INSTRUCTION

for medical use of the medicinal product

 

Ceftriaxone Ananta

 

Composition:

Active substance: ceftriaxone;

Each vial contains sodium ceftriaxone equivalent to ceftriaxone 1 g or 2 g.

Dosage form. Powder for solution for injections.

Basic physical and chemical properties: White to yellowish slightly gygroscopic crystalline powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Other beta-lactam antibiotics. The third generation cephalosporins. Ceftriaxone.

ATC code: J01D D04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

When ceftriaxone is attached to penicillin-binding proteins, it inhibits the synthesis of bacteria cell wall. As a result the biosynthesis of the cell wall (peptidoglycan) stops. This causes a bacterial cell lysis and its death.

Resistance

Bacterial resistance to ceftriaxone may be developed as a result of one or several following mechanisms:

• Hydrolysis of beta-lactamases, including broad spectrum beta-lactamases, carbapenemases and Amp C enzymes that can be induced or sustainably suppressed in some aerobic gram-negative bacteria.
• Reduced affinity of penicillin-binding proteins to ceftriaxone.
• Outer membrane impermeability of gram-negative bacteria.
• Bacterial efflux pump.

Breakpoints in sensitivity testing

Breakpoints for the minimum inhibitory concentration are set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

Pathogen	Method of dilution (minimum inhibitory concentration, mg/L)
	Susceptible	Resistant
Enterobacteriaceae	≤ 1	˃ 2
Staphylococcus spp.	a.	a.
Streptococcus spp. (groups А, В, С and G)	b.	b.
Streptococcus pneumoniae	≤ 0.5c.	˃ 2
Viridans Streptococci	≤ 0.5	˃ 0.5
Haemophilus influenzae	≤ 0.12c.	˃ 0.12
Moraxella catarrhalis	≤ 1	˃ 2
Neisseria gonorrhoeae	≤ 0.12	˃ 0.12
Neisseria meningitidis	≤ 0.12c.	˃ 0.12
Not related to species	≤ 1d.	˃ 2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1. Conclusion about susceptibility was made on the basis of susceptibility to cefoxitin;
2. Conclusion about susceptibility was made on the basis of susceptibility to penicillin;
3. . Isolates with a minimum inhibitory concentration exceeding the breakpoints of susceptibility are rare. If this occurs, a re-test should be carried out. If it’s confirmed then sent to the reference laboratory
4. Breakpoints refer to a daily intravenous dose 1 g × 1 and a high dose at least 2 g × 1

 

Commonly susceptible species

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible) ^£, coagulase-negative staphylococci (methicillin-susceptible)^£, Streptococcus pyogenes (group А), Streptococcus agalactiae (group В), Streptococcus pneumoniae, Streptococcus Viridans.

Gram-negative aerobes

Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providentia spp., Treponema pallidum.

Species which may acquire resistance

Gram-positive aerobes

Staphylococcus epidermidis⁺, Staphylococcus haemolyticus⁺, Staphylococcus hominis⁺.

Gram-negative aerobes

Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli^%, Klebsiella pneumoniae^%, Klebsiella oxytoca^%, Morganella morganii, Proteus vulgaris, Serratia marcescens.

Anaerobes

Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.

Resistant organisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others

Сhlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum

£ All methicillin-resistant staphylococci resistant to ceftriaxone.

+ Resistance rate 50% in at least one region.

% The strains producing broad spectrum beta-lactamase that are always resistant.

Pharmacokinetics.

Absorption.

Intramuscular administration

After intramuscular injection, the average peak ceftriaxone concentration level in plasma is approximately half of that observed after the intravenous administration of the equivalent dose. After a single intramuscular injection of 1 g of the preparation, its maximum concentration in blood plasma is achieved in 2 - 3 hours after the administration and makes 81 mg/L. After intramuscular administration the area under the curve "concentration-time" in blood plasma is equal to that after the equivalent intravenous dose.

Intravenous administration

After intravenous bolus administration of ceftriaxone at a dose of 500 mg and 1 g, the average peak concentration level of ceftriaxone in blood plasma is approximately 120 and 200 mg/L, respectively. After intravenous infusion of ceftriaxone at a dose of 500 mg, 1 g and 2 g, the concentration of ceftriaxone in blood is approximately 80, 150 and 250 mg/L, respectively.

Distribution.

The volume of ceftriaxone distribution is 7 - 12 L. Concentrations exceeding the minimum inhibitory concentrations for most significant pathogens of infections are found in the tissues including the lungs, heart, biliary tracts, liver, tonsils, middle ear and nasal mucosa, bones, as well as cerebrospinal, pleural and synovial fluids and prostatic secretion. The increase of the average peak plasma concentration by 8 - 15% (Cmax) was observed at re-administration. In most cases, the balanced state was achieved during 48-72 hours, depending on the route of administration.

Penetration into certain tissues

Ceftriaxone penetrates into the brain membranes. Penetration is more pronounced in case of inflammation of the brain membranes. The mean peak concentration of ceftriaxone in the cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without inflammation of the brain. The peak concentration of ceftriaxone in the cerebrospinal fluid is achieved approximately in 4 – 6 hours after intravenous infection. Ceftriaxone permeates through the placental barrier, and its presence is expected at low concentrations in breast milk (see section "Pregnancy and lactation").

Binding to proteins

Ceftriaxone is reversibly bound to albumin. The binding to plasma proteins is about 95% with a plasma concentration below 100 mg/L. The binding is saturable, and the degree of binding decreases with the increase of concentrations (up to 85% with blood plasma concentration of 300 mg / l).

Biotransformation

Ceftriaxone is not susceptible to systemic metabolism but it is transformed into inactive metabolites under the influence of intestinal flora.

Excretion.

The total plasma clearance of ceftriaxone (bound and unbound) is 10 - 22 mL/min. The renal clearance is 5 - 12 mL/min. and 50-60% of ceftriaxone is excreted unchanged by the kidneys, primarily by glomerular filtration.  In addition 40-50% of ceftriaxone is excreted unchanged with the bile. The half-life of ceftriaxone in adults is about 8 hours.

Patients with renal or liver insufficiency

The pharmacokinetics of ceftriaxone is minimally altered in patients with impaired renal and liver function. The insignificantly increased half-life (less than 2-fold) is observed in patients with severe renal impairment.

In patients with impaired renal function no increase in the elimination half-life is explained by the compensatory increased renal clearance due to the increase in compensatory renal clearance. This also occurs as a result of the increased free fraction of ceftriaxone in the blood plasma, which contributes to the paradoxical increase of the total clearance of the drug and its volume of distribution that happens simultaneously to the general clearance.

Elderly

In elderly persons aged up from 75 years, the average elimination half-life is usually 2 to 3 times higher than in the young adult group.

Children

The half-life of ceftriaxone is prolonged in newborns up to 14 days. The level of free ceftriaxone may further be increased as a result of such factors as reduced glomerular filtration and protein binding dysfunction. In children, the elimination half-life is lower than in newborns or adults.

Plasma clearance and total ceftriaxone distribution are higher in newborns, infants and children than in adults.

Linearity / Nonlinearity

Pharmacokinetics of ceftriaxone has a nonlinear character. All major pharmacokinetic parameters based on total preparation concentrations, excluding the elimination half-life, are dose-dependent. Nonlinearity is the result of saturation of binding to blood plasma proteins. Therefore, for the general ceftriaxone it is observed in blood plasma but for free ceftriaxone (unbound) it is not.

Pharmacokinetic / pharmacodynamic interconnection

As with other beta-lactams, the pharmacokinetic/pharmacodynamic index having the best correlation with in vivo efficacy is the percentage of the dosing interval in which the unbound concentration is above the minimum inhibitory concentration of ceftriaxone for the individual target species (i.e. %T ˃ minimum inhibitory concentration).

Clinical particulars.

Indications.

Ceftriaxone Ananta is indicated in the treatment of the following infections in adults and children, including newborns (from the birth):

• - bacterial meningitis;
• - community-acquired pneumonia;
• - hospital pneumonia;
• - acute otitis media;
• - intra-abdominal infections;
• - complicated urinary tract infections (including pyelonephritis);
• - infection of bones and joints;
• - complicated skin and soft tissue infections;
• - gonorrhoea;
• - syphilis;
• - bacterial endocarditis.

Ceftriaxone Ananta can be used for as follows:

• - treatment of acute complication of chronic obstructive pulmonary disease in adults;
• - treatment of disseminated Lime borreliosis (early (stage II) and late (stage III)) in adults and children, including newborns over 15 days of age;
• - preoperative prevention of infections at the site of surgical intervention;
• - monitoring of patients with neutropenia, who developed a fever with a suspected bacterial infection;
• - treatment of patients with bacteraemia developed due to any of the above-mentioned infections or if any of the above-mentioned infections is suspected.

Ceftriaxone Ananta should be prescribed in combination with other antibacterials if the possible range of bacterial pathogens does not fall within its scope of action (see "Precautions for use").

Official recommendations for the appropriate use of antibacterial agents should be considered.

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin. Presence of severe hypersensitivity reactions (e.g. anaphylactic reactions) to any other type of beta-lactam antibacterial agents in history (penicillins, monobactam and carbapenems).

Ceftriaxone is contraindicated for:

Premature newborns ≤ 41 weeks, considering the term of intrauterine development (gestational age + age after birth)*

Full-term newborns (≤ 28 days of age):

• - with hyperbilirubinemia, jaundice, hypoalbuminemia or acidosis, because these are the conditions in which bilirubin binding is likely to be impaired*;
• - if they require (or are expected to require) intravenous calcium introduction, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see “Precautions for use” and “Adverse reactions”).

* In vitro studies have shown that ceftriaxone can displace bilirubin from blood serum albumin, which leads to the risk of development of bilirubin encephalopathy in these patients.

Contraindications of lidocaine must be excluded before intramuscular injections of ceftriaxone when lidocaine is used as a solvent (see “Precautions for use”). See instructions for medical use of lidocaine, especially section "Contraindications".

Ceftriaxone solutions containing lidocaine should never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Ceftriaxone Ananta in vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies, using adult and neonatal plasma from umbilical cord blood, demonstrated that neonates have shown an increased risk of precipitation of ceftriaxone-calcium. (see sections “Routes of administration and dosage”, “Contraindications”, “Precautions for use”, “Adverse reactions”, “Incompatibility”).

The co-administration of the drug with oral anticoagulants can increase the effect of vitamin K antagonist and the risk of haemorrhages. It is often recommended to check the international normalized ratio and correct the dose of vitamin K antagonist both during and after ceftriaxone therapy (see section "Adverse Reactions").

There are controversial data regarding the potential increase of the toxic effects of aminoglycosides on the kidneys when used concomitantly with cephalosporins. In these cases, it is necessary to thoroughly follow the recommendations for monitoring the level of aminoglycosides (and kidney function) in clinical practice.

Antagonistic effects were observed during in vitro studies when chloramphenicol was used in combination with ceftriaxone. Clinical significance of these data is unknown.

No cases of interaction between ceftriaxone and calcium preparations for oral administration or interaction between ceftriaxone for intramuscular administration and calcium-containing preparations (for intravenous or oral administration) have been registered.

Patients using ceftriaxone may have false-positive results in Coombs test.

Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods such as copper reduction methods for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be carried out enzymatically.

Renal impairment was not observed after concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Concomitant use of probenecid does not reduce the excretion of ceftriaxone.

 

Precautions for use.

Hypersensitivity reactions.

As with other beta-lactam antibiotics, the cases of severe hypersensitivity reactions, sometimes with fatal outcome, were reported (see section "Adverse Reactions"). In case of severe hypersensitivity reactions, ceftriaxone should be immediately discontinued and appropriate measures should be initiated. Before initiating ceftriaxone therapy, it is necessary to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, cephalosporins or other beta-lactam drugs. Ceftriaxone should be given with caution to patients with a history of non-severe hypersensitivity to other beta-lactam preparations.

The cases of severe adverse skin reactions have been reported (Stevens-Johnson syndrome or Lyell's syndrome / toxic epidermal necrolysis); However, the frequency of these events is unknown (see section "Adverse reactions").

Interaction with medicinal products containing calcium.

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term newborns aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different infusion systems. According to the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than newborns, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies have demonstrated that newborns have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.

In patients of any age, ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV solutions, even via different infusion systems or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another via different infusion lines at different sites or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments, which do not carry a similar risk of precipitation. If use of ceftriaxone is considered necessary in patients requiring continuous parenteral nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solutions could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between the solutions. (see sections “Contraindications”, “Adverse reactions”, “Pharmacokinetics” and “Incompatibility”).

Children.

Safety and effectiveness of Ceftriaxone Ananta in neonates, infants and children have been established for the dosages mentioned in "Routes of administration and dosage". Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.

Ceftriaxone Ananta is contraindicated for preterm and full-term newborns at the risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated haemolytic anaemia.

The cases of immune-mediated haemolytic anaemia have been reported in patients receiving cephalosporin antibacterial agents, including Ceftriaxone Ananta (see section "Adverse Reactions"). Severe cases of haemolytic anaemia, including those with a fatal outcome, were reported during the treatment with Ceftriaxone Ananta in adults and children.

If anaemia occurs in patients during the treatment with ceftriaxone, the diagnosis of anaemia associated with cephalosporin should be considered. Ceftriaxone should be discontinued until the etiology of the disease is established.

Long-term treatment.

In case of long-term treatment a detailed blood test should be carried out regularly.

Colitis / overgrowth of insensitive microorganisms.

The incidences of colitis and pseudomembranous colitis associated with the use of antibacterial agents have been reported during the use of almost all antibacterial agents, including ceftriaxone. The severity of these diseases can vary from mild to life threatening. Therefore, it is important to consider the possibility of such diagnosis in patients who experienced diarrhoea during or after the administration of ceftriaxone (see section "Adverse Reactions"). Discontinuous of ceftriaxone treatment and the use of appropriate remedies against Clostridium difficile should be considered. Medicinal products inhibiting peristalsis should not be used.

As with other antibacterial agents, superinfections caused by resistant microorganisms may occur.

Severe renal and hepatic insufficiency.

In case of severe renal and liver insufficiency, a careful clinical monitoring of the safety and efficacy of the preparation is recommended (see "Routes of administration and dosage").

Effect on the results of serological studies.

Coombs test may give false-positive results when using Ceftriaxone Ananta. Ceftriaxone Ananta can also cause false-positive results of the assay for galactosemia (see section "Adverse Reactions").

Non-enzymatic methods for glucose determination in urine may give false-positive results. Urine-glucose determination during therapy with ceftriaxone should be carried out by enzymatic methods of analysis (see section "Adverse reactions").

Sodium.

Each gram of the preparation contains 3.6 mmol of sodium.

This should be taken into account for patients on a controlled sodium diet.

Spectrum of antibacterial activity.

Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable for use as monotherapy in the treatment of certain types of infections, unless the pathogen kind has already been confirmed (see section "Routes of administration and dosage"). In the case of polymicrobial infections, when suspected pathogens are resistant to ceftriaxone microorganisms, the use of additional antibiotics should be considered.

Lidocaine use.

If lidocaine solution is used as a solvent, ceftriaxone can only be administered intramuscularly. Before administering the drug, the contraindications to lidocaine use, precautions and other relevant information provided in the instructions for the medical use of lidocaine (see "Contraindications") should be considered. In any case, the solution of lidocaine cannot be administered intravenously.

Cholelithiasis.

In the case of the presence of shadows on the sonogram, the possibility of the formation of ceftriaxone calcium salt precipitates should be considered. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder, and the incidence rate became higher when ceftriaxone was used at a dose of 1 g per day and more. Caution should be taken when using the drug for children. These precipitates disappear after discontinuation of ceftriaxone therapy. In rare cases, the formation of ceftriaxone precipitate calcium salt was accompanied by symptomatology. If the symptoms occurred, conservative non-surgical treatment is recommended. Based on the results of the benefit-risk assessment of the particular case, a physician should decide on the discontinuance of the drug use in each specific case (see section "Adverse Reactions").

Cholestasis.

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with Ceftriaxone Ananta (see section "Adverse reactions"). Most patients had risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. It cannot be excluded that the initiating or additional factor of such development of this disorder may be the formation of precipitates in the bile ducts as a result of the use of Ceftriaxone Ananta.

Nephrolithiasis.

The cases of kidney stones formation that disappeared after ceftriaxone discontinuation have been reported (see "Adverse reactions"). In case symptoms occur, an ultrasound examination should be performed. Based on the results of the assessment of the risk-benefit in a particular case, a physician should make a decision regarding the use of the preparation for patients with a history of kidney stones or hypercalcaemia.

Disposal of unused medicinal agent or agent with expired storage life.

Ingress of the medicinal product into the external environment should be minimized.

The medicinal product should not be disposed in sewage or household waste. Use the so-called waste collection system to utilize the medicinal product, if available.

Pregnancy and lactation.

Pregnancy.

Ceftriaxone gets through the placental barrier. There are limited data on the use of ceftriaxone in pregnant women. Animal studies give no evidence of direct or indirect harmful effects on the embryo/fetus, peri- and postnatal development. Ceftriaxone can be used during pregnancy, particularly in the first trimester only if the benefit overweighs the risk.

Lactation.

Low concentrations of ceftriaxone is excreted into human milk, but no therapeutic effect is expected during the use of the drug in for infants who are being breastfed. However, the risk of developing diarrhea and fungal infection of the mucous membranes can not be excluded. It is necessary to consider the possibility of sensitization. Considering the benefits of breast-feeding for the child and the benefits of therapy for the woman, it is necessary to decide whether to stop using ceftriaxone or to stop breast-feeding.

Fertility.

Studies of reproductive function have not revealed any signs of undesirable effects on male or female fertility.

Effects on reaction rate while driving vehicles and operating machinery.

Side effects such as dizziness, which may affect the ability to drive vehicles or work with complicated mechanisms, may occur during the treatment with ceftriaxone (see section "Adverse reactions"). Patients should be careful while driving or working with other mechanisms.

Routes of administration and dosage.

Dosage

The dose of the preparation depends on the severity, sensitivity, localization and type of infection, as well as on the age and function of the liver and kidneys of the patient.

The following doses are recommended for these indications. In particularly severe cases, the highest dose of the recommended range should be used.

Adults and children aged over 12 years (≥ 50 kg)

Dose of ceftriaxone *	Frequency of administration **	Indications
1 – 2 g	Once a day	Community-acquired pneumonia Acute complication of chronic obstructive pulmonary disease intra-abdominal infections Complicated urinary tract infections (including pyelonephritis)
2 g	Once a day	Nosocomial pneumonia Complicated skin and soft tissue infections Infections of bones and joints
2 – 4 g	Once a day	Monitoring patients with neutropenia who developed fever and suspected bacterial infection Bacterial endocarditis Bacterial meningitis

 

 

 

 

 

 

 

 

 

 

 

 

 

 

* The highest dose from the recommended range should be considered when bacteremia is documentally confirmed.

** In case of doses exceeding 2 g per day, the twice a day administration should be considered (with 12-hour intervals).

 

Adults and children aged over 12 years (≥ 50 kg) requiring special dosage regimens

Acute otitis media

A single intramuscular dose of 1 - 2 g of Cefrtiaxone Ananta can be used.

Some data suggest that when the patient's condition is severe or previous therapy was ineffective, ceftriaxone may be effective when administered intramuscularly at a dose of 1-2 g per day during 3 days.

Preoperative prevention of infections at the site of surgical intervention

2 g once before surgery.

Gonorrhea

A single dose is 500 mg intramuscularly.

Syphilis

The recommended dosages are 500 mg – 1 g once a day with an increased dose up to 2 g once a day during 10 to 14 days for neurosyphilis. Recommendations for dosage in syphilis, including neurosyphilis, are based on limited data. National or local recommendations should also be considered.

Disseminated Lyme borreliosis (early (II stage) and late (III stage))

2 g once a day during 14 - 21 days. Recommended duration of treatment varies. National or local recommendations should also be considered.

Children

Newborns, infants and children aged 15 days to 12 years (˂ 50 kg)

The usual adult doses should be used for children with a body weight up from 50 kg.

Dose of ceftriaxone *	Frequency of administration**	Indications
50 – 80 mg/kg	Once a day	Intra-abdominal infections, Complicated urinary tract infections (including pyelonephritis), Community-acquired pneumonia, Nosocomial pneumonia
50 – 100 mg/kg (maximum – 4 g)	Once a day	Complicated skin and soft tissue infections, Bone and joint infections, Monitoring of patients with neutropenia who developed fever and suspected bacterial infection
80 – 100 mg/kg (maximum – 4 g g)	Once a day	Bacterial meningitis
100 mg/kg (maximum – 4 g)	Once a day	Bacterial endocarditis

* The highest dose from the recommended range should be considered when bacteremia is documentally confirmed.

** In case of doses exceeding 2 g per day, the twice a day administration should be considered (12-hour intervals).

Newborns, infants and children aged 15 days to 12 years (˂50 kg) requiring special dosage regimens.

Acute otitis media

For the initial treatment of acute otitis media, a single intramuscular injection of Ceftriaxone Ananta at a dose of 50 mg/kg can be used. Some data suggest that Ceftriaxone Ananta may be effective when administered intramuscularly at a dose of 50 mg/kg per day within 3 days if the child's condition is severe or previous therapy was ineffective.

Preoperative prevention of infections at the site of surgical intervention.

50 – 80 mg/kg once before surgery.

Syphilis

The recommended dosages are 75 – 100 mg/kg once a day (maximum – 4 g) during 10 to 14 days. Recommendations for dosage in syphilis, including neurosyphilis, are based on limited data. National or local recommendations should also be considered.

Disseminated Lyme borreliosis (early (II stage) and late (stage III))

50 - 80 mg/kg once a day during 14 – 21 days. Recommended duration of treatment varies. National or local recommendations should also be considered.

Newborns aged under 14 days

Ceftriaxone Ananta is contraindicated for preterm infants ≤ 41 weeks, considering the duration of intrauterine development (gestational age + age after birth).

 

Dose of ceftriaxone *	Frequency of administration**	Indications
20 – 50 mg/kg	Once a day	Intra-abdominal infections, Complicated skin and soft tissue infections, Complicated urinary tract infections (including pyelonephritis), Community-acquired pneumonia, Nosocomial pneumonia, Bone and joint infections, Monitoring patients with neutropenia who developed fever and suspected bacterial infection
50 mg/kg	Once a day	Bacterial meningitis Bacterial endocarditis

* The highest dose from the recommended range should be considered when bacteremia is documentally confirmed.

 

Do not exceed the maximum daily dose of 50 mg/kg.

 

Newborns aged under 14 days requiring special dosage regimens.

Acute otitis media

For the initial treatment of acute otitis media, a single intramuscular injection of Ceftriaxone Ananta at a dose of 50 mg/kg can be used.

Preoperative prevention of infections at the site of surgical intervention.

20 – 50 mg/kg once before surgery.

Syphilis

The recommended dosage is 50 mg/kg once a day during 10 to 14 days. Recommendations for dosage in syphilis, including neurosyphilis, are based on limited data. National or local recommendations should also be considered.

Duration of therapy

The duration of therapy varies on the course of the disease. As with antibiotic therapy in general, administration of ceftriaxone should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial infection eradication has been confirmed.

The elderly

These dosages may not be adjusted for elderly patients if renal and hepatic functions are satisfactory.

Patients with liver impairment

Available data suggests that there is no need to adjust the dose for patients with mild to moderate liver insufficiency, if the kidney function is intact.

There are no available data regarding the patients with severe liver insufficiency (see section Pharmacokinetics).

Patients with renal impairment

In patients with impaired renal function, there is no need to reduce the dosage of ceftriaxone provided liver function is intact. Only in cases of pre-terminal renal failure (creatinine clearance <10 mL/min) the daily dosage should be not more than 2 g.

In patients undergoing dialysis, no additional supplementary dose is required. Ceftriaxone is not eliminated from the body by peritoneal dialysis or haemodialysis. A thorough clinical monitoring of the safety and efficacy of the drug is recommended.

Patients with severe renal and liver impairment

In severe renal impairment accompanied by liver insufficiency, a thorough clinical monitoring of the safety and efficacy of the drug is recommended.

Routes of administration

Intramuscular injection

Ceftriaxone Ananta may be administered by deep intramuscular injection. Intramuscular injection should be administered at the centre of a relatively large muscle. It is recommended to inject no more than 1 g at one site.

If lidocaine is used as a solvent, the resulting solution should never be administered intravenously (see section "Contraindications"). For detailed information, it is recommended to see the instructions for medical use of lidocaine.

The use of lidocaine involves preliminary test to determine individual sensitivity to this preparation.

Intravenous injection

Ceftriaxone Ananta can be administered by intravenous infusion lasting not less than 30 minutes (preferred route) or by slow intravenous injection lasting not more than 5 minutes. Intravenous intermittent administration should be performed within 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or more should be administered by infusion to infants and children under 12 years of age. In newborns, doses should be intravenously administered within 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Precautions for use"). The intramuscular injection should be considered when the intravenous route of administration is impossible or less acceptable for the patient. Doses higher than 2 g should be administered intravenously.

Ceftriaxone is contraindicated for newborns (≤28 days) if they require (or are expected to require) calcium-containing intravenous solutions, including infusion solutions containing calcium, such as parenteral nutrition, due to the risk of ceftriaxone calcium precipitate formation (see section "Contraindications").

Calcium-based solvents such as a Ringer's solution or a Hartmann’s solution can not be used to dissolve ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, since precipitate may be formed. The formation of ceftriaxone calcium salt precipitates can also occur when ceftriaxone is mixed with solutions containing calcium in the same infusion system for intravenous administration. Ceftriaxone must not be mixed or concomitantly administrated with solutions containing calcium (see sections "Contraindications", "Precautions for use" and "Incompatibility").

For the preoperative prevention of infections, ceftriaxone should be administered 30 to 90 minutes before surgical intervention at the site of surgical intervention.

Діти.

The drug should be used for children according to the dosage given in "Routes of administration and dosage".

Overdose.

In case of overdose, nausea, vomiting, and diarrhoea might occur. Ceftriaxone concentration cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse reactions.

Commonly observed adverse reactions are eosinophilia, leukopenia, thrombocytopenia, diarrhoea, rash, and increased levels of liver enzymes.

The frequency of adverse reactions to ceftriaxone was determined according to clinical studies.

Adverse reactions were classified as follows:

Very common             (≥ 1/10);

Common                     (≥ 1/100 < 1/10);

Uncommon                 (≥ 1/1000 < 1/100);

Rare                             (≥ 1/10000 < 1/1000);

Of unknown frequency (No available data).

Infections and invasions: Uncommon – fungal infections of the genitals; Rare – pseudomembranous colitis^b; Of unknown frequency^а – superinfections^b.

Blood and lymphatic system disorders: Common – eosinophilia, leukopenia, thrombocytopenia; Uncommon – granulocytopenia, anaemia, coagulation disorders; Of unknown frequency – haemolytic anaemia^b, agranulocytosis.

Immune system disorders: Of unknown frequency^а – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b.

Nervous system disorders: Uncommon – headache, dizziness; Of unknown frequency^а – convulsions.

Ear and Labyrinth disorders: Of unknown frequency^а – vertigo.

Respiratory, thoracic and mediastinal disorders: Rare – bronchospasm.

Gastro-intestinal disorders: Common – diarrhoea^a, watery stool; Uncommon – nausea, vomiting; Of unknown frequency^а – pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: Common – increased levels of liver enzymes; Of unknown frequency^а – precipitates in the gallbladder^b, nuclear jaundice.

Skin and subcutaneous tissue disorders: Common – rash; Uncommon – itching; Rare – urticaria; Of unknown frequency^а – Stevens-Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, acute generalized exanthematosus pustulosis.

Renal and urinary disorders: Rare – haematuria, glucosuria; Of unknown frequency^а – oliguria, the formation of precipitates in the kidneys (reversible).

General disorders and administration site conditions: Uncommon – phlebitis, pain at the injection site, fever; Rare – oedema, chills.

Data of laboratory tests: Uncommon: increased blood creatinine concentrations; Of unknown frequency^а – False-positive results of Coombs test^b, false-positive results of galactosemia^b test, false-positive results of non-enzymatic methods for glucose test^b.

^а Based on post-marketing reports. Since the information about these reactions voluntarily comes from an uncertain number of people, it is impossible to estimate their frequency reliably. In this regard, it is characterized as unknown frequency.

^b See "Precautions for use".

Infections and invasions.

Cases of diarrhoea after ceftriaxone administration might be caused by Clostridium difficile. The appropriate amount of fluid and electrolytes should be prescribed (see section "Precautions for use").

Ceftriaxone calcium salt precipitates.

Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and full-term neonates (aged < 28 days) treated with ceftriaxone and calcium medications intravenously. In autopsy, in the lungs and kidneys ceftriaxone calcium salt precipitates were observed. There is a high risk of precipitate formation in newborns due to the small volume of blood and prolonged elimination half-life of ceftriaxone (see sections "Contraindications", "Precautions for use" and "Pharmacodynamics").

The cases of precipitate formation in the kidneys were mainly reported in children up from 3 years of age receiving high daily doses (e.g. ≥ 80 mg/kg/day) or total doses of more than 10 g, as well as having additional risk factors (e.g. limited fluid intake or bed rest). The risk of precipitates formation increases in patients who are deprived of mobility, or in patients undergoing dehydration. Precipitates may be asymptomatic or be accompanied by symptoms. They may cause renal failure and anuria, and may disappear after discontinuation of ceftriaxone treatment (see "Precautions for use").

The cases of ceftiraxone calcium precipitate formation in the gallbladder were mainly reported in patients treated with doses higher than standard recommended doses. According to prospective studies, the incidence of precipitates formation in children subjected to intravenous administration was different. In some studies it was more than 30%. At slow administration of the preparation (20 - 30 minutes), the incidence of precipitates formation was noticeably lower. The formation of precipitates is usually not accompanied by symptoms, but in rare cases, there were clinical symptoms such as pain, nausea, and vomiting. In such cases, symptomatic treatment is recommended. The precipitates usually disappear after discontinuation of ceftriaxone treatment (see section "Precautions for use").

Storage life.

2 years.

Storage conditions.

Keep out of reach of children.

Store in the original package at a temperature not exceeding 25°C.

The prepared solution should be kept for no more than 6 hours at room temperature and no more than 24 hours at a temperature from 2 to 8°C.

Incompatibility.

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

Do not mix or add to other medicines other than those listed in "Routes of administration and dosage". Ceftriaxone should not be mixed with calcium-based solutions, such as Ringer’s solution or Hartmann’s solution, because precipitates can form. Ceftriaxone should not be mixed or administered simultaneously with calcium-containing solutions, including solutions for parenteral nutrition (see "Routes of administration and dosage", "Precautions for use" and "Adverse reactions").

Package.

1 g or 2 g of the preparation in a glass vial closed with a rubber stopper and an aluminium cap with a flip-off component, one vial in a box.

Terms of dispensing.

On prescription.

Manufacturer.

Swiss Parenterals Ltd.

Manufacturer’s registered address.

BlockII, Unit№ 402, 412-414 KeralaIndustrialEstate, GIDC, NrBavla, Ahmedabad, Gujarat, 382 220, India

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, SW6 2PY, London, United Kingdom.

Date of  last review. 02.01.2019.