Rocephin^® (Powder) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

ATC Code

J01DD04 (Ceftriaxone)

Active Substance

Ceftriaxone (Rec.INN registered by WHO)

Dosage Forms

	Rocephin®	Powder for preparation of solution for intravenous administration 1 g: vial 1 pc. in a set with solvent
	Rocephin®	Powder for preparation of solution for intramuscular administration 1 g: vial 1 pc. in a set with solvent
	Rocephin®	Powder for preparation of solution for intravenous and intramuscular administration 1 g: vial 1 or 143 pcs. in a set with solvent
	Rocephin®	Powder for preparation of solution for infusion 2 g, vial 1 pc.
	Rocephin®	Powder for preparation of solution for intravenous administration 250 mg: vial 5 pcs. in a set with solvent
	Rocephin®	Powder for preparation of solution for intramuscular administration 250 mg: vial 5 pcs. in a set with solvent
	Rocephin®	Powder for preparation of solution for intravenous administration 500 mg: vial 1 pc. in a set with solvent
	Rocephin®	Powder for preparation of solution for intramuscular administration 500 mg: vial 1 pc. in a set with solvent

Dosage Form, Packaging, and Composition

Powder for preparation of solution for intramuscular administration from white to yellowish-orange color.

Solvent 1% lidocaine solution – 2 ml.

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.

Powder for preparation of solution for intramuscular administration from white to yellowish-orange color.

Solvent 1% lidocaine solution – 2 ml.

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.

Powder for preparation of solution for intramuscular administration from white to yellowish-orange color.

Solvent 1% lidocaine solution – 3.5 ml.

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.

Powder for preparation of solution for intravenous administration from white to yellowish-orange color.

Solvent water for injections – 5 ml.

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.

Powder for preparation of solution for intravenous administration from white to yellowish-orange color.

Solvent water for injections – 5 ml.

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.

Powder for preparation of solution for intravenous administration from white to yellowish-orange color.

Solvent water for injections – 10 ml.

Glass vials (1) in a set with solvent (amp. 1 pc.) – cardboard packs.

Powder for preparation of solution for intravenous and intramuscular administration from white to yellowish-orange color.

Glass vials (1) – cardboard packs.

Powder for preparation of solution for infusion from white to yellowish-orange color.

Glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Third generation cephalosporin

Pharmacotherapeutic Group

Antibiotic-cephalosporin

Pharmacological Action

Antibiotic of the cephalosporin group of the third generation for parenteral use. It is characterized by a prolonged action.

The bactericidal activity of ceftriaxone is due to the suppression of the synthesis of cell membranes. In vitro, Ceftriaxone has a broad spectrum of action against gram-negative and gram-positive microorganisms. It is highly resistant to most β-lactamases (both penicillinases and cephalosporinases) produced by gram-positive and gram-negative bacteria.

Active against the following microorganisms.

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 (groups not A, not B), Streptococcus viridans, Streptococcus pneumoniae.

Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. As a rule, Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are also resistant.

Gram-negative aerobes Acinetobacter lwoffi, Acinetobacter anitratus (mainly, A. baumannii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, Alcaligenes-like bacteria, Borrelia burgdorferi, Capnocytophaga spp., Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter spp.* (including Enterobacter aerogenes*, Enterobacter cloacae*), Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella spp. (including Moraxella catarrhalis, Moraxella osloensis), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris*, Pseudomonas spp. (including Pseudomonas fluorescens*), Providentia spp. (including Providentia rettgeri*), Salmonella spp. (including Salmonella typhi), Serratia spp.* (including Serratia marcescens*), Shigella spp., Vibrio spp., Yersinia spp. (including Yersinia enterocolitica).

* Some isolates of these species are resistant to ceftriaxone, mainly due to the production of chromosomally encoded β-lactamases.

** Some isolates of these species are resistant due to the production of a number of plasmid-mediated β-lactamases.

Many strains of the above microorganisms, polyresistant to other antibiotics such as aminopenicillins and ureidopenicillins, first and second generation cephalosporins and aminoglycosides, are sensitive to ceftriaxone. Treponema pallidum is sensitive to ceftriaxone in vitro and in animal experiments. Clinical trials show that Ceftriaxone has good efficacy against primary and secondary syphilis. With very few exceptions, clinical isolates of P. aeruginosa are resistant to ceftriaxone.

Anaerobes Bacteroides spp. (bile-sensitive)*, Clostridium spp. (except C. difficile), Fusobacterium spp. (including Fusobacterium nucleatum), Gaffkia anaerobica (formerly called Peptococcus), Peptostreptococcus spp.

* Some isolates of these species are resistant to ceftriaxone due to β-lactamase production.

Many strains of β-lactamase-producing Bacteroides spp. (in particular, B. fragilis) are resistant to Ceftriaxone. Clostridium difficile is also resistant.

Sensitivity to ceftriaxone can be determined by the disk diffusion method or by the serial dilution method on agar or broth, using a standard technique similar to that recommended by the National Committee for Clinical Laboratory Standards (NCCLS). NCCLS has established the following criteria for evaluating the test results for ceftriaxone.

For determination, disks with ceftriaxone should be used, because in vitro studies have shown that Ceftriaxone is active against individual strains that show resistance when using disks intended for the entire group of cephalosporins.

Instead of NCCLS standards, other well-standardized standards, such as DIN and ICS, which allow adequate interpretation of the sensitivity status, can also be used to determine the sensitivity of microorganisms.

Pharmacokinetics

The pharmacokinetics of ceftriaxone is nonlinear.

All major pharmacokinetic parameters based on total drug concentrations, except for the half-life, are dose-dependent.

Absorption

C_max in plasma after a single intramuscular injection of 1 g of the drug is about 81 mg/L and is reached within 2-3 hours after administration. AUC after intravenous and intramuscular administration is the same. This means that the bioavailability of ceftriaxone after intramuscular administration is 100%.

Distribution

The V_d of ceftriaxone is 7-12 L. After administration at a dose of 1-2 g, Ceftriaxone penetrates well into body tissues and fluids. For more than 24 hours, its concentrations significantly exceed the minimum inhibitory concentrations for most pathogens in more than 60 tissues and fluids (including lungs, heart, biliary tract, liver, tonsils, middle ear and nasal mucosa, bones, as well as cerebrospinal, pleural and synovial fluids and prostate secretion). After intravenous use, Ceftriaxone rapidly penetrates into the cerebrospinal fluid, where bactericidal concentrations against susceptible microorganisms persist for 24 hours.

Ceftriaxone reversibly binds to albumin, and the degree of binding decreases with increasing concentration, decreasing, for example, from 95% at a plasma concentration of less than 100 mg/L to 85% at a concentration of 300 mg/L. Due to the lower concentration of albumin in the tissue fluid, the proportion of free ceftriaxone in it is higher than in plasma.

Ceftriaxone penetrates through inflamed meninges in children, including newborns. 24 hours after intravenous administration of Rocephin^® at doses of 50-100 mg/kg body weight (to newborns and infants, respectively), the concentrations of ceftriaxone in the cerebrospinal fluid exceed 1.4 mg/L. C_max in the cerebrospinal fluid is reached approximately 4 hours after intravenous administration and averages 18 mg/L. In bacterial meningitis, the average concentration of ceftriaxone in the cerebrospinal fluid is 17% of the plasma concentration, in aseptic meningitis – 4%. In adult patients with meningitis, 2-24 hours after administration of a dose of 50 mg/kg body weight, the concentrations of ceftriaxone in the cerebrospinal fluid are many times higher than the minimum inhibitory concentrations for the most common causative agents of meningitis.

Ceftriaxone crosses the placental barrier and is excreted in small concentrations in breast milk.

Metabolism

Ceftriaxone does not undergo systemic metabolism, but is converted into inactive metabolites under the action of intestinal flora.

Excretion

The total plasma clearance of ceftriaxone is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of ceftriaxone is excreted unchanged in the urine, and 40-50% is excreted unchanged in the bile. T_1/2 in adults is about 8 hours.

Pharmacokinetics in special clinical cases

In newborns, about 70% of the dose is excreted in the urine. In infants during the first 8 days of life, as well as in persons over 75 years of age, T_1/2 is 2 or 3 times longer than in adults.

In case of impaired renal or hepatic function, the pharmacokinetics of ceftriaxone changes insignificantly, only a slight increase in T_1/2 is noted. If only renal function is impaired, excretion with bile increases; if only hepatic function is impaired, excretion through urine increases.

Indications

Infectious and inflammatory diseases caused by pathogens sensitive to the drug:

• Sepsis;
• Meningitis;
• Disseminated Lyme borreliosis (early and late stages of the disease);
• Infections of the abdominal organs (peritonitis, infections of the biliary tract and gastrointestinal tract);
• Infections of bones, joints, soft tissues, skin, as well as wound infections;
• Infections in patients with weakened immunity;
• Infections of the kidneys and urinary tract;
• Infections of the respiratory tract, especially pneumonia;
• Infections of ENT organs;
• Infections of the genital organs, including gonorrhea.

Perioperative prevention of infections.

ICD codes

Dosage Regimen

Adults and children over 12 years of age are prescribed 1-2 g once a day (every 24 hours). In severe cases or for infections caused by pathogens with only moderate sensitivity to ceftriaxone, the daily dose can be increased to 4 g.

Newborns (under 2 weeks of age) are prescribed at a dose of 20-50 mg/kg of body weight once a day. The daily dose should not exceed 50 mg/kg of body weight. When determining the dose, no distinction should be made between full-term and premature infants.

Infants and young children (aged 15 days to 12 years) are prescribed the drug at a dose of 20-80 mg/kg of body weight once a day. Children weighing over 50 kg are prescribed adult doses. The intravenous drug at a dose of 50 mg/kg or higher should be administered by drip over at least 30 minutes.

No dose adjustment is required for elderly patients.

The duration of treatment depends on the course of the disease. As always with antibiotic therapy, administration of Rocephin^® should be continued for at least 48-72 hours after normalization of body temperature and confirmation of pathogen eradication.

Experiments have shown synergy between Rocephin^® and aminoglycosides against many gram-negative bacteria. Although the increased efficacy of such combinations is not always predictable, it should be considered in severe, life-threatening infections, such as those caused by Pseudomonas aeruginosa. Due to the pharmaceutical incompatibility of ceftriaxone and aminoglycosides, they should be administered separately at the recommended doses for each.

For bacterial meningitis in infants and young children, treatment is started with a dose of 100 mg/kg (but not more than 4 g) once a day. After identification of the pathogen and determination of its sensitivity, the dose can be reduced accordingly. The best results for meningococcal meningitis were achieved with a treatment duration of 4 days, for meningitis caused by Haemophilus influenzae – 6 days, and for Streptococcus pneumoniae – 7 days.

For Lyme borreliosis, adults and children are prescribed a dose of 50 mg/kg (maximum daily dose – 2 g), once a day for 14 days.

For gonorrhea (caused by penicillinase-producing and non-penicillinase-producing strains), Rocephin^® is administered intramuscularly as a single dose of 250 mg.

For the prevention of postoperative infections, depending on the degree of infectious risk, Rocephin^® is administered as a single dose of 1-2 g, 30-90 minutes before the start of surgery. For operations on the colon and rectum, the simultaneous (but separate) administration of Rocephin^® and one of the 5-nitroimidazoles, for example, ornidazole, has proven effective.

In patients with impaired renal function, there is no need to reduce the dose if liver function remains normal. The daily dose of Rocephin^® should not exceed 2 g only in cases of preterminal renal failure (creatinine clearance less than 10 ml/min).

In patients with impaired liver function, there is no need to reduce the dose if renal function remains normal.

In cases of combined severe renal and hepatic impairment, the plasma concentration of ceftriaxone should be regularly monitored and its dose adjusted if necessary. Patients on hemodialysis do not require additional administration of the drug after the session. However, the serum concentration of ceftriaxone should be monitored for possible dose adjustment, as the elimination rate in these patients may be reduced.

Rules for preparation and administration of solutions

Although the prepared solutions retain their physical and chemical stability for 6 hours at room temperature (or for 24 hours at a temperature of 2-8°C (35.6-46.4°F)), it is better to use the solutions immediately after preparation. Depending on the concentration and storage duration, the color of the solutions may vary from pale yellow to amber. The color of the solution does not affect the efficacy or tolerability of the drug.

For intramuscular injection, 250 mg or 500 mg of Rocephin^® is dissolved in 2 ml, and 1 g in 3.5 ml of 1% lidocaine solution and injected deep into the gluteal muscle. It is recommended not to inject more than 1 g in one site. The solution containing lidocaine must not be administered intravenously.

For intravenous injection, 250 mg or 500 mg of Rocephin^® is dissolved in 5 ml, and 1 g in 10 ml of sterile water for injections; it is administered intravenously slowly over 2-4 minutes.

Intravenous infusion should last at least 30 minutes. To prepare the solution, dilute 2 g of Rocephin^® 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, 5% fructose, 6% dextran in 5% glucose solution, 6-10% hydroxethylated starch, water for injections. Rocephin^® solutions must not be mixed or added to solutions containing other antibiotics or other solvents, except for those listed above, due to possible incompatibility.

Adverse Reactions

The following adverse reactions were observed during the use of Rocephin^®, which resolved either spontaneously or after discontinuation of the drug.

From the digestive system: (about 2%) – soft stools or diarrhea, nausea, vomiting, stomatitis, glossitis; sometimes (<1%) – taste disturbance; rarely – precipitation of calcium salts of ceftriaxone in the gallbladder with corresponding symptoms, pancreatitis, increased activity of liver enzymes (ALT, AST), alkaline phosphatase, hyperbilirubinemia, jaundice; in isolated cases (<0.01%) – pseudomembranous colitis.

From the hematopoietic system (about 2%) – eosinophilia, leukopenia; sometimes (<1%) – granulocytopenia, hemolytic anemia; in individual cases, agranulocytosis (< 500 cells/μl), with most cases developing after 10 days of treatment and use of the drug in a total dose of 20 g or more.

From the blood coagulation system sometimes (<1%) – thrombocytosis, thrombocytopenia, increased thromboplastin and prothrombin time; rarely – nosebleeds, decreased prothrombin time; in isolated cases (<0.01%) – coagulation disorders.

Dermatological reactions (about 1%) – rash, allergic dermatitis, itching, urticaria, edema; in individual cases – exudative multiforme erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

Allergic reactions rarely – serum sickness, anaphylactic or anaphylactoid reactions.

From the urinary system: rarely – oliguria, hematuria, increased serum creatinine concentration; in isolated cases (<0.01%) – formation of concretions in the kidneys, mainly in children over 3 years of age who received the drug either in high daily doses (≥ 80 mg/kg/day) or in a total dose of more than 10 g, and also had additional risk factors (including limited fluid intake, bed rest). The formation of kidney stones may be asymptomatic or clinically manifest, may lead to renal failure and is reversible after discontinuation of Rocephin^® therapy.

From the CNS rarely – headache, dizziness, seizure.

From the respiratory system allergic pneumonitis, bronchospasm.

Other rarely – genital mycosis, vaginitis, increased body temperature, chills, increased sweating, flushes, palpitations.

Local reactions : very rarely – phlebitis after intravenous administration. This can be avoided by administering the drug slowly over 2-4 minutes. Intramuscular injection without the use of lidocaine is painful.

Contraindications

• Hypersensitivity to cephalosporins.

The drug should be prescribed with caution in case of hypersensitivity to penicillins, in newborns with hyperbilirubinemia (especially premature infants), and during lactation (breastfeeding).

Use in Pregnancy and Lactation

The safety of Rocephin^® use in pregnant women has not been established. Ceftriaxone crosses the placental barrier. During pregnancy, especially in the first trimester, the drug should be prescribed only for strict indications.

Preclinical experimental studies of reproduction did not reveal embryotoxic, fetotoxic, teratogenic effects or other adverse effects of the drug on male and female fertility, the birth process, or perinatal and postnatal development of the fetus.

Ceftriaxone is excreted in breast milk in small concentrations. Caution should be exercised when prescribing it during lactation (breastfeeding).

Use in Hepatic Impairment

In patients with impaired liver function, there is no need to reduce the dose if renal function remains normal.

In cases of combined severe renal and hepatic impairment, the plasma concentration of ceftriaxone should be regularly monitored and its dose adjusted if necessary. Patients on hemodialysis do not require additional administration of the drug after the session. However, the serum concentration of ceftriaxone should be monitored for possible dose adjustment, as the elimination rate in these patients may be reduced.

Use in Renal Impairment

In patients with impaired renal function, there is no need to reduce the dose if liver function remains normal. The daily dose of Rocephin^® should not exceed 2 g only in cases of preterminal renal failure (creatinine clearance less than 10 ml/min).

In cases of combined severe renal and hepatic impairment, the plasma concentration of ceftriaxone should be regularly monitored and its dose adjusted if necessary. Patients on hemodialysis do not require additional administration of the drug after the session. However, the serum concentration of ceftriaxone should be monitored for possible dose adjustment, as the elimination rate in these patients may be reduced.

Pediatric Use

Children over 12 years of age are prescribed 1-2 g once a day (every 24 hours). In severe cases or for infections caused by pathogens with only moderate sensitivity to ceftriaxone, the daily dose can be increased to 4 g.

Newborns (under 2 weeks of age) are prescribed at a dose of 20-50 mg/kg of body weight once a day. The daily dose should not exceed 50 mg/kg of body weight. When determining the dose, no distinction should be made between full-term and premature infants.

Infants and young children (aged 15 days to 12 years) are prescribed the drug at a dose of 20-80 mg/kg of body weight once a day. Children weighing over 50 kg are prescribed adult doses. The intravenous drug at a dose of 50 mg/kg or higher should be administered by drip over at least 30 minutes.

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

When using Rocephin^®, as with other cephalosporins, even with careful history taking, the possibility of anaphylactic shock cannot be excluded. In patients with hypersensitivity to penicillin, the possibility of cross-allergic reactions should be kept in mind.

When using Rocephin^®, as with treatment with other antibiotics, superinfections may develop.

In patients with renal failure, dose adjustment is usually not required because Ceftriaxone is excreted in urine and bile. It is recommended to periodically determine the concentration of the drug in the blood.

In patients with impaired renal and liver function, the daily dose of Rocephin^® should not exceed 2 g without monitoring the concentration of the drug in the blood.

Rare cases of changes in prothrombin time have been described in patients receiving Rocephin^®. Patients with vitamin K deficiency (impaired synthesis, malnutrition) may require monitoring of prothrombin time during therapy and administration of vitamin K (10 mg/week) if prothrombin time is increased before or during therapy.

After the use of ceftriaxone, usually in doses exceeding the standard recommended ones, shadows were detected on gallbladder ultrasound, which were mistakenly taken for stones. They represent precipitates of the calcium salt of ceftriaxone, which disappear after completion or discontinuation of Rocephin^® therapy. Such changes rarely cause any symptoms, but even in such cases, only conservative treatment is recommended. If these phenomena are accompanied by clinical symptoms, the decision to discontinue the drug is made by the attending physician.

Rare cases of pancreatitis have been described in patients receiving Rocephin^®, possibly due to obstruction of the biliary tract. Most of these patients already had risk factors for biliary stasis, such as previous therapy, severe diseases, and total parenteral nutrition. In this case, the triggering role of precipitates formed under the influence of Rocephin^® in the biliary tract in the development of pancreatitis cannot be excluded.

Caution should be exercised when prescribing Rocephin^® to newborns with hyperbilirubinemia. Rocephin^® should not be used in newborns, especially premature infants, who are at risk of developing bilirubin encephalopathy.

With long-term treatment, the blood picture should be regularly monitored.

In rare cases, during treatment with Rocephin^®, patients may have false-positive Coombs test results. Like other antibiotics, Rocephin^® may give a false-positive result in the test for galactosemia. False-positive results may also be obtained when determining glucose in urine, therefore, during therapy with Rocephin^®, glucosuria, if necessary, should be determined only by the enzymatic method.

Overdose

Treatment consists of symptomatic therapy. There is no specific antidote. Hemodialysis and peritoneal dialysis are not effective.

Drug Interactions

With simultaneous use of Rocephin^® in high doses and potent diuretics (for example, furosemide), no impairment of renal function was observed.

There are no indications that Rocephin^® increases the nephrotoxicity of aminoglycosides.

The use of ethanol after administration of Rocephin^® was not accompanied by a disulfiram-like reaction. Ceftriaxone does not contain an N-methylthiotetrazole group that could cause ethanol intolerance and bleeding, which is inherent in some other cephalosporins.

Probenecid does not affect the excretion of Rocephin^®.

Bacteriostatic antibiotics reduce the bactericidal effect of ceftriaxone.

In vitro, antagonism between chloramphenicol and ceftriaxone was found.

Pharmaceutical interaction

Rocephin^® should not be added to infusion solutions containing calcium, for example, Hartmann’s and Ringer’s solutions.

Ceftriaxone is incompatible and should not be mixed with amsacrine, vancomycin, fluconazole and aminoglycosides.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

The prepared solution can be stored at room temperature for no more than 6 hours or in the refrigerator (at a temperature of 2-8°C (35.6-46.4°F)) for no more than 24 hours.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.