushes,” allergic pneumonitis, nasal bleeding, jaundice, palpitations, serum sickness, and anaphylactic or anaphylactoid reactions.

He has described isolated fatal cases of precipitate formation in the lungs and kidneys from autopsy studies in neonates receiving ceftriaxone and calcium-containing solutions. In some cases, a single venous access was used, and precipitate formation was observed directly in the intravenous system. At least one case with a lethal outcome was also described with different venous accesses and at different times of administration of ceftriaxone and calcium-containing solutions. However, autopsy results showed no precipitates in this neonate. Similar cases have been observed only in newborns (see section “Special indications”).

The formation of ceftriaxone precipitates in the urinary tract has been reported mainly in children receiving either high daily doses of the drug (≥80 mg/kg per day) or cumulative doses greater than 10 g, as well as those with additional risk factors (dehydration, bed rest). The formation of precipitates in the kidneys may be asymptomatic or manifest clinically and may lead to ureteral obstruction and postrenal acute renal failure. This adverse event is reversible and resolves after discontinuation of ceftriaxone therapy.

General disorders and disorders at the site of administration:

Phlebitis after intravenous administration. It can be avoided by injecting the drug slowly for 5 minutes, preferably into a large vein.

Impact on laboratory test results:

Patients may experience false-positive Coombs test results. As with other antibacterials, ceftriaxone may give false-positive results for galactosemia. False-positive results may also be obtained when determining glucose in the urine by non-enzymatic methods, so during therapy with ceftriaxone glucosuria, if necessary, should be determined only by the enzymatic method.

Ceftriaxone may cause unreliable decrease in glycemic values obtained with some blood glucose monitoring devices. Refer to the instructions for use of the device used. Alternative methods of blood glucose determination should be used if necessary.

Overdose

Symptoms: Nausea, vomiting and diarrhea.

Treatment

Symptomatic. Hemodialysis and peritoneal dialysis are ineffective.

There is no specific antidote.

Pregnancy use

Pregnancy. Ceftriaxone crosses the placental barrier. Safety of use in pregnancy in women has not been established. Preclinical reproductive studies have shown no embryotoxic, fetotoxic, teratogenic effects or other adverse effects of the drug on fecundity of males and females, the process of childbirth, perinatal and postnatal fetal development. The use of ceftriaxone in pregnancy, especially in the first trimester, is allowed only under strict indications, provided that the estimated benefit to the mother exceeds the potential risk to the fetus.

The period of breastfeeding. In low concentrations ceftriaxone passes into breast milk. The effect of ceftriaxone on the breastfed baby is unlikely when used by the mother in therapeutic doses. Nevertheless, the risk of diarrhea, fungal mucous membrane infections and hypersensitivity reactions in the child cannot be excluded. Breastfeeding should be discontinued or cease/abstain from ceftriaxone therapy, taking into account the benefits of breastfeeding for the baby and the benefits of therapy for the mother.