Ceftriaxone-ACOS, 2 g

Pharmacotherapeutic group

Cephalosporin antibiotic

ATX code: J01DD04

Pharmacodynamics:

Ceftriaxone is a parenteral cephalosporin III generation antibiotic.

The bactericidal activity of ceftriaxone is due to suppression of cell wall synthesis.

In vitro ceftriaxone has a broad spectrum of action against Gram-negative and Gram-positive micro-granisms. It is highly resistant to most β-lactamases (both penicillinases and cephalosporinases) produced by Gram-positive and Gram-negative bacteria.

Ceftriaxone is generally active against the following microorganisms.

Gram-positive aurebes

Staphylococcus aureus (mticillin-sensitive) coagulase-negative staphylococci Streptococcus pyogenes (β-hemolytic group A) Streptococcus agalactiae (β-hemolytic group B) β-hemolytic streptococci (neither A nor B groups) Streptococcus viridans Streptococcus pneumoniae.

Note. Methicillin-resistant Staphylococcusspp. are resistant to cephalosporins including ceftriaxone. EnterococcusfaecalisEnterococcusfaecium and Listeriamonocytogenes are also generally resistant.

Gram-negative aerobes

AcinetobacterIwoffiiAcinetobacteranitratus (mainly A. baumannii)* AeromonashydrophilaAlcaligenesfaecalisAlcaligenesodorans alkaligen-like bacteria BorreliaburgdorferiCapnocytophagaspp. Citrobacterdiversus (including C. amalonaticus) Citrobacterfreundii* EscherichiacoliEnterobacteraerogenes* Enterobactercloacae* Enterobacterspp. (others)* HaemophilusducreyiHaemophilusinfluenzaeHaemophilusparainfluenzaeHafniaalveiKlebsiellaoxytocaKlebsiellapneumoniae** Moraxellacatarrhalis (previously called Branhamellacatarrhalis) MoraxellaosloensisMoraxellaspp. (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 marcescens* Serratia spp. (other)* Shigella spp. Vibrio spp. Yersinia enterocolitica Yersinia spp. (others).

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

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

Note. Many strains of the above microorganisms are multiresistant to other antibiotics such as aminopenicillins and ureidonecillins first and second generation cephalosporins and aminoglycosides are sensitive to ceftriaxone. Treponoma pallidum is sensitive to ceftriaxone in vitro and in animal experiments. Clinical trials show that ceftriaxone has good efficacy against primary and secondary syphilis. With very few exceptions, clinical isolates of P.aeruginosa are resistant to ceftriaxone.

The anaerobes

Bacteroidesspp. (bile-sensitive)* Clostridiumspp. (except C. difficile) Fusobacterium nucleatum Fusobacterium spp. (other) Gaffkya anaerobica (formerly called Peptococcus) Peptostreptococcus spp.

* Some isolates of these species are resistant to ceftriaxone because of the formation of β-lactamases. Note. Many strains of β-lactamase-producing Bacteroidesspp. (particularly B. fragilis) are resistant. Clostridiumdifficile is also resistant.

Sensitivity to ceftriaxone can be determined by disc-diffusion or serial dilution on agar or broth using a standard methodology similar to that recommended by the Institute of Clinical and Laboratory Standards (ICLS).

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

In place of the ICLS standards, other well-standardized guidelines can be used to recommend the sensitivity of microorganisms, for example DIN (Deutsches Institut für Normung) and ICS (International Collaborative Study) guidelines that allow an adequate interpretation of the sensitivity status.

Pharmacokinetics:

The pharmacokinetics of ceftritaxone are non-linear. 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. Nonlinearity is characteristic for pharmacokinetic parameters depending on the total concentration of ceftriaxone in blood plasma (not only free ceftriaxone) and is explained by saturation of binding of the drug to blood plasma proteins.

Intake

The maximum plasma concentration after a single intramuscular administration of 1 g of the drug is about 81 mg/l and is reached within 2-3 hours after administration. The areas under the curve “plasma concentration – time” after intravenous and intramuscular administration are the same. This means that bioavailability of ceftriaxone after intramuscular administration is 100%.

After intravenous bolus administration of 500 mg and 1 g of ceftriaxone average maximum plasma concentrations were 120 mg/l and 200 mg/l, respectively. After intravenous infusion of 500 mg of 1 g and 2 g of ceftriaxone, the plasma concentrations of the drug were approximately 80,150 and 250 mg/L, respectively. After intramuscular injection, mean maximum plasma ceftriaxone concentrations were approximately twice as low as after intravenous administration of an equivalent dose of the drug.

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 minimal suppressive concentrations for most infectious agents in more than 60 tissues and fluids (including lungs, heart, biliary tracts, liver, tonsils, middle ear and nasal mucosa, bones, and cerebrospinal pleural and synovial fluid and prostate secretion).

After intravenous administration ceftriaxone rapidly penetrates into the cerebrospinal fluid where bactericidal concentrations against susceptible microorganisms persist for 24 hours.

Protein binding

Ceftriaxone binds reversibly to albumin. The degree of binding is approximately 95% with values of ceftriaxone concentration in plasma of at least 100 mg/l.

For ceftriaxone bound to plasma protein increases with increasing concentration as the binding is saturable and is about 85% at plasma concentration values of 300 mg/l.

Perfusion to selected tissues

Ceftriaxone penetrates the brain membranes to the greatest extent when they are inflamed. The average maximum concentration of ceftriaxone in the cerebrospinal fluid reaches 25% of the plasma concentration of ceftriaxone in patients with bacterial meningitis and only 2% of the plasma 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% is excreted unchanged by the intestine. The half-life of ceftriaxone in adults is about 8 hours.

Pharmacokinetics in special clinical cases

Newborn 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, plasma concentrations of free ceftriaxone may be further increased due to low glomerular filtration and 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 newborn infants and children younger than 12 years compared to those in adults.

Patients with impaired renal or hepatic function have little change in the pharmacokinetics of ceftriaxone with only a slight increase in the half-life (less than 2-fold), even in patients with severe renal impairment.

The 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 and corresponding increase of total ceftriaxone nonrenal clearance.

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 the increased plasma concentration of free ceftriaxone which contributes to a paradoxical increase of total drug clearance against the background of increased volume of distribution.

Patients of advanced age

The elimination half-life is, on average, two to three times longer in patients over 75 years of age 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 and gastrointestinal tract infections); bone infections of joints soft tissue skin as well as wound infections; infections in immunocompromised patients; kidney and urinary tract infections; respiratory infections especially pneumonia and ENT organ infections; genital infections including gonorrhea.

Perioperative prevention of infections.

Active ingredient

Ceftriaxone

Composition

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

The active substance: ceftriaxone sodium – 2.142 g (in terms of ceftriaxone – 2 g).

How to take, the dosage

Standard dosing regimen

Intravenous intramuscularly.

Adults and children over 12 years of age ≥50 kg: 1-2 g once daily (every 24 hours). In severe cases or in infections whose causative agents have only moderate sensitivity to ceftriaxone the daily dose can be increased to 4 g.

The duration of treatment depends on the course of the disease. As always with antibiotic therapy, administration of ceftriaxone-ACOS should be continued for at least 48-72 hours after normalization of temperature and confirmation of eradication of the pathogen.

The course of treatment is usually 4-14 days; in complicated infections a longer course may be required. The course of treatment for infections caused by Streptococcuspyogenes should be at least 10 days.

Injection

The general rule is to use solutions immediately after preparation.

The prepared solutions retain their physical and chemical stability for 6 hours at room temperature (or 24 hours at 2-8 °C). Depending on the concentration and duration of storage, the color of solutions may vary from pale yellow to amber. The coloration of the solution does not affect the effectiveness or tolerability of the drug.

For intramuscular injection, 500 mg of Ceftriaxone-ACOS is dissolved in 2 ml and 1 g in 35 ml of 1% lidocaine solution and injected deep into a large enough muscle (buttock). It is recommended to inject no more than 1 g into the same muscle.

The solution containing lidocaine should not be administered intravenously.

For intravenous injection, 500 mg of Ceftriaxone-ACOS is dissolved in 5 ml and 1 g in 10 ml of sterile water for injection; it is administered intravenously slowly over 5 minutes, preferably into a large vein.

The intravenous infusion should last at least 30 minutes. For solution preparation 2 g of Ceftriaxone-ACOS is diluted in 40 ml of one of the following infusion solutions without calcium ions: 09 % sodium chloride solution 045 % sodium chloride solution + 25 % dextrose solution 5 % dextrose solution 10 % dextrose solution 6 % dextran solution in 5 % dextrose solution 6-10 % hydroxyethyl starch solution water for injection. Ceftriaxone-ACOS solutions should not be mixed or added to solutions containing other antimicrobials or other solvents except those listed above due to possible incompatibility.

Celeftriaxone-ACOS solutions for intravenous administration and their subsequent dilution should not be prepared using solvents containing calcium such as Ringer’s solution or Hartmann’s solution due to possible precipitate formation. Precipitate formation of calcium salts of ceftriaxone can also occur when Ceftriaxone-ACOS and calcium-containing solutions are mixed using the same venous access.

Ceftriaxone should not be used concomitantly with calcium-containing solutions for intravenous administration, including prolonged infusions of calcium-containing solutions such as parenteral nutrition using a Y-connector. For all groups of patients except infants, sequential administration of ceftriaxone-ACOS and calcium-containing solutions is possible with careful flushing of infusion systems between infusions with compatible fluid (see section “Interaction with other medicinal products”).

There have been no reports of interactions between ceftriaxone and oral calcium-containing drugs or interactions between ceftriaxone for intramuscular administration and calcium-containing drugs (for intravenous or oral administration).

Dosage in special cases

Patients with impaired liver function

In patients with impaired liver function there is no need to reduce the dose if there is no renal impairment.

Patients with impaired renal function

In patients with impaired renal function there is no need to reduce the dose if there is no hepatic impairment. The daily dose of Ceftriaxone-ACOS should not exceed 2 g only in cases of renal impairment with creatinine clearance less than 10 ml/min. Ceftriaxone-ACOS is not excreted in hemodialysis or peritoneal dialysis; therefore, no additional dose of Ceftriaxone-ACOS is required after dialysis completion.

If severe renal and hepatic impairment are combined, the efficacy and safety of the drug should be closely monitored.

Patients elderly and senile

The usual doses for adults without adjustment for age provided there is no severe renal or hepatic impairment.

Children

Newborn infants and children less than 12 years of age

The following dosing regimens are recommended when Ceftriaxone-ACOS is prescribed once daily:

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

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

– Children with a body weight greater than 50 kg are prescribed adult doses.

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 treated or who are 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 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.

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 identification of the causative agent and determination of its sensitivity the dose can be reduced accordingly.

The best results with meningococcal meningitis were achieved with a treatment duration of 4 days with meningitis caused by Haemophilusinfluenzae – 6 days Streptococcuspneumoniae – 7 days.

Lyme disease

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

Gonorrhea caused by penicillin- and penicillin-negative strains).

Single intramuscular injection of 250 mg Ceftriaxone-ACOS in adult patients and children over 12 years of age ≥50 kg.

Acute otitis media

In the treatment of acute otitis media in children, a single intramuscular injection of 50 mg/kg (but no more than 1 g) is recommended.

In adults, a single intramuscular dose of 1-2 g is recommended. According to limited data in severe cases or in case of ineffectiveness of previous therapy, Ceftriaxone-ACOS may be effective with intramuscular administration in a dose of 1-2 g per day for 3 days.

Prevention of postoperative infections

Depending on the degree of infection risk, 1-2 g of Ceftriaxone- AKOS is administered once 30-90 minutes before surgery. Simultaneous (but separate, see “Dosage and administration”) administration of ceftriaxone- AKOS and one of the 5-nitroimidazoles such as ornidazole has proven to be a good choice during operations on the colon and rectum.

Interaction

When concomitant use of high doses of ceftriaxone-ACOS and “loop” diuretics (e.g., furosemide) no renal dysfunction was observed. There are conflicting data on the likelihood of increased nephrotoxicity of aminoglycosides when using them with cephalosporins, so it is necessary to monitor renal function and blood concentrations of aminoglycosides. Alcohol consumption after administration of Ceftriaxone-ACOS was not accompanied by a disulfiram-like reaction. Ceftriaxone does not contain N-methylthiotetrazole group, which could cause ethanol intolerance and bleeding, which is inherent in some other cephalosporins. Probenecid does not affect the excretion of Ceftriaxone-ACOS.

Bacteriostatic antibiotics reduce the bactericidal effect of ceftriaxone.

In vitro antagonism has been found between chloramphenicol and ceftriaxone.

Calcium-containing solvents such as Ringer’s solution or Hartmann’s solution should not be used when preparing ceftriaxone-ACOS solutions for intravenous administration and subsequent dilution due to possible precipitate formation. Formation of precipitates of calcium salts of ceftriaxone can also occur when mixing Ceftriaxone-ACOS 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 Y-connector.

For all patient groups except infants, sequential administration of ceftriaxone and calcium-containing solutions is possible with careful flushing of infusion systems between infusions with compatible fluid. To evaluate the interaction of ceftriaxone and calcium with concentrations, two in vitro studies were conducted one using adult blood plasma and the other using cord blood plasma of a newborn. 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.

Decreased plasma ceftriaxone concentrations were observed with calcium at 6 mM (24 mg/dL) or higher for adult plasma and at 4 mM (16 mg/dL) or higher for neonatal plasma, indicating an increased risk of calcium salts of ceftriaxone in neonates (see Sections “Administration and Doses” “Contraindications”).

Ceftriaxone is pharmaceutically incompatible with amsacrine vancomycin fluconazole and aminoglycosides.

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

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 for severe life-threatening infections such as those caused by Pseudomonasaeruginosa.

Special Instructions

Hypersensitivity reactions

As with other β-lactam antibiotics, severe hypersensitivity reactions, including fatal, have been reported. In case of severe hypersensitivity reactions, therapy with Ceftriaxone-ACOS should be immediately cancelled and appropriate emergency treatment measures should be taken. Before starting therapy with Ceftriaxone-ACOS it is necessary to establish whether the patient has had hypersensitivity reactions to ceftriaxone cephalosporins or severe hypersensitivity reactions to other β-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 β-lactam antibiotics (penicillins monobactams and carbapenems).

The development of severe life-threatening or fatal skin hypersensitivity reactions (Stevens-Johnson syndrome or Lyell syndrome/toxic epidermal necrolysis) and drug reactions with eosinophilia and systemic symptoms (DRESS syndrome) have been reported. The frequency of these reactions is unknown.

Yarisch-Herxheimer reaction (JHR) may occur shortly after treatment with ceftriaxone in some patients with spirochaetal infection. The reaction usually goes away on its own or can be managed with symptomatic treatment.

If a reaction occurs, antibiotic treatment should not be discontinued.

The sodium content

The 1 g of Ceftriaxone-ACOS contains 36 mmol of sodium. This should be taken into account in patients on a sodium-controlled diet.

Hemolytic anemia

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

Diarrhea caused by Clostridium difficile

As with most antibacterials, cases of diarrhea caused by Clostridium difficile (C. difficile) of varying severity, from mild diarrhea to fatal colitis, have been reported with ceftriaxone treatment. Treatment with antibiotics suppresses normal colon flora and induces the growth of C. difficile. In turn, C. difficile produces toxins A and B, which are factors in the pathogenesis of C. difficile-induced diarrhea. Toxin-producing strains of C. difficile cause infections with a high risk of complications and mortality due to their possible resistance to antimicrobial therapy and treatment may require colectomy. The possibility of C. difficile-induced diarrhea in all patients with diarrhea after antibiotic therapy must be kept in mind. A careful history must be taken, as there are cases of C. difficile diarrhea more than 2 months after antibiotic therapy. If C. difficile diarrhea is suspected or confirmed, current non-C. difficile antibiotic therapy may need to be withdrawn. Appropriate treatment with fluid and electrolyte protein antibiotic therapy against C. difficile should be prescribed according to clinical indications. Drugs inhibiting intestinal peristalsis should not be used.

Superinfections

As with treatment with other antibacterial drugs, superinfections can develop.

Protrombin time changes

Rare cases of changes in prothrombin time have been described in patients treated with Ceftriaxone-ACOS. Patients with vitamin K insufficiency (impaired synthesis) may require monitoring of prothrombin time during therapy and administration of vitamin K (10 mg/week) if prothrombin time increases before or during therapy.

The formation of ceftriaxone calcium salt precipitates

Fatal reactions have been described as a result of deposits of ceftriaxone-calcium precipitates in the lungs and kidneys of newborns. 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 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 calcium-containing drugs for oral administration and 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, formation of which is most likely in pediatric patients. Precipitates rarely give any symptoms and disappear after completion or discontinuation of therapy with Ceftriaxone-ACOS. If these phenomena are accompanied by clinical symptoms, conservative non-surgical 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 of any other calcium-containing drugs. Ceftriaxone-ACOS should not be mixed or administered simultaneously in children and adult patients with calcium-containing infusion solutions, even using different venous accesses (see sections “Contraindications” “Interaction with other medicinal products” subsection “Post-registration monitoring”).

Pancreatitis

Rare cases of pancreatitis have been described in patients treated with Ceftriaxone-ACOS, possibly due to biliary obstruction. Most of these patients had prior risk factors for biliary tract congestion, such as previous therapy, severe illness and complete parenteral nutrition. At the same time we cannot exclude a trigger role in the development of pancreatitis of precipitates in the biliary tract formed under the influence of ceftriaxone-ACOS.

The drug ceftriaxone-ACOS should not be used in newborns, especially premature infants with a risk of bilirubin encephalopathy (see “Contraindications” section).

Long-term treatment

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

Blood count monitoring

In long-term treatment, regular complete blood counts should be performed.

Serologic studies

False-positive results of the Coombs test for galactosemia in the determination of glucose in the urine may be noted during treatment with ceftriaxone (glucosuria is recommended to be determined only by enzymatic method).

Influence on the ability to drive vehicles and work with machines:

There are no data on the effect of the drug on driving vehicles and working with machines and mechanisms. However, during the therapy by Ceftriaxone- AKOS one should be careful when driving vehicles and operating machinery due to the possibility of dizziness and other adverse reactions which may affect the ability to control vehicles and mechanisms.

Contraindications

Hypersensitivity

Hypersensitivity to ceftriaxone and any other component of the drug.

Hypersensitivity to cephalosporins.

He has a history of severe hypersensitivity reactions (e.g., anaphylactic reactions) to other β-lactam antibiotics (penicillins monobactams and carbapenems).

Perinatally born children

Perinatally born children under 41 weeks of age inclusive (total gestational and chronological age) use of ceftriaxone is contraindicated.

Preterm infants (<28-day-old)

Hyperbilirubinemia jaundice or acidosis hypoalbuminemia in newborns (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 potassium-containing solutions in newborns.

In newborns (≤28 days) who are already prescribed or expected to receive intravenous calcium-containing solutions including prolonged calcium-containing infusions e.g. during parenteral nutrition due to the risk of precipitation 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 some cases a single venous access was used and precipitate formation was observed directly in the intravenous system, and at least one fatal case has been described with different venous accesses and at different times of administration of ceftriaxone and calcium-containing solutions. Such cases have been observed only in neonates (see subsection “Post-registration follow-up”).

Lidocaine

Before performing an intramuscular ceftriaxone injection using lidocaine, the presence of contraindications to lidocaine must be excluded. Contraindications for the use of lidocaine are listed in the instructions for medical use of lidocaine. Ceftriaxone solutions containing lidocaine should not be administered intravenously.

Cautions:

The period of breastfeeding.

Severe hypersensitivity reactions to other β-lactam antibiotics (monobactam penicillins and carbapenems) in history.

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 isolated cases.

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

Infectious and parasitic diseases: infrequent – genital mycoses; rare – pseudomembranous colitis.

Disorders of blood and lymphatic system: frequently – eosinophilia leukopenia thrombocytopenia; rarely – granulocytopenia anemia coagulopathy.

Nervous system disorders: infrequent – headache and dizziness.

Respiratory system disorders of the thorax and mediastinum: rarely – bronchospasm.

Gastro-intestinal disorders: frequently – diarrhea loose stools; infrequently – nausea vomiting.

Hepatic and biliary tract disorders: frequently – increased activity of liver enzymes (aspartate aminotransferase (AST) alanine aminotransferase (ALT) alkaline phosphatase (ALP)).

Skin and subcutaneous tissue disorders: common – rash; infrequent – itching; rare – urticaria.

Renal and urinary tract disorders: rare – hematuria glucosuria.

General disorders and disorders at the injection site: 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 follow-up

The following describes the adverse events observed with the use of Ceftriaxone-ACOS during the post-registration period. It is not always possible to determine the frequency of adverse events observed and their association with the use of Ceftriaxone-ACOS because the exact size of the patient population cannot be determined.

Gastrointestinal disorders: pancreatitis stomatitis glossitis taste disorders.

Blood disorders of the lymphatic system: thrombocytosis increased thromboplastin and prothrombin time decreased prothrombin time hemolytic anemia. Individual cases of agranulocytosis (< 500 cells/μl) have been described, most of them developing after 10 days of treatment and using a cumulative dose of 20 g or more.

Immune system disorders: anaphylactic shock hypersensitivity Jarisch-Herxheimer reaction.

Dermatological and subcutaneous tissue disorders: acute generalized exanthematous pustulosis and individual cases of severe adverse reactions (erythema multiforme exudative Stevens-Johnson syndrome toxic epidermal necrolysis (Lyell syndrome) drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Nervous system disorders: seizures.

Hearing and labyrinth disorders: vertigo.

Infectious and parasitic diseases: superinfections.

The following adverse reactions are also known: formation of precipitates of calcium salts of ceftitaxone in the gallbladder with associated symptoms bilirubin encephalopathy hyperbilirubinemia oliguria increased sweating “flushes” allergic pneumonitis nasal bleeding jaundice palpitations serum illness and anaphylactic or anaphylactoid reactions.

He has described isolated fatal cases of precipitates in the lungs and kidneys from autopsy studies in neonates receiving ceftaxone and potassium-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 fatal outcome was also described with different venous accesses and at different times of administration of ceftriaxone and calcium-containing solutions. However, on autopsy no precipitates were found in this newborn. Similar cases have been observed only in newborns (see section “Special indications”).

Lack of ceftriaxone precipitates in the urinary tract have been observed in children receiving either high daily doses of the drug (≥80 mg/kg/day) or cumulative doses greater than 10 g and those with additional risk factors (dehydration and bed rest). Precipitate formation 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 disappears after discontinuation of Ceftriaxone-ACOS therapy.

General disorders and disorders at the injection site: phlebitis after intravenous administration. It can be avoided by injecting the drug slowly for 5 minutes, preferably into a large vein.

The intramuscular injection without lidocaine is painful.

Impact on laboratory test results

False positive Coombs test results may be observed in patients treated with Ceftriaxone-ACOS. As other antibiotics, ceftriaxone-ACOS may give false-positive results for galactosemia. False-positive results may be obtained when determining glucose in the urine by non-enzymatic methods, so during therapy with Ceftriaxone-ACOS glucosuria should be determined only by enzymatic method if necessary.

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. If necessary, alternative methods of blood glucose determination should be used.

Overdose

Symptoms

Nausea, vomiting and diarrhea.

Treatment

Hemodialysis and peritoneal dialysis will not reduce drug concentrations in overdose. There is no specific antidote. Treatment of overdose is symptomatic.

Pregnancy use

Pregnancy

Ceftriaxone penetrates the placental barrier. The safety of use in pregnancy in women has not been established. Preclinical reproductive studies have shown no embryotoxic fetotoxic teratogenic effect or other adverse effects of the drug on fecundity of males and females during delivery, perinatal and postnatal development of the fetus. In pregnancy, especially in the first trimester, the drug should be administered only under strict indications on condition that the estimated benefit to the mother exceeds the potential risk to the fetus.

Breast-feeding period

In low concentrations ceftriaxone passes into breast milk. It is unlikely to have any effect on the breastfed child if the mother uses ceftriaxone in therapeutic doses; however, the risk of diarrhea, fungal infections of the mucous membranes, and hypersensitivity reactions in the child cannot be excluded.

Breastfeeding should be discontinued or cease/stop therapy with ceftriaxone in view of the benefits to the baby of breastfeeding and the benefits to the mother.