Triaphin-1000

INSTRUCTIONS for medical use of the medicinal product TRIAFINE-1000 (TRIAFINE-1000)

Composition:

Active substance: ceftriaxone;

1 vial contains sterile sodium ceftriaxone equivalent to anhydrous ceftriaxone 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: crystalline powder from white to yellowish-orange color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Third-generation cephalosporins. Ceftriaxone. ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins, resulting in the cessation of cell wall (peptidoglycan) biosynthesis, which in turn leads to bacterial cell lysis and death.

Resistance

Bacterial resistance to ceftriaxone may develop through one or more of the following mechanisms:

• hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases, carbapenemases, and Amp C enzymes, which may be inducible or stably derepressed in certain aerobic Gram-negative bacteria;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• decreased outer membrane permeability in Gram-negative bacteria;
• bacterial efflux pumps.

Susceptibility testing

The minimum inhibitory concentration (MIC) established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) is as follows:

Organisms	Minimum inhibitory concentration (MIC, mg/l)
	Susceptible (S ≤)	Resistant (R >)
Brucella melitensis (meningitis)	(2)1	(2)1
Cutibacterium acnes	0.062	0.062
Enterobacterales (other indications, except meningitis)	1	2
Enterobacterales (meningitis)	1	1
Haemophilus influenzae (other indications, except meningitis)	0.125	0.125
Haemophilus influenzae (meningitis)	0.125	0.125
Kingella kingae	0.06	0.06
Moraxella catarrhalis	1	2
Neisseria gonorrhoeae	0.125	0.125
Neisseria meningitidis (all indications, including prophylaxis)	0.125	0.125
Staphylococcus spp.	Note3	Note3
Streptococcus groups A, B, C and G	Note4	Note4
Streptococcus pneumoniae (other indications, except meningitis)	0.5	2
Streptococcus pneumoniae (meningitis)	0.5	0.5
Viridans group streptococci	0.5	0.5

1. For information on the use of breakpoints in parentheses, see https://www.eucast.org/eucastguidancedocuments/.
2. Isolates susceptible to benzylpenicillin may be considered susceptible to all beta-lactam agents with breakpoints (including those marked with an asterisk) without additional testing. Isolates resistant to benzylpenicillin must be tested for susceptibility to individual agents.
3. Susceptibility of staphylococci to cephalosporins is determined based on susceptibility to cefoxitin, except for cefixime, ceftazidime, ceftazidime-avibactam, cefditoren, and ceftolozane-tazobactam, which have no breakpoints and should not be used for staphylococcal infections. For oral administration, adequate exposure at the site of infection should be ensured. If use of cefotaxime and ceftriaxone is reported for treatment of methicillin-susceptible staphylococci, the following should be stated: "Susceptible, increased exposure" (I). Some methicillin-resistant S. aureus strains are susceptible to ceftaroline and ceftobiprole.
4. Susceptibility of group A, B, C, and G streptococci to cephalosporins is based on susceptibility to benzylpenicillin.

Clinical efficacy against specific pathogens

The prevalence of acquired resistance may vary geographically and over time for certain species; therefore, local resistance data should be available, especially when treating severe infections. If local resistance prevalence renders the utility of ceftriaxone questionable, at least for certain types of infection, expert consultation is recommended.

Generally susceptible organisms

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococcus group Viridans.

Gram-negative aerobes

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

Organisms that may develop 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 microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others

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

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

• Resistance frequency > 50% in at least one region.

% Strains producing extended-spectrum beta-lactamases are always resistant.

Pharmacokinetics.

Absorption.

Intramuscular administration

After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single 1 g intramuscular dose is 81 mg/L, reached within 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 injection of ceftriaxone at doses of 500 mg and 1 g, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g, and 2 g, plasma concentrations are approximately 80, 150, and 250 mg/L, respectively.

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in mean peak plasma concentration (Cmax) was observed upon repeated dosing; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak cerebrospinal fluid concentrations are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence in low concentrations is expected in breast milk (see section "Use during pregnancy or breastfeeding").

Plasma protein binding

Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the degree of binding decreases with increasing concentration (to 85% at a plasma concentration of 300 mg/L).

Biotransformation

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

Elimination

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

Patients with renal or hepatic impairment

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only slightly altered, with a minor increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

The moderately increased half-life in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced plasma protein binding and a corresponding increase in total ceftriaxone extrarenal clearance.

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This also results from an increased free fraction of ceftriaxone in plasma, leading to a paradoxical increase in total drug clearance, with volume of distribution increasing in parallel with total clearance.

Elderly patients

In patients aged 75 years and older, the mean elimination half-life is typically 2–3 times longer than in younger adults.

Children

The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as reduced glomerular filtration and impaired plasma protein binding. In children, the elimination half-life is shorter than in neonates or adults.

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

Linearity/non-linearity

The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except for elimination half-life, are dose-dependent based on total drug concentration and decrease to a lesser extent than proportionally with dose. Non-linearity is due to saturation of plasma protein binding, thus observed for total ceftriaxone in plasma but not for the free (unbound) fraction.

Pharmacokinetic/pharmacodynamic relationship

As with other beta-lactams, the pharmacokinetic/pharmacodynamic index that best correlates with in vivo efficacy is the percentage of the dosing interval during which the unbound concentration remains above the minimum inhibitory concentration of ceftriaxone for specific target organisms (i.e., % T > minimum inhibitory concentration).

Clinical characteristics.

Indications.

TRIAFIN-1000 should be used for the treatment of the following infections in adults and children, including full-term newborns (from birth):

• bacterial meningitis;
• community-acquired pneumonia;
• hospital-acquired pneumonia;
• acute otitis media;
• intra-abdominal infections;
• complicated urinary tract infections (including pyelonephritis);
• bone and joint infections;
• complicated skin and soft tissue infections;
• gonorrhea;
• syphilis;
• bacterial endocarditis.

TRIAFIN-1000 may be used for:

• treatment of acute exacerbation of chronic obstructive pulmonary disease in adults;
• treatment of disseminated Lyme borreliosis (early (Stage II) and late (Stage III)) in adults and children, including newborns aged 15 days and older;
• surgical prophylaxis of postoperative infections at the site of intervention;
• management of neutropenic patients who develop fever and are suspected of bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of these infections is suspected.

TRIAFIN-1000 should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special precautions").

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

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

Ceftriaxone is contraindicated:

in preterm infants ≤ 41 weeks of gestational age (gestational age + postnatal age)*;

in full-term newborns (≤ 28 days of age):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely impaired under these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing products or infusions of calcium-containing solutions, due to the risk of precipitation of calcium-ceftriaxone salt (see sections "Special precautions" and "Adverse reactions").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, thereby increasing the risk of bilirubin encephalopathy in these patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). See also the instructions for medical use of lidocaine, particularly the "Contraindications" section.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of the drug in vials or for further dilution of the reconstituted solution intended for intravenous administration, as precipitation may occur. Precipitates of calcium-ceftriaxone salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be co-administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn cord plasma have shown an increased risk of calcium-ceftriaxone salt precipitation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions", "Incompatibilities").

Concomitant use of the drug with oral anticoagulants may potentiate the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, and the dose of vitamin K antagonist should be appropriately adjusted during and after ceftriaxone therapy (see section "Adverse reactions").

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical practice recommendations for monitoring aminoglycoside levels (and renal function) is advised.

In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.

No cases of interaction between ceftriaxone and orally administered calcium-containing products or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration) have been reported.

Patients receiving ceftriaxone may exhibit false-positive results in the Coombs test.

Ceftriaxone, like other antibiotics, may cause false-positive results in galactosemia testing.

Similarly, when glucose in urine is tested using non-enzymatic methods, results may be falsely positive. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.

No renal function impairment has been observed following concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Kounis syndrome, a severe allergic reaction that can lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be taken. Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam medicinal products. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam agents.

Cases of severe skin reactions (Stevens–Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported during treatment with ceftriaxone; however, the frequency of these events is unknown (see section "Side effects").

Interaction with calcium-containing medicinal products.

Fatal cases of precipitation of ceftriaxone-calcium salt in lungs and kidneys have been reported in premature and full-term neonates up to 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. According to available scientific data, no confirmed cases of intravascular precipitates have been reported except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone-calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of patient age, even when different infusion systems or different infusion sites are used. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided that the drugs are administered through different infusion systems into different body sites, or that the infusion system is replaced or thoroughly flushed with physiological saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents whose use is not associated with such precipitation risk. If ceftriaxone use in patients requiring continuous nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", and "Incompatibilities").

Children.

The safety and efficacy of ceftriaxone in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from binding to serum albumin.

The medicinal product is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported during ceftriaxone treatment in both adults and children.

If anemia develops in a patient during ceftriaxone therapy, cefalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology is established.

Prolonged treatment.

During prolonged treatment, a complete blood count should be performed regularly.

Colitis/overgrowth of non-susceptible microorganisms.

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and administration of appropriate agents against Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be used.

As with other antibacterial agents, superinfections caused by microorganisms not susceptible to the drug may occur.

Severe renal and hepatic impairment.

In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended (see section "Dosage and administration").

Effect on serological test results.

When using the medicinal product TRIAFIN-1000, the Coombs test may yield false-positive results. Ceftriaxone may also cause false-positive results in galactosemia testing (see section "Side effects").

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During TRIAFIN-1000 therapy, urine glucose levels should be determined using enzymatic test methods (see section "Side effects").

The presence of ceftriaxone may falsely lower blood glucose values obtained by some blood glucose monitoring systems. Therefore, patients should consult the instructions for use of each system. Alternative testing methods should be used if necessary.

Sodium.

One gram of the medicinal product TRIAFIN-1000 contains 3.6 mmol of sodium. This should be taken into account in patients on a sodium-restricted diet.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for use as monotherapy in the treatment of certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant microorganisms are suspected, additional antibacterial agents should be considered.

Use of lidocaine.

If lidocaine solution is used as a solvent, ceftriaxone may only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine medicinal product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

In case of shadows observed on ultrasound, precipitation of ceftriaxone-calcium salt should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency during ceftriaxone therapy at doses of 1 g/day or higher. Particular caution should be exercised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone-calcium salt precipitation has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on an individual benefit-risk assessment (see section "Side effects").

Biliary stasis.

Cases of pancreatitis possibly caused by biliary tract obstruction have been reported in patients receiving TRIAFIN-1000 (see section "Side effects"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, and total parenteral nutrition. The formation of precipitates in the biliary tract due to TRIAFIN-1000 administration cannot be excluded as an initiating or contributing factor in the development of this condition.

Nephrolithiasis.

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Side effects"). In symptomatic cases, ultrasound examination should be performed. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician based on an individual benefit-risk assessment.

Jarisch-Herxheimer reaction (JHR).

In some patients with spirochetal infections, the Jarisch-Herxheimer reaction (JHR) may occur shortly after initiation of ceftriaxone therapy. JHR is usually a self-limiting condition or can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued if this reaction occurs.

Encephalopathy.

Encephalopathy has been reported during ceftriaxone therapy (see section "Side effects"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If encephalopathy associated with ceftriaxone is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Data on the use of ceftriaxone in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonic/fetal, peri- and postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the potential risk.

Breastfeeding.

Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. Sensitization is also possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

Reproductive function studies have not revealed any adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

During ceftriaxone therapy, side effects such as dizziness may occur, which can affect the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving vehicles or operating machinery.

Method of administration and dosage.

Dosage

The dose of the drug depends on the severity, sensitivity, localization, and type of infection, as well as on the patient's age and liver and kidney function.

The recommended dosages are listed below. In particularly severe cases, the highest of the recommended doses should be used.

Adults and children aged 12 years and older (≥ 50 kg).

Table 2

Dose of ceftriaxone*	Frequency of administration**	Indications
1–2 g	Once daily	Community-acquired pneumonia Acute exacerbation 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 Bone and joint infections
2–4 g	Once daily	Management of patients with neutropenia who develop fever and are suspected of bacterial infection Bacterial endocarditis Bacterial meningitis

* In cases of documented bacteremia, consideration should be given to using the highest recommended dose.

** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.

Indications in adults and children aged 12 years and older (≥50 kg) requiring special dosing regimens

Acute otitis media

A single intramuscular dose of 1–2 g of the drug may be used.

Some data suggest that in severe cases or when prior therapy has been ineffective, TRIAFIN-1000 administered intramuscularly at a dose of 1–2 g per day for 3 days may be effective.

Preoperative prophylaxis of surgical site infections

Single dose of 2 g before surgery.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

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

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

2 g once daily for 14–21 days. The recommended duration of treatment varies; national or local guidelines should also be considered.

Children

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

Children with a body weight of 50 kg should receive the standard adult doses.

Ceftriaxone dose*	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 febrile neutropenic patients suspected of bacterial infection
80–100 mg/kg (maximum – 4 g)	Once daily	Bacterial meningitis
100 mg/kg (maximum – 4 g)	Once daily	Bacterial endocarditis

* In cases of documented bacteremia, consideration should be given to using the highest recommended dose.

** When doses exceeding 2 g per day are used, consideration should be given to administering the drug twice daily (with a 12-hour interval).

Indications in infants and children aged 15 days to 12 years (<50 kg) requiring special dosing regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of TRIAFIN-1000 at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or failure of prior therapy, TRIAFIN-1000 may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Preoperative prophylaxis of surgical site infections

50–80 mg/kg as a single dose before surgery.

Syphilis

The generally recommended doses for children are 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.

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

50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.

Newborns aged 0–14 days

TRIAFIN-1000 is contraindicated in preterm infants with a postmenstrual age (gestational age + postnatal age) of less than 41 weeks.

Table 3

Dosage of ceftriaxone*	Frequency of administration	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 febrile neutropenic patients suspected of bacterial infection
50 mg/kg	Once daily	Bacterial meningitis Bacterial endocarditis

* In documented cases of bacteremia, consideration should be given to using the highest of the recommended doses.

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

Indications in neonates aged 0–14 days requiring special dosing regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of TRIAFIN-1000 at a dose of 50 mg/kg may be used.

Preoperative prophylaxis of surgical site infections

20–50 mg/kg as a single dose before surgery.

Syphilis

The generally recommended doses for children are 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.

Duration of treatment

The duration of treatment depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or until eradication of the bacterial infection is confirmed.

Geriatric patients

With adequate renal and hepatic function, dosage adjustment in elderly patients is not required.

Patients with hepatic impairment

Available data indicate that dose adjustment is not necessary in patients with mild to moderate hepatic impairment, provided renal function is normal.

There are no data available for patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

Patients with impaired renal function do not require dose reduction of ceftriaxone if renal function is not impaired. Only in patients with pre-terminal stage renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

Patients undergoing dialysis do not require additional doses of the drug after dialysis. Ceftriaxone is not eliminated by peritoneal dialysis or hemodialysis. Careful clinical monitoring of safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal dysfunction

In cases of concomitant severe impairment of both renal and hepatic function, careful clinical monitoring of the safety and efficacy of the drug is recommended.

Preparation of solutions for injection and infusion

Freshly prepared solutions are recommended. Ceftriaxone dissolves completely in the appropriate solvent within 150 seconds. The reconstituted solution is a clear yellow to brownish-yellow solution. Ceftriaxone should not be mixed in the same syringe with any other drug except 1% lidocaine hydrochloride solution (for intramuscular use only). The infusion line should be flushed after each administration.

Route of administration

Intramuscular administration

Use in adults and children aged 12 years and older (≥ 50 kg)

1 g of ceftriaxone should be dissolved in 3.5 mL of 1% lidocaine hydrochloride solution. The vial should be gently rolled between the palms and visually inspected to ensure complete dissolution and absence of particles. TRIAFIN-1000 may be administered by deep intramuscular injection. The intramuscular injection should be given into the center of a relatively large muscle. It is recommended not to administer more than 1 g at a single injection site.

Infants and children aged 15 days to 12 years (< 50 kg)

The displacement volume for 1 g of ceftriaxone is 0.71 mL in 1% lidocaine hydrochloride solution. This requires adjustment of the solvent volume to ensure dosing according to body weight (particularly in children under 12 years of age) when only a portion of the total solution is administered. To prepare a final solution concentration of 285 mg/mL, 1 g of ceftriaxone should be dissolved in 2.9 mL of 1% lidocaine hydrochloride solution.

If lidocaine is used as the solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, the package leaflet for lidocaine should be consulted.

Intravenous administration

Use in adults and children aged 12 years and older (≥ 50 kg)

1 g of ceftriaxone should be dissolved in 10 mL of water for injections. The vial should be gently rolled between the palms and visually inspected to ensure complete dissolution and absence of particles.

Alternatively, for intravenous infusion, the reconstituted solution should be transferred into 10 mL of one of the following calcium-free infusion solutions: 0.9% sodium chloride, water for injections.

TRIAFIN-1000 may be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins.

Infants and children aged 15 days to 12 years (< 50 kg)

Intravenous doses of 50 mg/kg or higher should be administered by infusion to infants and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special precautions"). The displacement volume for 1 g of ceftriaxone is 0.71 mL in water for injections and 1% lidocaine hydrochloride solution. This requires adjustment of the solvent volume to ensure dosing according to body weight (particularly in children under 12 years of age) when only a portion of the total solution is administered. To prepare a final solution concentration of 100 mg/mL, 1 g of ceftriaxone should be dissolved in 9.4 mL of water for injections.

Intramuscular administration should be considered only when intravenous administration is not feasible or less suitable for the patient. Doses exceeding 2 g should be administered intravenously.

TRIAFIN-1000 is contraindicated in neonates (≤ 28 days) who require (or are expected to require) treatment with calcium-containing intravenous solutions, including infusion solutions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone calcium salts (see section "Contraindications").

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to dissolve ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with solutions containing calcium (see sections "Contraindications", "Special precautions", and "Incompatibilities").

For preoperative prophylaxis of infections, ceftriaxone should be administered 30–90 minutes before surgery.

Instructions for reconstitution of the medicinal product prior to administration are provided above under the subsection "Preparation of solutions for injection and infusion".

Children.

TRIAFIN-1000 should be administered to children according to the dosing instructions specified in the section "Dosage and administration".

Overdose.

Symptoms of nausea, vomiting, and diarrhea may occur in case of overdose. Hemodialysis or peritoneal dialysis does not reduce excessive plasma concentrations of the drug. In case of overdose, nausea, vomiting, and diarrhea may occur. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse reactions.

The most commonly observed adverse reactions during ceftriaxone administration include eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

The frequency of adverse reactions to ceftriaxone was determined based on clinical trial data.

Events are classified by frequency as follows:

very common (≥ 1/10);
common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1000 to < 1/100);
rare (≥ 1/10000 to < 1/1000);
frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon – genital fungal infections; rare – pseudomembranous colitis^b; frequency not known^a – superinfections^b.

Blood and lymphatic system disorders: common – eosinophilia, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; frequency not known^a – hemolytic anemia^b, agranulocytosis.

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

Nervous system disorders: uncommon – headache, dizziness; frequency not known^a – seizures; rare – encephalopathy.

Ear and labyrinth disorders: frequency not known^a – vertigo.

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Gastrointestinal disorders: common – diarrhea^b, loose stools; uncommon – nausea, vomiting; frequency not known^a – pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: common – elevated liver enzymes; frequency not known^a – biliary precipitates^b, kernicterus, hepatitis^c, cholestatic hepatitis^b,c.

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

Renal and urinary disorders: rare – hematuria, glucosuria; frequency not known^a – oliguria, renal precipitates (reversible).

Cardiac disorders: not known – Kounis syndrome.

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

Investigations: uncommon – increased blood creatinine levels; frequency not known^a – false-positive Coombs test^b, false-positive galactosemia test^b, false-positive results in non-enzymatic methods for glucose testing^b.

^a Based on post-marketing reports. Since these reactions are voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency, hence the classification as "frequency not known".
^b See section "Special precautions for use".
^c Usually reversible after discontinuation of ceftriaxone.

Description of selected adverse reactions.

Infections and infestations.

Diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions for use").

Ceftriaxone calcium salt precipitates.

Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing solutions. Post-mortem examinations revealed ceftriaxone calcium precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone elimination half-life compared to adults (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

Cases of urinary tract precipitates have been reported, primarily in children receiving high doses of ceftriaxone (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, particularly in the presence of additional risk factors (e.g., limited fluid intake or bed rest). These precipitates may be symptomatic or asymptomatic, and may lead to ureteral obstruction and post-renal acute kidney injury. They typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Cases of ceftriaxone calcium precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. Prospective studies in children have shown variable rates of precipitate formation following intravenous administration, exceeding 30% in some studies. The incidence appears lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in the original packaging, protected from light. Prepared solutions should be stored for no more than 6 hours at temperatures not exceeding 25 °C, or for up to 24 hours in a refrigerator (2–8 °C).

Keep out of reach of children.

Incompatibilities.

TRIAFIN-1000 is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Do not mix or combine with other medicinal products except those specified in the section "Method of administration and dosage". In particular, diluents containing calcium (e.g., Ringer's solution, Hartmann's solution) must not be used to dissolve the contents of ceftriaxone vials or for further dilution of reconstituted solution for intravenous administration due to the risk of precipitate formation. TRIAFIN-1000 must not be mixed or administered simultaneously with calcium-containing solutions, including parenteral nutrition solutions (see sections "Method of administration and dosage", "Special precautions for use", and "Adverse reactions").

If combination therapy with another antibiotic and TRIAFIN-1000 is intended, the drugs must not be administered in the same syringe or in the same infusion solution.

Packaging.

1 vial of powder per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and location of operations.

VI/51B, P.O. Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.