Sanaxon t - 1000
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SANAXONE T - 1000 (SANAXONE T - 1000)
Composition:
Active substances: ceftriaxone, tazobactam;
One vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg, tazobactam sodium equivalent to tazobactam 125 mg.
Pharmaceutical form. Powder for solution for injection.
Main physicochemical properties: powder of almost white to yellow color.
Pharmacotherapeutic group.
Antibacterial agents for systemic use. Third-generation cephalosporins. Ceftriaxone and β-lactamase inhibitor. ATC code J01DD63.
Pharmacological properties.
Pharmacodynamics.
SANAXON T – 1000 is an antibacterial medicinal product, a fixed combination of ceftriaxone sodium, a third-generation cephalosporin antibiotic for parenteral administration, and tazobactam sodium, a β-lactamase inhibitor.
Ceftriaxone is a parenteral third-generation cephalosporin antibiotic with prolonged action. The bactericidal activity of ceftriaxone is due to inhibition of cell membrane synthesis. Ceftriaxone is active in vitro against most Gram-negative and Gram-positive microorganisms. Ceftriaxone is stable against most β-lactamases (both penicillinases and cephalosporinases) of Gram-positive and Gram-negative bacteria. Ceftriaxone is active in vitro against the following microorganisms:
Gram-positive aerobes: Staphylococcus aureus (methicillin-sensitive), coagulase-negative staphylococci, Streptococcus pyogenes (β-hemolytic, group A), Streptococcus agalactiae (β-hemolytic, group B), most other species of β-hemolytic streptococci, Streptococcus group viridans, Streptococcus pneumoniae.
Note. Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. Also, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes are resistant to ceftriaxone.
Gram-negative aerobes: Acinetobacter lwoffi, Acinetobacter anitratus (mainly A. baumannii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, Borrelia burgdorferi, Capnocytophaga spp., Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter aerogenes*, Enterobacter cloacae*, Enterobacter spp. (others)*, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarrhalis (formerly known as Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris*, Pseudomonas fluorescens*, Pseudomonas spp. (others)*, Providencia rettgeri*, Providencia spp. (others), Salmonella typhi, Salmonella spp. (nontyphoidal), Serratia marcescens*, Serratia spp. (others)*, Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (others).
* Some isolates of these species are resistant to ceftriaxone, mainly due to chromosomally mediated β-lactamase production.
** Some isolates of these species are resistant to ceftriaxone due to production of several plasmid-mediated β-lactamases.
Note. Many strains of the above-mentioned microorganisms, which are multidrug-resistant to antibiotics such as aminopenicillins and ureidopenicillins, first- and second-generation cephalosporins, and aminoglycosides, remain susceptible to ceftriaxone, except for clinical strains of P. aeruginosa resistant to ceftriaxone. Treponema pallidum is susceptible to ceftriaxone in vitro and in animal studies.
Anaerobes: Bacteroides spp. (bile-sensitive)*, Clostridium spp. (except C. difficile), Fusobacterium nucleatum, Fusobacterium spp. (others), Gaffkia anaerobica (formerly known as Peptococcus), Peptostreptococcus spp.
* Some isolates of these species are resistant to ceftriaxone, mainly due to β-lactamase production.
** Some isolates of these species are resistant to ceftriaxone due to β-lactamase production.
Note. Many strains of Bacteroides spp., particularly those producing β-lactamases (e.g., B. fragilis), are resistant to ceftriaxone. Clostridium difficile is resistant.
Tazobactam is a Class III β-lactamase inhibitor according to Richmond-Sykes classification: penicillinases and cephalosporinases. It is a derivative of the "penicillin nucleus", sulbactam (sulphone-penicillanic acid). Tazobactam irreversibly inhibits most β-lactamases produced by clinically important Gram-negative and Gram-positive aerobic and anaerobic bacteria by covalent binding to their enzymes. In particular, tazobactam has a high affinity for binding to plasmid-mediated β-lactamases, which are often responsible for resistance to penicillin and cephalosporin antibiotics. Tazobactam does not inhibit enzymes of Class A.
Additionally, tazobactam does not inhibit the activity of the following β-lactamases:
- AmpC-type β-lactamase enzymes (produced by Enterobacteriaceae);
- Serine-based carbapenemases (e.g., carbapenemases produced by Klebsiella pneumoniae);
- Metallo-β-lactamases (e.g., New Delhi metallo-β-lactamase);
- Class D β-lactamases of Ambler classification (OXA-carbapenemases).
Pharmacokinetics.
Absorption.
Intramuscular administration.
After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g is 81 mg/L and is 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 that greatly exceed the minimum inhibitory concentrations for most clinically significant pathogens are found in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated administration; 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 is up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also detected in breast milk in low concentrations (see section "Use during pregnancy or breastfeeding").
Protein binding.
Ceftriaxone reversibly binds to albumin. Plasma protein binding is about 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the degree of binding decreases as concentration increases (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 protein binding and the consequent increase in extrarenal clearance of total ceftriaxone.
In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This also occurs due to an increased free fraction of ceftriaxone in plasma, which leads to a paradoxical increase in total drug clearance, with a parallel increase in volume of distribution and 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 protein binding. In children, the elimination half-life is shorter than in neonates or adults.
Plasma clearance and volume of distribution of total ceftriaxone are higher in children than in adults.
Linearity/non-linearity.
The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent and decrease less than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding, and thus occurs for total ceftriaxone in plasma, but not for free (unbound) ceftriaxone.
Pharmacokinetic/pharmacodynamic relationship.
As with other β-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.
- Lower respiratory tract infections;
- Acute bacterial otitis media;
- Skin and soft tissue infections;
- Complicated urinary tract infections;
- Bone and joint infections;
- Gonorrhea;
- Septicemia;
- Intra-abdominal infections;
- Meningitis.
Contraindications.
Hypersensitivity to ceftriaxone or any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of β-lactam antibacterial agents (penicillins, monobactams, and carbapenems); renal and/or hepatic insufficiency; gastrointestinal disorders in medical history, particularly ulcerative colitis, enteritis, or antibiotic-associated colitis.
Ceftriaxone is contraindicated:
In preterm neonates aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*.
In term neonates (aged ≤ 28 days):
- With hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired under these conditions*,
- Who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of calcium-ceftriaxone salts (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 such patients.
Prior to intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). Refer to the lidocaine prescribing information, particularly regarding contraindications.
Solutions of ceftriaxone containing lidocaine must never be administered intravenously.
Interaction with other medicinal products and other forms of interaction.
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to dissolve ceftriaxone in vials or to dilute reconstituted solution for intravenous administration, due to the likelihood of precipitation of calcium-ceftriaxone salts. Precipitation of calcium-ceftriaxone salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Ceftriaxone must not be co-administered intravenously with calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site system. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and neonatal umbilical cord blood have shown an increased risk of calcium-ceftriaxone salt precipitation in neonates (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions").
Concomitant use of the medicinal product with oral anticoagulants may enhance the anti-vitamin K effect 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 both during and after ceftriaxone therapy (see section "Adverse reactions").
There are conflicting data regarding the potential for increased nephrotoxic effects 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.
Ceftriaxone must not be mixed with amikacin, vancomycin, fluconazole, or aminoglycosides.
No renal function impairment has been observed when high doses of ceftriaxone are administered concomitantly with potent diuretics such as furosemide.
Ceftriaxone contains an N-methylthiotetrazole side chain, which may cause ethanol intolerance and bleeding, as seen with some other cephalosporins. In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.
There are no reports of interaction between ceftriaxone and orally ingested calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (administered intravenously or orally).
Patients receiving ceftriaxone may exhibit false-positive results in the Coombs test.
Like other antibiotics, ceftriaxone 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, glucose levels in urine should be determined using enzymatic methods. Bacteriostatic agents may interfere with the bactericidal action of cephalosporins. Ceftriaxone may reduce the efficacy of hormonal oral contraceptives. Therefore, additional (non-hormonal) contraceptive methods are recommended during treatment and for 1 month after completion of therapy.
Probenecid does not affect the elimination of ceftriaxone.
Alcohol. Reactions such as facial flushing, increased sweating, headache, and tachycardia have been reported when alcohol is consumed during and within 5 days after treatment with cefoperazone. No disulfiram-like (antabuse-like) effects have been observed after alcohol consumption immediately following ceftriaxone administration. Similar reactions have been reported with other cephalosporins. Patients should be cautious when consuming alcoholic beverages during treatment with this medicinal product. Solutions containing ethanol must not be used when artificial nutrition (oral or parenteral) is administered.
Special precautions for use.
Hypersensitivity reactions.
As with other ceftriaxone-containing cephalosporins, cases of anaphylactic reactions (including anaphylactic shock) with fatal outcomes have been reported, even in patients without a prior history of severe hypersensitivity. Before 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 β-lactam agents. The drug should be used with caution in patients with a history of mild hypersensitivity to other β-lactam drugs.
In the event of allergic reactions, the drug should be discontinued immediately and appropriate treatment initiated.
The risk of anaphylactic reactions is increased in patients with a history of anaphylaxis and in those with hypersensitivity reactions to various allergens; therefore, the drug should be used cautiously in patients with a predisposition to allergic diathesis.
Cases of severe skin adverse reactions (Stevens–Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) associated with ceftriaxone use have been reported, which may be life-threatening or fatal; however, the frequency of these events is unknown (see section "Adverse reactions").
Jarisch–Herxheimer reaction.
Shortly after initiating ceftriaxone therapy, some patients with spirochete infections may experience a Jarisch–Herxheimer reaction (JHR). This reaction usually resolves spontaneously or can be managed symptomatically. Antibiotic treatment should not be discontinued due to the occurrence of this reaction.
The drug may increase prothrombin time. Therefore, in suspected vitamin K deficiency, prothrombin time should be monitored.
Colitis / overgrowth of resistant microorganisms.
Diarrhea associated with Clostridium difficile , ranging from mild to severe colitis with fatal outcomes, may occur during treatment with nearly all antibacterial agents, including ceftriaxone and tazobactam. Antibacterial agents alter the normal flora of the colon, leading to overgrowth of Clostridium difficile . Clostridium difficile produces toxins A and B, which contribute to the development of Clostridium difficile -associated diarrhea. Hyperproducing toxin strains of Clostridium difficile are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and require colectomy. Clostridium difficile -associated diarrhea should be considered in all patients receiving antibiotics. A detailed medical history should be obtained, as Clostridium difficile -associated diarrhea may occur up to 2 months after discontinuation of antibacterial agents. Discontinuation of the drug and initiation of appropriate therapy against Clostridium difficile should be considered. Antiperistaltic agents should not be used.
As with other antibacterial agents, superinfections caused by microorganisms resistant to the drug may occur.
Depending on clinical indications, appropriate fluid and electrolyte management, protein supplementation, antibiotic therapy effective against Clostridium difficile , and surgical evaluation should be provided.
Prolonged use of ceftriaxone may lead to difficulties in controlling drug-resistant microorganisms. Therefore, careful monitoring of patients is required. Appropriate measures should be taken if superinfection occurs.
Antibacterial spectrum.
Ceftriaxone has a limited antibacterial spectrum and may be inadequate as monotherapy for certain types of infections, except when the causative pathogen has been confirmed (see section "Dosage and administration"). In cases of polymicrobial infections involving microorganisms resistant to ceftriaxone, additional antibiotics should be considered.
Cholelithiasis.
If shadows are observed on ultrasound, the possibility of calcium ceftriaxone salt precipitates should be considered.
Echogenic shadows in the gallbladder, which may be mistaken for gallstones, have been observed on ultrasound, with increased frequency at ceftriaxone doses of 1 g/day or higher. Particular caution is required when using the drug in children. These precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, calcium ceftriaxone salt precipitates have 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 benefit-risk assessment (see section "Adverse reactions").
Biliary stasis.
Isolated cases of pancreatitis, possibly due to obstruction of the biliary tract, have been reported in patients receiving ceftriaxone. Most of these patients had risk factors for biliary stasis, such as prior extensive therapy, cholestasis, or biliary sludge formation, including severe illness and total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone/tazobactam use cannot be excluded as an initiating or contributing factor.
Nephrolithiasis.
Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). 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 benefit-risk assessment.
Immune-mediated hemolytic anemia.
Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone. Severe hemolytic anemia, including fatal cases, have been reported during ceftriaxone therapy in both adults and children.
If anemia develops during ceftriaxone therapy, ceftriaxone-associated hemolytic anemia should be considered, and ceftriaxone should be discontinued until the etiology is established.
Long-term therapy.
During prolonged therapy, complete blood counts should be performed regularly.
Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions , even when administered through separate infusion systems.
Fatal precipitates of calcium ceftriaxone salt in the lungs and kidneys have been reported in term and preterm neonates under 1 month of age who received ceftriaxone and calcium-containing drugs simultaneously. Cases of intravascular precipitates have also been reported in patients of other age groups after simultaneous administration of ceftriaxone and intravenous calcium-containing solutions. In at least one of these cases, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. Therefore, calcium-containing intravenous solutions must not be administered to neonates and patients of other age groups within at least 48 hours after the last dose of the drug (see section "Contraindications").
Confirmed cases of intravascular precipitates have not been reported except in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing drugs. In vitro studies have shown that neonates have an increased risk of calcium ceftriaxone salt precipitate formation compared to patients of other age groups.
Ceftriaxone must not be mixed or administered simultaneously with any intravenous solutions containing calcium, regardless of patient age, even when using different infusion systems or administering drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the drugs are administered through different infusion systems into different body sites or the infusion system is thoroughly flushed with saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents not associated with this precipitation risk. If ceftriaxone use in patients requiring continuous parenteral nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and into different body sites. Alternatively, TPN infusion may be paused during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications," "Adverse reactions," and "Incompatibilities").
Children.
Ceftriaxone, a component of the drug, may displace bilirubin from albumin binding sites in serum. Therefore, the drug is contraindicated in preterm and term neonates with hyperbilirubinemia at risk of developing bilirubin encephalopathy (see section "Contraindications").
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").
For patients with impaired renal function but normal hepatic function, dose adjustment is not required. In patients with renal impairment (creatinine clearance <10 mL/min), the daily dose of ceftriaxone should not exceed 2 g. For patients with impaired hepatic function but preserved renal function, dose reduction is not necessary.
In cases of concomitant severe liver and kidney disease, serum ceftriaxone concentrations should be monitored regularly. Dose adjustment after hemodialysis is not required. Caution should be exercised when administering ceftriaxone to patients with renal impairment who are also receiving aminoglycosides and diuretics.
Effect on serological test results.
In isolated cases, false-positive Coombs test results may occur during drug use. As with other antibiotics, the drug may cause false-positive galactosemia tests. False-positive results may also occur in urine glucose testing; therefore, during ceftriaxone therapy, urine glucose should be tested only by enzymatic methods if necessary.
For patients undergoing hemodialysis, dose adjustment after the procedure is not required, but serum drug concentration should be monitored, as elimination may be accelerated in these patients.
Important information about excipients.
Sodium.
One gram of the drug contains 3.6 mmol of sodium. This should be considered if the patient is on a sodium-controlled diet.
Use of lidocaine.
When lidocaine solution is used as a solvent, ceftriaxone may be administered only intramuscularly. Before administration, contraindications, warnings, and other relevant information provided in the lidocaine product information should be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.
Disposal of unused or expired drug.
Environmental contamination with the drug should be minimized. The drug must not be disposed of in wastewater or household waste. Disposal should be performed via a designated waste collection system, if available.
Use during pregnancy or breastfeeding.
Pregnancy.
Ceftriaxone crosses the placental barrier. Data on ceftriaxone use in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonic/fetal, perinatal, or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the risk.
Breastfeeding.
Ceftriaxone passes into breast milk in low concentrations, and no adverse effects on breastfed infants are expected with 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 discontinue/abandon 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 shown evidence of adverse effects on male or female fertility.
Ability to affect reaction speed when driving or operating machinery.
There are no data on the effect of ceftriaxone on reaction speed; however, if dizziness occurs, driving or operating complex machinery should be avoided.
Method of Administration and Dosage
Administer intravenously or intramuscularly.
Dosage.
The dose of the medicinal product depends on the severity, susceptibility, localization, and type of infection, as well as on the patient's age and liver and kidney function.
The following doses are general recommendations for the specified indications. In particularly severe cases, the highest dose within the recommended range should be used.
Adults and children aged 12 years and older (≥ 50 kg): 1–2 g (calculated as ceftriaxone) once daily (every 24 hours). In severe cases or infections caused by pathogens with only moderate sensitivity to the medicinal product, the daily dose may be increased up to 4 g (calculated as ceftriaxone).
Indications in adults and children aged 12 years and older (≥ 50 kg) requiring special treatment regimens:
Acute otitis media.
A single intramuscular dose of 1–2 g of the medicinal product (calculated as ceftriaxone) may be administered.
Some data suggest that in cases of severe condition or previous ineffective therapy, the drug may be effective when administered intramuscularly at a dose of 1–2 g daily for 3 days.
Gonorrhea.
For the treatment of gonorrhea, a single intramuscular dose of 500 mg (calculated as ceftriaxone) is recommended.
Children.
Neonates (up to 14 days) (doses are given calculated as ceftriaxone): 20–50 mg/kg body weight once daily. The daily dose should not exceed 50 mg/kg body weight.
Contraindicated in preterm neonates under 41 weeks (gestational age + chronological age).
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 the medicinal product at a dose of 50 mg/kg may be administered.
Children aged 15 days to 12 years (< 50 kg): 50–100 mg/kg body weight once daily.
Lower respiratory tract infections: 50–80 mg/kg once daily.
Abdominal infections: 50–80 mg/kg once daily.
Complicated urinary tract infections: 50–80 mg/kg once daily.
Skin and soft tissue infections: 50–100 mg/kg (but not more than 4 g calculated as ceftriaxone) once daily.
Bone and joint infections: 50–100 mg/kg (but not more than 4 g calculated as ceftriaxone) once daily.
For bacterial meningitis in infants and children aged 15 days to 12 years, initiate treatment with a dose of 80–100 mg/kg (but not more than 4 g calculated as ceftriaxone) once daily. Once the causative agent is identified and its susceptibility determined, the dose may be reduced accordingly.
Indications in neonates, 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 the medicinal product at a dose of 50 mg/kg may be administered. Some data suggest that in cases of severe condition or previous ineffective therapy, the drug may be effective when administered intramuscularly at a dose of 50 mg/kg daily for 3 days. Children with body weight exceeding 50 kg should receive adult doses. The total daily dose for children should not exceed 2 g (calculated as ceftriaxone).
Intravenous doses of 50 mg/kg or higher should be administered by infusion over at least 30–60 minutes.
Duration of treatment.
The duration of treatment depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, the medicinal product should be continued for 48–72 hours after the disappearance of fever or until eradication of the bacterial infection is confirmed.
Elderly patients.
No dose adjustment is required in elderly patients with normal kidney and liver function.
Patients with hepatic impairment.
Available data indicate that dose adjustment is not necessary in patients with mild to moderate hepatic impairment if renal function is normal.
There are no study data available for patients with severe hepatic impairment (see section "Pharmacokinetics").
Patients with renal impairment.
For patients with mild to moderate renal impairment, there is no need to reduce the dose.
Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min), the daily dose should not exceed 2 g (calculated as ceftriaxone). Patients with severe hepatic and renal dysfunction.
In cases of concomitant severe renal and hepatic impairment, plasma concentrations of ceftriaxone should be monitored regularly, and the dose adjusted as necessary.
Careful clinical monitoring of the safety and efficacy of the medicinal product is recommended in patients with concomitant severe renal and hepatic impairment.
For patients undergoing hemodialysis, there is no need to administer an additional dose after dialysis. Ceftriaxone is not eliminated by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the medicinal product is recommended. However, serum concentrations of ceftriaxone should be monitored for possible dose adjustment, as elimination may be reduced in these patients. The daily dose of the medicinal product in patients undergoing hemodialysis should not exceed 2 g (calculated as ceftriaxone).
Preparation of solutions.
Prepare solutions immediately before use.
Intramuscular injection.
For intramuscular injection, dissolve the contents of the vial in 3.5 mL of 1% lidocaine solution; administer injection deeply into the gluteal muscle. The drug may be administered by deep intramuscular injection. Intramuscular injection should be performed into the center of a relatively large muscle. It is recommended not to administer more than 1 g at one site (calculated as ceftriaxone).
If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is recommended to consult the lidocaine package insert.
Intravenous injection.
For intravenous injection, dissolve the contents of one vial of the medicinal product in 10 mL of sterile water for injection.
Intravenous infusion.
To prepare the infusion solution, dissolve the contents of the vial of the medicinal product in 40 mL of one of the following calcium-free infusion solutions: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% glucose solution, water for injection. Due to possible incompatibility, solutions containing ceftriaxone and tazobactam must not be mixed with solutions containing other antibiotics, either during preparation or administration. Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to dissolve the medicinal product in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of calcium salts of ceftriaxone may also occur when the medicinal product is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, the drug must not be administered intravenously simultaneously with calcium-containing solutions (see sections "Contraindications," "Special precautions," and "Incompatibility"), including long-term infusion solutions containing calcium, such as parenteral nutrition (see "Interaction with other medicinal products and other forms of interaction").
The drug may be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection lasting more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion to infants and children up to 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"). Intramuscular administration should be considered when intravenous administration is not feasible or less acceptable for the patient. Doses exceeding 2 g should be administered intravenously.
The drug 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 calcium salts of ceftriaxone (see section "Contraindications").
Children.
Administer to children according to the recommendations provided in the section "Method of Administration and Dosage."
The drug is contraindicated for use in neonates aged ≤ 28 days when treatment with intravenous calcium-containing solutions is required (or expected), including intravenous infusions containing calcium, such as parenteral nutrition, due to the risk of precipitation of calcium salts of ceftriaxone (see section "Method of Administration and Dosage").
Cases of fatal pulmonary and renal precipitation have been reported in neonates and preterm infants following concomitant administration of ceftriaxone and calcium-containing products. In some of these cases, the same intravenous infusion systems were used for administering ceftriaxone and calcium-containing solutions, and precipitation was observed in some infusion systems.
Overdose.
Symptoms: information on cases of overdose with the medicinal product in humans is limited. In overdose, nausea, vomiting, and diarrhea may occur. High concentrations of β-lactam antibiotics in cerebrospinal fluid may cause neurological reactions, including seizures.
Treatment: excessive plasma concentrations of ceftriaxone cannot be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Symptomatic therapy is recommended for the management of overdose.
Side effects.
Infections and infestations: candidiasis, fungal genital tract infections, secondary fungal infections and infections caused by resistant microorganisms, superinfections.
Blood and lymphatic system disorders: eosinophilia, neutropenia (associated with prolonged use, reversible), leukopenia, leukocytosis, lymphopenia, granulocytopenia, anemia including hemolytic anemia, thrombocytopenia, thrombocytosis, basophilia, increased/decreased prothrombin time, coagulation disorders, hypoprothrombinemia, agranulocytosis (less than 500 mm³), predominantly after administration of a total dose of 20 g. Blood counts should be monitored regularly during prolonged treatment.
Gastrointestinal disorders: loose stools, diarrhea, nausea, vomiting, flatulence, stomatitis, taste disturbances, glossitis; pancreatitis, possibly developed due to biliary tract obstruction. Precipitates formed by ceftriaxone in the biliary tract may have contributed to pancreatitis; pseudomembranous enterocolitis has been reported.
Hepatobiliary disorders: pseudocholelithiasis of the gallbladder, precipitates of calcium ceftriaxone salt in the gallbladder with corresponding symptoms in children, reversible cholelithiasis in children, increased activity of liver transaminases and alkaline phosphatase, hyperbilirubinemia, nuclear jaundice, hepatitis1, cholestatic hepatitis1,2.
Skin and subcutaneous tissue disorders: skin rashes; allergic dermatitis; pruritus; urticaria; swelling, including angioneurotic edema; acute generalized exanthematous pustulosis, exanthema; exudative multiform erythema; Stevens–Johnson syndrome; toxic epidermal necrolysis (Lyell’s syndrome); drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions").
Renal and urinary disorders: increased blood urea and creatinine concentrations, oliguria, hematuria, glucosuria; cylindruria, interstitial nephritis.
Neurological disorders: headache, dizziness, tremor, seizures.
Cardiac disorders: increased or decreased blood pressure, palpitations.
Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm.
Immune system disorders: anaphylactic or anaphylactoid reactions, anaphylactic shock, hypersensitivity, Jarisch–Herxheimer reaction.
Ear and labyrinth disorders: vertigo.
General disorders: fever, chills, serum sickness, edema, epistaxis, weakness.
Local reactions: following intravenous administration – phlebitis, pain, induration along the vein; following intramuscular administration – pain at injection site. Intramuscular injection without lidocaine is painful.
Impact on laboratory test results.
Increased blood creatinine levels. In isolated cases, patients treated with this medicinal product may show false-positive results in the Coombs test. As with other antibiotics, the drug may cause false-positive results in galactosemia testing. False-positive results may also occur in urine glucose testing; therefore, during treatment with this drug, glucosuria should be assessed only by enzymatic methods if necessary.
Cases of diarrhea following ceftriaxone use may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions").
Precipitates of calcium ceftriaxone salt.
Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and full-term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing solutions. Post-mortem examinations revealed precipitates of calcium ceftriaxone salt in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer elimination half-life of ceftriaxone compared to adults (see sections "Contraindications", "Special precautions").
Cases of precipitate formation in the kidneys, primarily in children aged 3 years and older, have been reported in patients receiving high daily doses of the drug (≥ 80 mg/kg/day) or cumulative doses exceeding 10 g, as well as in patients with additional risk factors (limited fluid intake, bed rest). The risk of precipitate formation increases in immobilized patients or in those with dehydration. Renal precipitate formation may be asymptomatic or clinically evident and may lead to renal failure, which resolves after discontinuation of ceftriaxone treatment.
Cases of calcium ceftriaxone salt precipitate formation in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. According to prospective studies in children, the incidence of precipitate formation following intravenous administration of the drug varied, in some studies exceeding 30%. The incidence appears to be lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with clinical 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").
1 Usually reversible upon discontinuation of ceftriaxone.
2 See section "Special precautions".
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after medicinal product registration 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.
2 years.
Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging.
Keep out of reach and sight of children.
Incompatibilities.
The medicinal product must not be mixed with calcium-containing solutions such as Ringer’s solution or Hartmann’s solution, including parenteral nutrition solutions, due to the potential formation of precipitates.
Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, aminoglycosides, and other antibiotics.
Packaging.
1 vial per cardboard pack.
Prescription status.
Prescription only.
Manufacturer.
Sens Laboratory Pvt. Ltd.
Manufacturer’s address and place of business.
VI/51B, Post Box No. 2, Kothuvally, Pala, Kottayam – 686 573, Kerala, India.