INSTRUCTIONS

for medical use of the medicinal product

 

EFMERIN

 

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.

Ceftriaxone inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins. This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

Resistance

Bacterial resistance to ceftriaxone may be due to one or more of the following mechanisms:

• hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases, carbapenemases and Amp C enzymes that may be induced or stably depressed in certain aerobic Gram-negative bacterial species.
• reduced affinity of penicillin-binding proteins for ceftriaxone.
• outer membrane impermeability in Gram-negative organisms.
• bacterial efflux pump.

Susceptibility testing breakpoints

Minimum inhibitory concentration breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Pathogen	Dilution Test (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 group 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. Susceptibility inferred from cefoxitin susceptibility;
2. Susceptibility inferred from penicillin susceptibility;

с. Isolates with a ceftriaxone MIC above the susceptible breakpoint are rare and, if found, should be re-tested and, if confirmed, should be sent to a reference laboratory

1. Breakpoints apply to a daily intravenous dose of 1 g × 1 and a high dose at least 2 g × 1

 

Clinical efficacy against specific pathogens

The prevalence of acquired resistance may vary geographically and with time for selected species. Local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of ceftriaxone in at least some types of infections is questionable.

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, Viridans group Streptococci.

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

Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g is about 81 mg/l and is reached in 2 - 3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/L respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively.

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. Concentrations well above the minimal inhibitory concentrations of most relevant pathogens are detectable in tissue including lung, heart, biliary tract, liver, tonsil, middle ear and nasal mucosa, bone, and in cerebrospinal, pleural, prostatic and synovial fluids. An 8–15 % increase in mean peak plasma concentration (Cmax) is seen on repeated administration. Steady state is reached in most cases within 48–72 hours depending on the route of administration.

Penetration into particular tissues

Ceftriaxone penetrates the meninges. Penetration is greatest when the meninges are inflamed. Mean peak ceftriaxone concentrations in CSF in patients with bacterial meningitis are reported to be up to 25 % of plasma levels compared to 2 % of plasma levels in patients with uninflamed meninges. Peak ceftriaxone concentrations in CSF are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is excreted in the breast milk at low concentrations (see "Pregnancy and lactation").

Protein binding

Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/L. Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/L).

Metabolism

Ceftriaxone is not metabolised systemically; but is converted to inactive metabolites by the intestinal flora.

Elimination

Plasma clearance of total ceftriaxone (bound and unbound) is 10–22 ml/min. Renal clearance is 5–12 ml/min. 50–60 % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40–50 % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.

Patients with renal or hepatic impairment

In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered with the half-life slightly increased (less than two fold), even in patients with severely impaired renal function.

The relatively modest increase in half-life in renal impairment is explained by a compensatory increase in non-renal clearance, resulting from a decrease in protein binding and corresponding increase in non-renal clearance of total ceftriaxone.

In patients with hepatic impairment, the elimination half-life of ceftriaxone is not increased, due to a compensatory increase in renal clearance. This is also due to an increase in plasma free fraction of ceftriaxone contributing to the observed paradoxical increase in total drug clearance, with an increase in volume of distribution paralleling that of total clearance.

Elderly

In elderly aged over 75 years, the average elimination half-life is usually 2 to 3 times that of young adults.

Children

The half-life of ceftriaxone is prolonged in neonates from birth to 14 days of age. The levels of free ceftriaxone may be further increased by factors such as reduced glomerular filtration and altered protein binding. During childhood, the half-life is lower than in neonates or adults.

The plasma clearance and volume of distribution of total ceftriaxone are greater in neonates, infants and children than in adults.

Linearity/non-linearity

The pharmacokinetics of ceftriaxone are non-linear and all basic pharmacokinetic parameters, except the elimination half-life, are dose dependent if based on total drug concentrations, increasing less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone but not for free (unbound) ceftriaxone.

Pharmacokinetic/pharmacodynamic relationship

As with other beta-lactams, the pharmacokinetic/pharmacodynamic index demonstrating the best correlation with in vivo efficacy is the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration of ceftriaxone for 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-acquired 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.

Efmerin may be used for:

• - the treatment of acute exacerbations of chronic obstructive pulmonary disease in adults;
• - the treatment of disseminated Lyme borreliosis (early (stage II) and late (stage III)) in adults and children including neonates from 15 days of age;
• - the pre-operative prophylaxis of surgical site infections;
• - the management of neutropenic patients with fever that is suspected to be due to a bacterial infection;
• - the treatment of patients with bacteraemia that occurs in association with any of the infections listed above, or is suspected to be associated with, any of the infections listed above.

Efmerin should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum (see "Precautions for use").

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

 

Contraindications.

Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients. History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).

Ceftriaxone is contraindicated for:

Premature neonates ≤ 41 weeks, considering the term of intrauterine development (gestational age + chronological age)*

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) intravenous calcium treatment, or calcium-containing infusions due to the risk of precipitation of a ceftriaxonecalcium salt (see “Precautions for use”, “Adverse reaction” and “Incompatibility”).

* In vitro studies have shown that ceftriaxone can displace bilirubin from its serum albumin binding sites leading to a possible risk of bilirubin encephalopathy in these patients.

Contraindications to lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine solution is used as a solvent (see “Precautions for use”). See information in the Summary of Product Characteristics of lidocaine, especially "Contraindication".

Ceftriaxone solutions containing lidocaine should never be administered intravenously.

 

Interaction with other medicinal products and other forms of interaction.

Calcium-containing diluents, such as Ringer's solution or Hartmann's solution, should not be used to reconstitute Efmerin 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 intravenous 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”).

Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently and the posology of the anti-vitamin K drug is adjusted accordingly, both during and after treatment with ceftriaxone (see "Adverse Reactions").

There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins. The recommended monitoring of aminoglycoside levels (and renal function) in clinical practice should be closely adhered to in such cases.

In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. The clinical relevance of this finding is unknown.

There have been no reports of an interaction between ceftriaxone and oral calcium- containing products or interaction between intramuscular ceftriaxone and calcium- containing products (intravenous or oral).

In patients treated with ceftriaxone, the Coombs' test may lead to false-positive test results.

Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia.

Likewise, non-enzymatic methods for glucose determination in urine may yield false- positive results. For this reason, glucose level determination in urine during therapy with ceftriaxone should be carried out enzymatically.

No impairment of renal function has been observed after concurrent administration of large doses of ceftriaxone and potent diuretics (e.g. furosemide).

Simultaneous administration of probenecid does not reduce the elimination of ceftriaxone.

 

Precautions for use.

Hypersensitivity reactions.

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported (see "Adverse Reactions"). In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftriaxone is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

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 (see "Adverse Reactions").

Interaction with calcium containing products.

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 intravenous 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 in premature and full-term neonates at risk of developing bilirubin encephalopathy (see "Contraindications").

Immune-mediated haemolytic anaemia.

An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone (see "Adverse Reactions"). Severe cases of haemolytic anaemia, including fatalities, have been reported during ceftriaxone treatment in both adults and children.

If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin- associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined.

Long-term treatment.

During prolonged treatment complete blood count should be performed at regular intervals.

Colitis / overgrowth of non-susceptible microorganisms.

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftriaxone (see "Adverse Reactions"). Discontinuation of therapy with ceftriaxone and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.

Severe renal and hepatic insufficiency.

In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacy is advised (see "Method of administration and dosage").

Interference with serological testing.

Interference with Coombs tests may occur, as Efmerin may lead to false-positive test results. Ceftriaxone can also lead to false-positive test results for galactosaemia (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").

The use of ceftriaxone may give false reduction in blood glucose levels obtained by means of separate glucose control systems. Refer to the operating instructions for each individual system. If necessary, use alternative testing methods.

Sodium.

This medicinal product contains 3.6 mmol of sodium. This should be taken into account for patients on a controlled sodium diet.

Antibacterial spectrum.

Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable for use as a single agent for the treatment of some types of infections unless the pathogen has already been confirmed (see "Method of administration and dosage"). In polymicrobial infections, where suspected pathogens include organisms resistant to ceftriaxone, administration of an additional antibiotic should be considered.

Use of lidocaine.

If lidocaine solution is used as a solvent, ceftriaxone solutions must only be used for intramuscular injection. Contraindications to lidocaine, warnings and other relevant information as detailed in the Summary of Product Characteristics of lidocaine must be considered before use (see "Contraindications"). The lidocaine solution should never be administered intravenously.

Biliary lithiasis.

When shadows are observed on sonograms, consideration should be given to the possibility of precipitates of calcium ceftriaxone. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder and have been observed more frequently at ceftriaxone doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of ceftriaxone therapy. Rarely precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of ceftriaxone treatment should be considered by the physician based on specific benefit risk assessment (see "Adverse Reactions").

Biliary stasis.

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. A trigger or cofactor of Efmerin-related biliary precipitation cannot be ruled out.

Renal lithiasis.

Cases of renal lithiasis have been reported, which is reversible upon discontinuation of ceftriaxone (see "Adverse reactions"). In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the physician based on specific benefit risk assessment.

Jarisch-Herxheimer reaction (JHR).

Jarisch-Herxheimer 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.

Encephalopathy.

Ceftriaxone-related encephalopathy has been reported (see "Adverse reactions"), especially in elderly patients with severe renal impairment (see "Method of administration and dosage") or central nervous system disorders. If ceftriaxone-related encephalopathy is suspected (e.g., decreased consciousness, altered mental status, myoclonus, convulsions), discontinuation of ceftriaxone should be considered.

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 indicate direct or indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal development. Ceftriaxone should only be administered during pregnancy and in particular in the first trimester of pregnancy if the benefit outweighs the risk.

Breastfeeding.

Ceftriaxone is excreted into human milk in low concentrations but at therapeutic doses of ceftriaxone no effects on the breastfed infants are anticipated. However, a risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded. The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility.

Reproductive studies have shown no evidence of adverse 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 and use machines, may occur during ceftriaxone treatment (see "Adverse reactions"). Patients should be cautious when driving or operating machinery.

 

Method of administration and dosage.

Dosage

The dose of the preparation depends on the severity, susceptibility, site and type of infection and on the age and hepato-renal function of the patient.

The doses recommended in the tables below are the generally recommended doses in these indications. In particularly severe cases, doses at the higher end of the recommended range should be considered.

Adults and children over 12 years of age (≥ 50 kg)

Ceftriaxone dosage *	Treatment frequency **	Indications
1 – 2 g	Once daily	Community-acquired pneumonia Acute exacerbations of chronic obstructive pulmonary disease intra-abdominal infections Complicated urinary tract infections (including pyelonephritis)
2 g	Once daily	Hospital-acquired pneumonia Complicated skin and soft tissue infections Infections of bones and joints
2 – 4 g	Once daily	Management of neutropenic patients with fever that is suspected to be due to a bacterial infection Bacterial endocarditis Bacterial meningitis

* In documented bacteraemia, the higher end of the recommended dose range should be considered.

** Twice daily (12 hourly) administration may be considered where doses greater than 2 g daily are administered.

Indications for adults and children over 12 years of age (≥ 50 kg) that require specific dosage schedules.

Acute otitis media

A single intramuscular dose of Efmerin 1–2 g can be given.

Limited data suggest that in cases where the patient is severely ill or previous therapy has failed, Ceftriaxone may be effective when given as an intramuscular dose of 1-2 g daily for 3 days.

Pre-operative prophylaxis of surgical site infections

2 g as a single pre-operative dose.

Gonorrhoea

500 mg as a single intramuscular dose.

Syphilis

The generally recommended doses are 500 mg–1 g once daily increased to 2 g once daily for neurosyphilis for 10–14 days. The dose recommendations in syphilis, including neurosyphilis, are based on limited data. National or local guidance should be taken into consideration.

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

2 g once daily for 14–21 days. The recommended treatment durations vary and national or local guidelines should be taken into consideration.

Children

Neonates, infants and children 15 days to 12 years of age (< 50 kg)

For children with bodyweight of 50 kg or more, the usual adult dosage should be given.

Dose of ceftriaxone *	Frequency of administration**	Indications
50 – 80 mg/kg	Once daily	Intra-abdominal infections, Complicated urinary tract infections (including pyelonephritis), Community-acquired pneumonia, Hospital-acquired pneumonia
50 – 100 mg/kg (maximum – 4 g)	Once daily	Complicated skin and soft tissue infections, Bone and joint infections, Management of neutropenic patients with fever that is suspected to be due to a bacterial infection
80 – 100 mg/kg (maximum – 4 g)	Once daily	Bacterial meningitis
100 mg/kg (maximum – 4 g)	Once daily	Bacterial endocarditis

* In documented bacteraemia, the higher end of the recommended dose range should be considered.

** Twice daily (12 hourly) administration may be considered where doses greater than 2 g daily are administered.

Indications for neonates, infants and children 15 days to 12 years (< 50 kg) that require specific dosage schedules.

Acute otitis media

For the initial treatment of acute otitis media, a single intramuscular dose of Efmerin 50 mg/kg can be given. Limited data suggest that in cases where the child is severely ill or initial therapy has failed, ceftriaxone may be effective when given as an intramuscular dose of 50 mg/kg daily for 3 days.

Pre-operative prophylaxis of surgical site infections.

50–80 mg/kg as a single pre-operative dose..

Syphilis

The generally recommended doses are 75–100 mg/kg (max 4 g) once daily for 10–14 days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. National or local guidance should be taken into consideration.

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

50–80 mg/kg once daily for 14–21 days. The recommended treatment durations vary and national or local guidelines should be taken into consideration.

Neonates 0-14 days

Efmerin is contraindicated for premature neonates ≤ 41 weeks, considering the duration of intrauterine development (gestational age + chronological age).

Ceftriaxone dosage*	Treatment frequency**	Indications
20 – 50 mg/kg	Once daily	Intra-abdominal infections, Complicated skin and soft tissue infections, Complicated urinary tract infections (including pyelonephritis), Community-acquired pneumonia, Hospital-acquired pneumonia, Bone and joint infections, Management of neutropenic patients with fever that is suspected to be due to a bacterial infection
50 mg/kg	Once daily	Bacterial meningitis Bacterial endocarditis

* In documented bacteraemia, the higher end of the recommended dose range should be considered.

A maximum daily dose of 50 mg/kg should not be exceeded.

 

Indications for neonates 0-14 days that require specific dosage schedules.

Acute otitis media

For the initial treatment of acute otitis media, a single intramuscular dose of Efmerin 50 mg/kg can be given.

Pre-operative prophylaxis of surgical site infections.

20 - 50 mg/kg as a single pre-operative dose.

Syphilis

The generally recommended dose is 50 mg/kg once daily for 10–14 days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. National or local guidance should be taken into consideration.

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.

Patients with hepatic impairment

Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment provided renal function is not impaired.

There are no study data in patients with severe hepatic impairment (see “Pharmacokinetics”).

Patients with renal impairment

In patients with impaired renal function, there is no need to reduce the dosage of ceftriaxone provided hepatic function is not impaired. Only in cases of preterminal renal failure (creatinine clearance < 10 ml/min) should the ceftriaxone dosage not exceed 2 g daily.

In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Ceftriaxone is not removed by peritoneal- or haemodialysis. Close clinical monitoring for safety and efficacy is advised.

Patients with severe hepatic and renal impairment

In patients with both severe renal and hepatic dysfunction, close clinical monitoring for safety and efficacy is advised.

Method of administration

Intramuscular injection

Efmerin can be administered by deep intramuscular injection. Intramuscular injection should be injected 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"). The information in the Summary of Product Characteristics of lidocaine should be considered.

Intravenous injection

Efmerin can be administered by intravenous infusion over at least 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 in infants and children up to 12 years of age should be given by infusion. In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see "Contraindications" and "Precautions for use"). Intramuscular administration should be considered when the intravenous route is not possible or less appropriate for the patient. For doses greater than 2 g intravenous administration should be used.

Ceftriaxone is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition, because of the risk of precipitation of ceftriaxone-calcium (see "Contraindications").

Diluents containing calcium, such as a Ringer's solution or a Hartmann’s solution should not be used to reconstitute ceftriaxone 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 intravenous administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see "Contraindications", "Precautions for use" and "Incompatibility").

For pre-operative prophylaxis of surgical site infections, ceftriaxone should be administered 30-90 minutes prior to surgery.

Reconstitution

For intramuscular injection, it is necessary to reconstitute:

• 0.5 g in 2 ml of Lidocaine 1% solution;
• 1 g in 3.5 ml of Lidocaine 1% solution.

For intravenous injection, it is necessary to reconstitute:

• 0.5 g in 5 ml of water for injection;
• 1 g in 10 ml of water for injection.

For intravenous infusion, dissolve 2 g of Efmerin in 40 ml of one of the following calcium ion-free infusion solutions: sodium chloride 0.9%, sodium chloride 0.45% + glucose 2.5%, glucose 5%, glucose 10%, dextran 6 % in glucose 5% solution, 6-10% hydroxyethylated starch, water for injection.

The working volume of Efmerin 2 g is 1.37 ml in water for injection.

When adding 40 ml of water for injection, the final concentration of the reconstituted solution is 48.34 mg/ml.

The use of freshly prepared solutions is recommended. The reconstituted solution (with 1% lidocaine hydrochloride solvent) is stable for 24 hours when stored at 2-8 °C or for 6 hours when stored at room temperature.

Ceftriaxone should not be mixed in the same syringe with any drug other than 1% lidocaine hydrochloride solution (for intramuscular injection only).

The infusion line should be flushed after each administration.

 

Children.

Efmerin should be used for children according to the dosage given in "Method of administration and dosage".

 

Overdose.

In overdose, the symptoms of nausea, vomiting and diarrhoea can occur. Ceftriaxone concentrations cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdose should be symptomatic.

 

Adverse reactions.

The most frequently reported adverse reactions for ceftriaxone are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased.

Data to determine the frequency of ceftriaxone adverse reactions was derived from clinical trials. The following convention has been used for the classification of frequency:

Very common             (≥ 1/10);

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

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

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

Not known                 (cannot be estimated from the available data).

Infections and invasions: uncommon – genital fungal infection; rare – pseudo-membranous colitis^b; not known^а – superinfections^b.

Blood and lymphatic system disorders: common – eosinophilia, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; not known^а – haemolytic anaemia^b, agranulocytosis.

Cardiac disorders: not known^а – Kounis syndrome^b.

Immune system disorders: not known^а – anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, hypersensitivity reaction^b, Jarisch-Herxheimer reaction^b.

Nervous system disorders: uncommon – headache, dizziness; rare – encephalopathy; not known^а – convulsion.

Ear and labyrinth disorders: not known^а – vertigo.

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Gastro-intestinal disorders: common – diarrhoea^b, loose stool; uncommon – nausea, vomiting; not known^а – pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: common – hepatic enzyme increased; not known^а – Gall bladder precipitation^b, kernicterus, hepatitis^c, hepatitis cholestatic^b,c.

Skin and subcutaneous tissue disorders: common – rash; uncommon – itching; rare – urticaria; not known^а – Stevens-Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, acute generalized exanthematous pustulosis, drug rush with eosinophilia and systemic symptoms (DRESS)^b.

Renal and urinary disorders: rare – haematuria, glycosuria; not known^а – oliguria, renal precipitation (reversible).

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

Investigations: uncommon: blood creatinine increased; not known^а – Coombs test false positive^b, galactosaemia test false positive^b, non-enzymatic methods for glucose determination false positive^b.

^а Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.

^b See "Precautions for use".

^с Usually reversible upon discontinuation of ceftriaxone.

 

Infections and infestations.

Reports of diarrhoea following the use of ceftriaxone may be associated with Clostridium difficile. Appropriate fluid and electrolyte management should be instituted (see "Precautions for use").

Ceftriaxone-calcium salt precipitation.

Rarely, severe, and in some cases, fatal, adverse reactions have been reported in pre-term and full-term neonates (aged < 28 days) who had been treated with intravenous ceftriaxone and calcium. Precipitations of ceftriaxone-calcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in neonates is a result of their low blood volume and the longer half-life of ceftriaxone compared with adults (see "Contraindications", "Precautions for use" and "Pharmacodynamics").

Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g. ≥ 80 mg/kg/day) or total doses exceeding 10 grams and who have with other risk factors (e.g. fluid restrictions or confinement to bed). This event may be asymptomatic or symptomatic, and may lead to ureteric obstruction and postrenal acute renal failure, but is usually reversible upon discontinuation of ceftriaxone (see "Precautions for use").

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, primarily in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitation with intravenous application - above 30 % in some studies. The incidence appears to be lower with slow infusion (20 - 30 minutes). This effect is usually asymptomatic, but the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting in rare cases. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone (see "Precautions for use").

 

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after the registration of a medicinal product is of great importance. It enables the monitoring of the benefit/risk ratio associated with the use of the medicinal product. Healthcare professionals should report all suspected adverse reactions via the national pharmacovigilance system.

 

Shelf life.

2 years.

 

Storage conditions.

Keep out of reach of children.

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

The reconstituted solution must be kept for not more than 6 hours at room temperature and not more than 24 hours at 2 to 8 °C.

 

Incompatibility.

Ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

Do not mix or add to other medicines except those mentioned in "Method of administration and dosage". Ceftriaxone should not be mixed with diluents containing calcium, such as Ringer's solution or Hartmann's solution, because a precipitate can form. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions, including total parenteral nutrition (see "Method of administration and dosage", "Precautions for use" and "Adverse reactions").

Separate syringes or solutions must be used for combination with other antibiotics.

 

Packaging.

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.

 

Date of last update.

03.01.2025