Composition:
active substance: ceftriaxone;
1 vial contains sodium ceftriaxone equivalent to ceftriaxone 1 g or 2 g.

Dosage form. Powder for solution for injection.
Basic physical and chemical properties: White to yellowish 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.
Mode of action.
When ceftriaxone 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 in 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):

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. с. Isolates with a minimum inhibitory concentration exceeding the breakpoints of susceptibility are rare. If this occurs, a re-test should be carried out.
   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)¹, coagulase-negative staphylococci (methicillin-susceptible)¹, 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 for which acquired resistance may be a problem
Gram-positive aerobes
Staphylococcus epidermidis², Staphylococcus haemolyticus², Staphylococcus hominis².
Gram-negative aerobes
Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli³, Klebsiella pneumoniae³, Klebsiella oxytoca³, Morganella morganii, Proteus vulgaris, Serratia marcescens.
Anaerobes
Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.
Inherently 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
1 All methicillin-resistant staphylococci are resistant to ceftriaxone.
2 Resistance rate> 50% in at least one region.
3 The strains producing broad spectrum beta-lactamase are always resistant.

Pharmacokinetics.
Absorption.
Intramuscular administration
After intramuscular injection, the mean peak ceftriaxone concentration 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 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 mean peak concentration of ceftriaxone in 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 tract, liver, tonsils, middle ear and nasal mucosa, bones, as well as cerebrospinal, pleural and synovial fluids and prostatic secretion. The increase of mean peak plasma concentration by 8 - 15% (Cmax) was observed at re-administration. In most cases the balanced state was achieved in 48-72 hours, depending on the route of administration.
Penetration into certain tissues
Ceftriaxone penetrates into the brain membranes. Penetration is more pronounced when 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 permeate through the placental barrier, and its presence is expected at low concentrations in breast milk (see "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 increasing concentrations (up to 85% with a plasma concentration of 300 mg / l).
Metabolism
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 hepatic insufficiency
The pharmacokinetics of ceftriaxone is minimally altered in patients with impaired renal and hepatic function. The insignificantly increased elimination half-life (less than 2-fold) is observed in patients with severe renal impairment.
In the case of impaired kidney function the relatively moderate increase of the elimination half-life is explained by the compensatory increased extrarenal clearance caused by the reduced binding to proteins and the increased extrarenal clearance of total ceftriaxone. In patients with impaired liver function, the elimination half-life of ceftriaxone is not increased due to the compensatory increased renal clearance. This occurs as a result of increased free fraction of ceftriaxone in the blood plasma. This contributes to the paradoxical increase of the total clearance and its volume of distribution that happens simultaneously.
Elderly
In elderly persons aged over 75 years, the average elimination half-life is usually 2 to 3 times longer than in the young adult group.
Children
The half-life of ceftriaxone is prolonged in newborns up to 14 days of age. The level of free ceftriaxone may further be increased as a result of factors such as reduced glomerular filtration and protein binding. 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 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;
• - gonorrhea;
• - syphilis;
• - bacterial endocarditis.

Efmerin 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 of 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.

Efmerin 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. There is a 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 conditions in which bilirubin binding is likely to be impaired*;
• - if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see “Precautions for use” and “Adverse reaction”).

* In vitro studies have shown that ceftriaxone can displace bilirubin from serum albumin, which leads to the risk of development of bilirubin encephalopathy in these patients.
Contraindications of lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine is used as a solvent (see “Precautions for use”). See instructions for medical use of lidocaine, especially "Contraindication".
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 Efmerin vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially, of one 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 “Method of administration and dosage”, “Contraindications”, “Precautions for use”, “Adverse reactions”, “Incompatibility”).
The co-administration of Efmerin with oral anticoagulants can increase the effect of vitamin K antagonist and the risk of bleeding. 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 "Adverse Reactions").
There are controversial evidences regarding the potential increase of the toxic effects of aminoglycosides on the kidneys when they used along with cephalosporins. In these cases, you should thoroughly follow the recommendations for monitoring the level of aminoglycosides (and kidney function) in clinical practice.
Antagonistic effects were observed in vitro study 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-containg 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 in concomitant administration at 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 "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.
In the course of ceftriaxone treatment the cases of severe adverse skin reactions have been reported (Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis and drug rush with eosinophilia and systemic symptoms (DRESS)) that may be life-threatening or fatal); however, the frequency of these events is unknown.
Jarisch-Herxheimer reaction (JHR).
Jarish-Herksheimer reaction (JHR) may occur in some patients with spirochetosis at the start of ceftriaxone treatment. JHR is generally a self-limiting condition and symptomatic treatment may be prescribed. In the event of such reaction, antibiotic treatment should not be discontinued.
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 intravenous lines. In 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 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 lines 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 if infusion lines at different sites are used 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 nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between solutions. (see “Contraindications”, “Adverse reactions”, “Pharmacokinetics” and “Incompatibility”).
Children.
Safety and effectiveness of ceftriaxone in neonates, infants and children have been established for the dosages mentioned in "Method of administration and dosage". Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.
Efmerin is contraindicated to preterm and full-term newborns at the risk of developing bilirubin encephalopathy (see "Contraindications").
Immune-mediated hemolytic anemia.
The cases of immune-mediated hemolytic anemia have been reported in patients receiving cephalosporin antibacterial agents, including ceftriaxone (see "Adverse Reactions"). Severe cases of hemolytic anemia, including those with a fatal outcome, were reported during treatment with ceftriaxone in adults and children.
If anemia occurs in patients during the ceftriaxone treatment, the diagnosis of anemia associated with cephalosporin should be considered. Ceftriaxone should be discontinued until the etiology of the disease is established.
Long-term treatment.
In 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 in the background of 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 diarrhea during or after the administration of ceftriaxone (see "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 hepatic insufficiency, a careful clinical monitoring of the safety and efficacy of the preparation is recommended (see "Method of administration and dose").
Effect on the results of serological studies.
Coombs test may give false-positive results when using Efmerin. Ceftriaxone can also cause false-positive results of the assay for galactosemia (see "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 "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 infection, unless the pathogen has already been confirmed (see "Method 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.
If lidocaine solution is used as a solvent, ceftriaxone can only be administered intramuscularly. Before administering Efmerin, the contraindications to lidocaine use, precautions and other relevant information provided in the instructions for the medical use of lidocaine (see "Contraindications") are considered. In any case, the solution of lidocaine can not 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 used at a dose of 1 g per day and more. Caution should be taken when using Efmerin 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 to stop using the preparation (see "Adverse Reactions").
Cholestasis.
Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with ceftriaxone (see "Adverse reactions"). Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. It can not be excluded that the initiation or additional factor in the development of this disorder may be the formation of precipitates in the bile ducts as a result of the use of Efmerin.
Nephrolithiasis.
The cases of kidney stones formation that disappeared after ceftriaxone discontinuation have been reported (see "Adverse reactions"). In case of symptoms occurred, an ultrasound examination should be performed. Based on the results of the assessment of the risk-benefit of 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 product and drug with expired shelf-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 crosses the placental barrier. There are limited data on the use of ceftriaxone in pregnant women. Animal studies do not testify for direct or indirect harmful effects on the embryo/fetus, peri- and postnatal development. Ceftriaxone can be used during pregnancy, particularly in the first trimester if the benefit overweighs the risk only.
Lactation.
Low concentrations of ceftriaxone is excreted in human milk, but no therapeutic effect is expected during the use of Efmerin in therapeutic doses for infants. 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 ability to drive and use machines.
Side effects such as dizziness which may affect the ability to drive vehicles or work with complicated mechanisms may occur during ceftriaxone treatment (see "Adverse reactions"). Patients should be careful while driving or working with other mechanisms.

Method of administration and dosage.
Dosage
The dose of the preparation depends on the severity, sensitivity, localization and infection type, as well as 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)

* The highest dose from the recommended range should be considered when bacteremia documented.
** In case of doses exceeding 2 g per day, the twice a day administration should be considered (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 Efmerin 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 within 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 (stage III))
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 50 kg.

* The highest dose from the recommended range should be considered when bacteremia documented.
** 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 Efmerin at a dose of 50 mg/kg can be used. Some data suggest that ceftriaxone 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

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

* The highest dose from the recommended range should be considered when bacteremia documented.

Do not exceed the maximum daily dose 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 Efmerin 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 according to 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 eradication has been obtained.
Elderly
These dosages may not be adjusted for elderly patients if renal and hepatic functions are satisfactory.
Hepatic impairment
Available data suggests that there is no need to adjust the dose to patients with mild to moderate hepatic insufficiency if the kidney function is intact.
There are no available data regarding the patients with severe hepatic insufficiency (see Pharmacokinetics).
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 dosage is required. Ceftriaxone is not eliminated from the body by peritoneal dialysis or hemodialysis. A thorough clinical monitoring of the safety and efficacy of Efmerin is recommended.
Severe renal and hepatic impairment
In severe renal impairment accompanied by hepatic insufficiency, a thorough clinical monitoring of the safety and efficacy of Efmerin is recommended.
Method of administration
Intramuscular injection
Efmerin 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 "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 the individual sensitivity to this preparation.
Intravenous injection
Efmerin can be administered by intravenous infusion lasting not more 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. Newborns should be intravenously administered within 60 minutes to reduce the potential risk of bilirubin encephalopathy (see "Contraindications" and "Precautions for use"). The intramuscular injection should be considered when the intravenous route of administration is impossible or less acceptable to the patient. Doses higher than 2 g should be administered intravenously.
Ceftriaxone is contraindicated for newborns (≤28 days) if they require (or expected to be required) calcium-containing intravenous solutions, including infusion solutions containing calcium, such as parenteral nutrition, due to the risk of ceftriaxone calcium precipitate formation (see "Contraindications").
Calcium-based solvents such as a Ringer's solution or a Hartmann 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 a single infusion system for intravenous administration. Ceftriaxone must not be mixed or concomitantly administrated with solutions containing calcium (see "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.
Children.
Efmerin is used for children according to the dosage given in "Method of administration and dosage".

Overdose.
In the case of overdose nausea, vomiting, diarrhea can occur. Ceftriaxone concentration can not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

Adverse reactions.
Common adverse reactions are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and high 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);
Unknown                    (No available data).
Infections and invasions: Uncommon – fungal infections of the genitals; Rare – pseudomembranous colitis^b; Unknown^а – superinfections^b.
Blood and lymphatic system disorders: Common – eosinophilia, leukopenia, thrombocytopenia; Uncommon – granulocytopenia, anemia, coagulation disorders; Unknown – hemolytic anemia^b, agranulocytosis.
Immune system disorders: Unknown^а – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b, Jarisch-Herxheimer reaction.
Nervous system disorders: Uncommon – headache, dizziness; Unknown^а – convulsions.
Ear and Labyrinth disorders: Unknown^а – vertigo.
Respiratory, thoracic and mediastinal disorders: Rare – bronchospasm.
Gastro-intestinal disorders: Common – diarrhea^b, watery stool; Uncommon – nausea, vomiting; Unknown^а – pancreatitis^b, stomatitis, glossitis.
Hepatobiliary disorders: Common – high levels of liver enzymes; Unknown^а – precipitates in the gallbladder^b, nuclear jaundice.
Skin and subcutaneous tissue disorders: Common – rash; Uncommon – itching; Rare – urticaria; Unknown^а – Stevens-Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, acute generalized exanthematosus pustulosis, drug rush with eosinophilia and systemic symptoms (DRESS).
Renal and urinary disorders: Rare – hematuria, glucosuria; Unknown^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 – edema, chills.
Data of laboratory tests: Uncommon: increased blood creatinine concentrations; Unknown^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.
^b See "Precautions for use".
Infections and invasions.
Cases of diarrhea after ceftriaxone administration may be caused by Clostridium difficile. The appropriate amount of fluid and electrolytes should be prescribed (see "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 intravenous ceftriaxone and calcium medications. 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 "Contraindications", "Precautions for use" and "Pharmacodynamics").
The cases of precipitate formation in the kidney were mainly reported in children 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 had 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 the standard recommended dose. 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%. In slow administration of the preparation (20 - 30 minutes), the incidence of precipitates formation was lower obviously. 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, a symptomatic treatment is recommended. The precipitates usually disappear after discontinuation of ceftriaxone treatment (see "Precautions for use").

Shelf 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 not more than 6 hours at room temperature and not more than 24 hours at a temperature 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 "Method of administration and dosage". Ceftriaxone should not be mixed with calcium-based solutions, such as Ringer solution or Hartmann solution, because precipitates can form. Ceftriaxone should not be mixed or administered simultaneously with calcium-containing solutions, including solutions for parenteral nutrition (see "Method 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 aluminum cap with a flip-off component, one vial in a box.

Terms of dispensing. On prescription.

Manufacturer. Venus Remedies Limited.

Manufacturer’s registered address. Hill Top Industrial Estate, Jharmajri, EPIP Phase I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.

Applicant. Ananta Medicare Ltd.

Applicant’s registered address. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of last update. 17.01.2020.