Sanaxon plus – 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SANAXONE PLUS - 1000 (SANAXONE PLUS - 1000)

Composition:

Active substances: ceftriaxone, sulbactam;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg, sulbactam sodium equivalent to sulbactam 500 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder ranging from almost white to yellow in color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Third-generation cephalosporins. Ceftriaxone and β-lactamase inhibitor.

ATC code J01D D63.

Pharmacological properties.

Pharmacodynamics.

CAXON PLUS 1000 is a combination preparation containing:

− ceftriaxone (a third-generation cephalosporin) with a broad spectrum of activity against susceptible microorganisms during the phase of active multiplication by inhibiting the biosynthesis of the muropeptide of the cell membrane;

− sulbactam, an irreversible inhibitor of most major β-lactamases produced by penicillin-resistant microorganisms. Sulbactam exerts significant antibacterial activity only against Neisseriaceae, Acinetobacter calcoaceticus, Bacteroides spp., Branhamella catarrhalis, Pseudomonas cepacia. Sulbactam acts synergistically with penicillins and cephalosporins and also binds to certain proteins that inactivate penicillin; therefore, some susceptible strains exhibit increased sensitivity to the combination compared to monotherapy with a β-lactam antibiotic.

Sulbactam is active against (including β-lactamase-producing resistant strains):

− Gram-positive (aerobes): Staphylococcus aureus (methicillin-sensitive strains), coagulase-negative staphylococci, Streptococcus pyogenes (β-hemolytic, group A), Streptococcus agalactiae (β-hemolytic, group B), β-hemolytic streptococci (other than groups A and B), Streptococcus viridans, Streptococcus pneumoniae. It should be noted that methicillin-resistant Staphylococcus spp., as well as Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, are resistant to cephalosporins, including ceftriaxone;

− Gram-negative (aerobes): Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, alkali-like bacteria, Citrobacter diversus (including C. amalonaticus), Citrobacter freundii, Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter spp. (others), Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis (formerly known as Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, 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).

The combination of ceftriaxone and sulbactam, like ceftriaxone alone, is used for the treatment of gonorrhea and syphilis, since Treponema pallidum is sensitive to ceftriaxone in vitro and in animal experiments, and clinical trials have shown that ceftriaxone is highly effective against primary and secondary syphilis;

− anaerobes: Bacteroides spp. (including some strains of B. fragilis), Clostridium spp. (except C. difficile), Fusobacterium spp. (except F. mortiferum and F. varium), Gaffkia anaerobica (formerly known as Peptococcus), Peptostreptococcus spp.

Note. Many β-lactamase-producing strains of Bacteroides spp., including B. fragilis, as well as Clostridium difficile, are resistant to ceftriaxone.

Since the main active ingredient of the drug is ceftriaxone, susceptibility to sulbactam is determined based on susceptibility to ceftriaxone, which can be assessed by the disk diffusion method or by the serial dilution method on agar or broth.

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 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 prostate secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated dosing; steady-state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates the meninges. Penetration is more pronounced in the presence of meningeal inflammation. 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 meningeal inflammation. Peak concentrations in cerebrospinal fluid are achieved 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 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.

Excretion

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 twofold), even in patients with severe renal impairment.

The moderate increase in half-life in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and a corresponding increase in total ceftriaxone 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 an increased volume of distribution corresponding to the 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.

The 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 to a lesser extent than proportionally to the dose. Non-linearity is observed due to saturation of plasma protein binding, and thus it is evident for total ceftriaxone in plasma, but not for the free (unbound) fraction.

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;

‒ kidney and urinary tract infections;

‒ bone and joint infections;

‒ septicemia;

‒ intra-abdominal infections (peritonitis, biliary tract and gastrointestinal tract infections);

‒ meningitis;

‒ gonorrhea;

‒ surgical infection prophylaxis.

Contraindications.

Hypersensitivity to ceftriaxone, β-lactamase inhibitors, or to antibiotics belonging to the cephalosporin and penicillin groups. In patients with known penicillin hypersensitivity, cross-allergic reactions should be considered. 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 impairment; history of gastrointestinal disorders, 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 ceftriaxone calcium salt (see sections "Special precautions for use" 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.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use"). Refer to the lidocaine product information, particularly regarding contraindications.

Ceftriaxone solutions 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 reconstitute ceftriaxone in vials or to dilute reconstituted solution for intravenous administration, due to the risk of precipitation of ceftriaxone calcium salts. Precipitation of ceftriaxone calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Ceftriaxone must not be administered intravenously simultaneously with calcium-containing solutions, including calcium-containing parenteral nutrition solutions, via a Y-site infusion 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. A small number of fatal cases due to precipitation of ceftriaxone calcium salts in the lungs and kidneys of neonates have been reported. In some cases, venous access and timing of administration of ceftriaxone and calcium-containing solutions differed. In vitro studies using adult and neonatal umbilical plasma have shown an increased risk of ceftriaxone calcium salt precipitation in neonates (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Adverse reactions").

Concomitant use of ceftriaxone 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 adjusted appropriately during and after ceftriaxone therapy (see section "Adverse reactions").

Data on the potential for enhanced nephrotoxic effects of aminoglycosides when used concomitantly with cephalosporins are conflicting. In such cases, careful adherence to clinical monitoring recommendations for aminoglycoside levels (and renal function) is advised.

Ceftriaxone must not be mixed with amikacin, vancomycin, fluconazole, or aminoglycosides.

No renal function disturbances have been observed when high doses of ceftriaxone are used concomitantly with potent diuretics such as furosemide.

Ceftriaxone contains an N-methylthiotetrazole (NMTT) side chain, which may cause alcohol 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 interactions between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (administered intravenously or orally).

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

Like other antibiotics, ceftriaxone may cause false-positive galactosemia test results.

Similarly, false-positive glucose in urine results may occur when non-enzymatic methods are used for urine glucose testing. Therefore, during ceftriaxone therapy, urine glucose levels 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 ceftriaxone excretion.

Like other antibiotics, ceftriaxone may reduce the effectiveness of the typhoid vaccine, but this effect applies only to the attenuated Ty21a strain.

Alcohol. Reactions such as facial flushing, increased sweating, headache, and tachycardia have been reported when alcohol is consumed during treatment and within 5 days after treatment. No disulfiram-like (antabuse-like) effects were observed when alcohol was consumed immediately after ceftriaxone administration. Similar reactions have been observed with other cephalosporins. Patients should be cautious when consuming alcoholic beverages during treatment with this drug. Ethanol-containing solutions must not be used when administering artificial nutrition (oral or parenteral).

Special precautions for use.

Hypersensitivity reactions.

As with other cephalosporins, anaphylactic reactions (including anaphylactic shock) with fatal outcomes have been reported during ceftriaxone administration, even in patients without prior history of hypersensitivity. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). 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 β-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other β-lactam drugs. If allergic reactions occur, 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, ceftriaxone should be administered with caution to patients predisposed 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 "Side effects").

The drug may increase prothrombin time. Therefore, prothrombin time should be monitored if vitamin K deficiency is suspected.

Encephalopathy.

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

Jarisch–Herxheimer reaction.

Shortly after initiation of ceftriaxone therapy, some patients with spirochetal 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 such reactions.

The drug may increase prothrombin time. Therefore, prothrombin time should be monitored if vitamin K deficiency is suspected.

Colitis/overgrowth of resistant microorganisms.

Diarrhea associated with Clostridium difficile may occur during treatment with nearly all antibacterial agents, including ceftriaxone and sulbactam, ranging from mild diarrhea to fatal colitis. Antibacterial agents alter the normal gut flora, 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 may 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 two months after completion of antibacterial therapy. Discontinuation of ceftriaxone and initiation of appropriate therapy against Clostridium difficile should be considered. Antiperistaltic agents should not be used.

Appropriate fluid and electrolyte replacement, protein supplementation, antibiotic therapy effective against Clostridium difficile, and surgical evaluation should be provided as clinically indicated.

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

Prolonged use of ceftriaxone may lead to difficulties in controlling resistant microorganisms. Therefore, careful monitoring of patients is required. If superinfection occurs, appropriate measures should be taken.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate 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 organisms resistant to ceftriaxone, additional antibiotics should be considered.

Cholelithiasis.

Following administration of ceftriaxone, usually at doses exceeding standard recommended levels, ultrasound examination of the gallbladder may reveal shadows that are falsely interpreted as gallstones. These are precipitates of ceftriaxone calcium salt that resolve after discontinuation or cessation of ceftriaxone therapy. In rare cases, formation of ceftriaxone calcium salt precipitates has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on discontinuation of the drug based on individual benefit-risk assessment (see section "Side effects").

Biliary stasis.

Cases of pancreatitis possibly due to obstruction of biliary tracts have been reported in patients receiving ceftriaxone. Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, or total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone use cannot be excluded as a triggering or contributing factor.

Nephrolithiasis.

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

Children.

Ceftriaxone, a component of the drug, may displace bilirubin from albumin binding sites in blood serum. Therefore, ceftriaxone is contraindicated in premature and full-term newborns 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 safety and efficacy of the drug is recommended (see section "Dosage and administration").

For patients with impaired renal function but normal hepatic function, dosage adjustment is not required. In renal impairment (creatinine clearance below 10 mL/min), the daily dose of ceftriaxone should not exceed 2 g.

For patients with impaired hepatic function but preserved renal function, dosage adjustment is not necessary.

In cases of concomitant severe hepatic and renal 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.

Interaction with calcium-containing medicinal products.

In preterm and full-term infants under 1 month of age, fatal cases of ceftriaxone calcium salt precipitates in the lungs and kidneys have been reported. In at least one of these cases, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, confirmed cases of intravascular precipitates have not been reported except in newborns who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have shown that newborns have an increased risk of ceftriaxone calcium salt precipitate formation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering through different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided they are administered through different infusion systems at different body sites or the infusion system is replaced or thoroughly flushed with physiological 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 such precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous parenteral nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and at different body sites. Alternatively, TPN infusion may be paused during ceftriaxone infusion, and infusion systems flushed between administrations (see sections "Contraindications," "Side effects," and "Incompatibilities").

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"). Cases of severe hemolytic anemia, including fatal cases, have been reported in both adult and pediatric patients.

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

Long-term therapy.

During prolonged treatment, regular monitoring of blood parameters is recommended.

Sodium.

Ceftriaxone sodium and sulbactam sodium contain sodium, which should be taken into account in patients on a sodium-restricted diet.

Effect on serological test results.

The drug may cause false-positive results in the Coombs test. 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 treatment with the drug, urine glucose levels should be determined using enzymatic methods (see section "Side effects").

Use of lidocaine.

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

Disposal of medicinal product.

Environmental contamination by the medicinal product should be minimized. The drug must not be disposed of via wastewater or household waste. Any unused medicinal product after completion of treatment or expiry should be returned in its original packaging to the supplier (physician or pharmacist) for proper disposal.

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, peri- or 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 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 to discontinue/abandon ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

Reproductive studies have not shown adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted. Due to possible side effects such as dizziness, the drug may affect the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Administer intravenously or intramuscularly. Prior to administration, perform skin sensitivity tests for the antibiotic and lidocaine.

Adults and children aged 12 years and older: 1–2 g (calculated as ceftriaxone) once daily (every 24 hours). In severe cases or infections caused by pathogens with reduced sensitivity to ceftriaxone, the daily dose may be increased up to 4 g (calculated as ceftriaxone).

Newborns, infants, and children under 12 years of age.

The recommended doses below are for once-daily administration.

Newborns (up to 14 days of age). Doses are expressed in terms of ceftriaxone: 20–50 mg/kg body weight once daily. The daily dose must not exceed 50 mg/kg body weight. There is no difference in dosing between full-term and preterm infants.

Ceftriaxone is contraindicated in newborns ≤ 28 days of age when treatment with intravenous solutions containing calcium is required (or anticipated), including continuous intravenous infusions containing calcium (e.g., parenteral nutrition), due to the risk of precipitation of ceftriaxone-calcium salts (see section "Contraindications").

Newborns aged 15 days and children under 12 years of age. Doses are expressed in terms of ceftriaxone: 20–80 mg/kg body weight once daily. Children with body weight exceeding 50 kg should receive adult doses.

The total daily dose in children must not exceed 2 g (calculated as ceftriaxone).

Intravenous doses exceeding 50 mg/kg (calculated as ceftriaxone) must be administered by slow infusion over 30–60 minutes.

Elderly patients. Dose adjustment is not required in elderly patients.

Duration of treatment depends on the course of the disease. After normalization of body temperature and laboratory confirmation of pathogen eradication, the drug should be continued for at least an additional 48–72 hours.

Combination therapy.

Due to evidence of synergistic effects when ceftriaxone and aminoglycosides are used together against many Gram-negative microorganisms, they may be used in severe, life-threatening infections caused by Pseudomonas aeruginosa. However, enhanced efficacy of such combinations is not always predictable. Because of physical incompatibility between ceftriaxone and aminoglycosides, they must be administered separately at their recommended doses.

Dosage in special situations.

Meningitis

For bacterial meningitis in infants and children aged 15 days to 12 years, initiate treatment with 100 mg/kg (but not exceeding 4 g calculated as ceftriaxone) once daily. Once the causative organism is identified and its sensitivity determined, the dose may be reduced accordingly. Optimal treatment durations have been observed as follows:

Neisseria meningitidis – 4 days
Streptococcus pneumoniae – 7 days
Haemophilus influenzae – 6 days
Sensitive Enterobacteriaceae – 10–14 days

Gonorrhea caused by penicillinase-producing or non-penicillinase-producing strains: single intramuscular dose of 250 mg of the drug.

Prophylaxis of postoperative infections. Doses are expressed in terms of ceftriaxone. Depending on the level of infection risk, administer a single dose of 1–2 g (calculated as ceftriaxone) 30–90 minutes before the start of surgery. For procedures on the colon and rectum, simultaneously (but separately) administer a 5-nitroimidazole (e.g., ornidazole).

Renal impairment. Dose reduction is not required if liver function remains normal. Only in pre-terminal renal failure with creatinine clearance below 10 mL/min should the daily dose not exceed 2 g (calculated as ceftriaxone).

In patients undergoing dialysis, there is no need for additional dosing after dialysis; however, serum ceftriaxone concentration should be monitored (and dose adjusted if necessary), as elimination may be reduced in these patients.

The daily dose in dialysis patients must not exceed 2 g.

Hepatic impairment. Dose reduction is not required if renal function remains normal.

Severe renal or hepatic insufficiency

Plasma ceftriaxone concentrations should be monitored regularly, and dosage adjusted as necessary, since elimination may be reduced in such patients.

Reconstitution and administration instructions.

From a microbiological standpoint, the drug should be used immediately. If not used immediately, storage duration and conditions prior to use are the responsibility of the user and generally should not exceed 24 hours at 2–8 °C, unless reconstitution/dilution was performed under controlled and validated aseptic conditions.

For intramuscular injections: dissolve the vial contents in 3.5 mL of 1% lidocaine solution or 5 mL of water for injection; inject into the gluteal muscle. It is recommended not to administer more than 1 g at a single injection site.

If lidocaine is used as the solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, refer to the lidocaine product information.

Prior to using lidocaine, a sensitivity test should be performed to assess individual hypersensitivity to the agent.

For intravenous injections: dissolve the vial contents in 10 mL of water for injection; administer slowly intravenously over 2–4 minutes.

Intravenous infusion must last at least 30 minutes. To prepare the infusion solution, dissolve the vial contents in 40 mL of one of the following infusion solutions that do not contain calcium ions:

− 5% glucose solution
− 0.9% sodium chloride solution
− 5% glucose + 0.225% sodium chloride solution
− 5% glucose + 0.9% sodium chloride solution
− water for injection

Solvents containing calcium, such as Ringer’s solution or Hartmann’s solution, must not be used to reconstitute the drug in vials or to dilute the reconstituted solution for intravenous administration, due to the risk of ceftriaxone-calcium salt precipitation. Precipitation of ceftriaxone-calcium salts may also occur when the drug is mixed with calcium-containing solutions in the same intravenous infusion system. The drug must not be administered simultaneously

intravenously with calcium-containing solutions, including prolonged infusions containing calcium, such as parenteral nutrition. However, except in newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, provided the infusion system is thoroughly flushed between infusions with a compatible solution (see "Interaction with other medicinal products and other forms of interaction").

Children.

The drug is used in pediatric practice.

It is contraindicated in newborns ≤ 28 days of age when treatment with intravenous calcium-containing solutions is required (or anticipated), including intravenous infusions containing calcium, such as parenteral nutrition, due to the risk of ceftriaxone-calcium salt precipitation (see "Method of Administration and Dosage").

Cases of precipitation in lungs and kidneys leading to fatal outcomes have been reported in newborns and preterm infants following concomitant administration of ceftriaxone and calcium-containing products. In some of these cases, the same intravenous infusion system was used for both ceftriaxone and calcium-containing solutions, and precipitates were observed in some infusion lines.

Overdose.

Symptoms: Limited information is available on overdose cases. Overdose may result in intensification of adverse reactions.

Treatment: Hemodialysis or peritoneal dialysis are ineffective. No specific antidote exists. Treatment of overdose is symptomatic.

Adverse reactions.

Infections and infestations: candidiasis, genital fungal infections, secondary fungal infections and infections caused by resistant microorganisms, pseudomembranous colitis, superinfections.

Blood and lymphatic system disorders: eosinophilia, neutropenia, leukopenia, leukocytosis, lymphopenia, granulocytopenia, anemia including hemolytic anemia, thrombocytopenia, thrombocytosis, basophilia, increased/decreased prothrombin time, coagulation disorders, hypoprothrombinemia, agranulocytosis. Blood counts should be monitored regularly during prolonged therapy.

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 play a role in the development of pancreatitis; cases of pseudomembranous enterocolitis have been reported.

Hepatobiliary disorders: pseudocholelithiasis of the gallbladder, ceftriaxone calcium salt precipitates in the gallbladder with corresponding symptoms in children, reversible cholelithiasis in children, increased activity of liver transaminases and alkaline phosphatase, hyperbilirubinemia, kernicterus, hepatitis\textsuperscript{1}, cholestatic hepatitis\textsuperscript{1,2}.

Skin and subcutaneous tissue disorders: skin rashes; allergic dermatitis; pruritus; urticaria; edema, 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, precipitate formation in kidneys (reversible).

Nervous system disorders: headache and dizziness, tremor, convulsions, encephalopathy.

Cardiac disorders: increased or decreased blood pressure, palpitations, Coombs syndrome (frequency unknown).

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.

Effect on laboratory test results.

Increased serum creatinine levels. Rarely, patients treated with this drug 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 administration may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be administered (see section "Special precautions").

Ceftriaxone calcium salt precipitates.

Rare cases of severe adverse reactions, sometimes fatal, have been reported in premature and full-term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing solutions. Post-mortem examinations revealed ceftriaxone calcium salt precipitates 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 have been reported, primarily in children aged 3 years and older, who received high daily doses (≥ 80 mg/kg/day) or cumulative doses exceeding 10 g, as well as those with additional risk factors (limited fluid intake, bed rest). The risk of precipitate formation increases in immobilized patients or those who are dehydrated. Renal precipitate formation may be asymptomatic or clinically apparent and may lead to renal failure, which resolves after discontinuation of ceftriaxone therapy.

Cases of ceftriaxone calcium salt precipitate formation in the gallbladder have been reported, predominantly in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence rates of precipitate formation with intravenous administration, exceeding 30% in some studies. The incidence appears to be lower with slow infusion (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").

\textsuperscript{1} Usually reversible upon discontinuation of ceftriaxone.

\textsuperscript{2} See section "Special precautions".

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as 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 of children.

Incompatibilities.

The drug must never be added to infusion solutions containing calcium, such as Hartmann’s or Ringer’s solutions, including total parenteral nutrition solutions (see sections "Administration and dosage", "Special precautions", and "Adverse reactions"), due to the risk of precipitate formation! Calcium-containing solutions should also not be administered within 48 hours after the last dose of ceftriaxone. The drug is incompatible with amsacrine, vancomycin, fluconazole, aminoglycosides, and other antibiotics.

Packaging.

1 vial per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer’s address and location of operations.

VI/51B, Post Box No. 2, Kothuval, Pala, Kottayam – 686 573, Kerala, India.