Rocephin, 1 g

Pharmacotherapeutic group

Cephalosporin antibiotic

ATX code: J01DD04

Pharmacodynamics:

Ceftriaxone is a parenteral cephalosporin III generation antibiotic. Bactericidal activity of ceftriaxone is due to inhibition of cell wall synthesis. 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.

Ceftriaxone is generally active against the following microorganisms.

Gram-positive aerobes

Staphylococcus aureus (methicillin-sensitive) coagulase-negative staphylococci. Streptococcus pyogenes (β-haemolytic group A) Streptococcus agalactiae (β-haemolytic group B). β-haemolytic streptococci (neither group A nor B) Streptococcus viridans Streptococcus pneumoniae.

Note. Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins including ceftriaxone. Enterococcus faecalis Enterococcus faecium and Listeria monocytogenes are also generally resistant.

Gram-negative aerobes

Acinetobacter lwoffii Acinetobacter anitratus (mainly. A. baumannii)* Aeromonas hydrophila Alcaligenes faecalis Alcaligenes odorans alkaligen-like bacteria 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 (previously called Branhamella catarrhalis) Moraxella osloensis Moraxella spp. Morganella morganii Neisseria gonorrhoeae Neisseria meningitidis Pasteurella multocida Plesiomonas shigelloides Proteus mirabilis Proteus penneri* Proteus vulgaris* Pseudomonas fluorescens* Pseudomonas spp. (Providencia rettgeri* Providencia spp. (other) Salmonella typhi Salmonella spp. (nontyphoid) Serratia marcescens* Serratia spp. (other)* Shigella spp. Vibrio spp. Yersinia enterocolitica Yersinia spp. (others).

* Some isolates of these species are resistant to ceftriaxone mainly due to the formation of β-lactamases. encoded by chromosomes.

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

Note. Many strains of the above microorganisms are multiresistant 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 vilro 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

Bacteroidcs spp. (bile-sensitive)* Clostridium spp. (exceptC. difficile). Fusobacterium nucleatum Fusobacterium spp. (other) Gaffkya anaerobica (formerly called Peptococcus) Peptostreptococcus spp.

* Some isolates of these species are resistant to ceftriaxone because of lactamase formation.

Note. Many strains of β-lactamase-forming Bastreudens spp. (particularly B. fragilis) are resistant. Clostridium difficile is also resistant.

Sensitivity to ceftriaxone can be determined by disc-diffusion or serial dilutions on agar or broth using a standard methodology similar to that recommended by the Institute of Clinical and Laboratory Standards (ICLS).

Pharmacokinetics:

The pharmacokinetics of ceftriaxone are nonlinear. All major pharmacokinetic parameters based on total drug concentrations except for the elimination half-life are dose-dependent and increase in less than proportional proportion to its increase. Nonlinearity is characteristic for pharmacokinetic parameters depending on the total concentration of ceftriaxone in blood plasma (not only free ceftriaxone) and is explained by saturation of binding of the drug to blood plasma proteins.

Intake

The maximum plasma concentration after a single intramuscular administration of 1 g of the drug is about 81 mg/l and is reached within 2-3 hours after administration. The areas under the curve “plasma concentration – time” after intravenous and intramuscular administration are the same. This means that bioavailability of ceftriaxone after intramuscular administration is 100%.

After intravenous bolus administration of 500 mg and 1 g of ceftriaxone average maximum plasma concentrations were 120 mg/l and 200 mg/l, respectively. After intravenous infusion of 500 mg of 1 g and 2 g of ceftriaxone, the plasma concentrations of the drug were approximately 80,150 and 250 mg/L, respectively. After intramuscular injection, the values of average maximum plasma concentration of ceftriaxone were approximately twice as low as after intravenous administration of an equivalent dose of the drug.

Distribution

The volume of distribution of ceftriaxone is 7-12 liters. After administration in a dose of 1-2 g ceftriaxone penetrates well into tissues and body fluids. For more than 24 hours, its concentrations far exceed the minimal suppressive concentrations for most infectious agents in more than 60 tissues and fluids (including lungs, heart, biliary tracts, liver, tonsils, middle ear and nasal mucosa, bones, and cerebrospinal pleural and synovial fluid and prostate secretion).

After intravenous administration ceftriaxone rapidly penetrates into the cerebrospinal fluid where bactericidal concentrations against susceptible microorganisms persist for 24 hours.

Protein binding

Ceftriaxone binds reversibly to albumin. The degree of binding is approximately 95% when values of ceftriaxone concentration in blood plasma are less than 100 mg/l. The proportion of ceftriaxone bound to plasma protein decreases with increasing concentration as the binding is saturable and is about 85% at values of 300 mg/l.

Perfusion to selected tissues

Ceftriaxone penetrates the brain membranes to the greatest extent when they are inflamed. The average maximum concentration of ceftriaxone in the cerebrospinal fluid reaches 25% of the plasma concentration of ceftriaxone in patients with bacterial meningitis and only 2% of the plasma concentration in patients with non-inflamed cerebral membranes. The maximum concentration of ceftriaxone in the cerebrospinal fluid is reached 4-6 hours after its intravenous administration. Ceftriaxone passes through the placental barrier and enters breast milk in low concentrations.

Metabolism

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

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 by the kidneys and 40-50% – unchanged in the intestine. The half-life of ceftriaxone in adults is about 8 hours.

Pharmacokinetics in special clinical cases

Newborn infants and children younger than 12 years

In newborn children the half-life of ceftriaxone is longer compared to other age groups. During the first 14 days of life, plasma concentrations of free ceftriaxone may be further increased due to low glomerular filtration and features of the drug binding to blood plasma proteins. In pediatric patients the half-life is shorter than in newborns and adults.

The values of plasma clearance and volume of distribution of total ceftriaxone are higher in newborn infants and children younger than 12 years compared to those in adults.

Patients with impaired renal or hepatic function have little change in the pharmacokinetics of ceftriaxone with only a slight increase in the half-life (less than 2-fold), even in patients with severe renal impairment. Slight increase of ceftriaxone half-life in renal insufficiency can be explained by compensatory increase of chain clearance as a result of decrease of degree of binding to plasma proteins and corresponding increase of nonrenal clearance of general ceftriaxone.

In patients with hepatic insufficiency the half-life is not increased. In these patients there is a compensatory increase in renal clearance. This is also due to an increase in the plasma concentration of free ceftriaxone which contributes to a paradoxical increase in the overall clearance of the drug against an increase in the volume of distribution.

Patients in the elderly

The elimination half-life is on average two to three times longer in patients over 75 years of age than in adult patients.

Indications

Infections caused by susceptible strains of the indicated microorganisms:

– Lower respiratory tract infections caused by E.coli, H.influenzae, K.pneumoniae and other species, Staph.aureus, Strep.pneumoniae and other species (excluding enterococci);

– Urinary tract infections (complicated and uncomplicated) caused by E.coli, Klebsiella spp, P.mirabilis and P.vulgaris;

– bacterial sepsis caused by E.coli, H.influenzae, K.pneumoniae, Staph.aureus, Strep.pneumoniae and other species (except enterococci);

– skin infections caused by K.pneumoniae and P.mirabilis, Staph.aureus, Strep.pneumoniae and other species (except enterococci);

– bone and joint infections caused by Staph.aureus, Strep.pneumoniae and other species (except enterococci);

– intra-abdominal infections caused by E.coli and K.pneumoniae;

– meningitis caused by H.influenzae, N.meningitidis and Strep.pneumoniae (ceftriaxone should not be used to treat meningitis caused by L.monocytogenes);

– uncomplicated gonorrhea (cervical/urethral, pharynx and rectum) caused by N.gonorrhoeae (penicillinase- and nonpenicillinase-producing strains).

Active ingredient

Composition

One bottle of powder for preparation of a solution for intramuscular injection contains:

ceftriaxone 250 mg, 500 mg, 1 g (as ceftriaxone dinatrium salt 298.3 mg, 596.5 mg, 1.193 g).

Solvent: lidocaine solution 1%.

How to take, the dosage

Iv/v/m, dosing regimen, route and duration of administration depend on the indication, severity of the disease and patient’s condition.

The susceptibility testing. Bacteriological culture samples for pathogen identification and determination of sensitivity to ceftriaxone must be obtained prior to initiation of therapy. Therapy may be initiated before the results of susceptibility testing are known; however, treatment modification may be necessary if results are obtained.

Prevention. Preoperative administration of a single dose of 1 g of ceftriaxone may reduce the incidence of postoperative infections in patients who have undergone vaginal or abdominal hysterectomy, aortocoronary bypass surgery, or who are at high risk for infection after biliary tract surgery. If there is evidence of postoperative infection, specimens should be obtained for culturing to identify the pathogen(s) and prescribe appropriate therapy.

Interaction

Special Instructions

Hypersensitivity reactions

As with other β-lactam antibiotics, severe hypersensitivity reactions, including death, have been reported. In case of severe hypersensitivity reactions, therapy with Rocephin® should be immediately discontinued and appropriate emergency treatment measures taken. Before starting therapy with Rocephin® it is necessary to determine whether the patient has had hypersensitivity reactions to ceftriaxone cephalosporins or severe hypersensitivity reactions to other β-lactam antibiotics (penicillins monobactams and carbapenems).

Cautious use of ceftriaxone in patients with a history of non-serious hypersensitivity reactions to other β-lactam antibiotics (penicillins monobactams and carbapenems) should be observed.

The sodium content

1 g of Rocephin® contains 3.6 mmol of sodium. This should be considered in patients on a sodium-controlled diet.

Hemolytic anemia

As with other cephalosporins, autoimmune hemolytic anemia may occur with Rocephin® treatment. Cases of severe hemolytic anemia in adults and children have been reported, including cases with fatal outcome. If a patient on ceftriaxone therapy develops anemia, the diagnosis of cephalosporin-associated anemia cannot be excluded and treatment should be discontinued until the cause is determined.

Diarrhea caused by Clostridium difficile

As with most antibacterials, cases of diarrhea caused by Clostridium difficile (C. difficile) of varying severity, from mild diarrhea to fatal colitis, have been reported with ceftriaxone treatment. Treatment with antibiotics suppresses the normal colon microflora and provokes the growth of C. difficile. In turn, C. difficile produces toxins A and B, which are factors in the pathogenesis of diarrhea caused by C. difficile. C. difficile strains hyperproducing toxins are infectious agents with a high risk of complications and mortality due to their possible resistance to antimicrobial therapy treatment may require colectomy.

It is important to remember the possibility of C. difficile-induced diarrhea in all patients with diarrhea after antibiotic therapy. A careful history must be taken, as there have been cases of C. difficile diarrhea more than 2 months after antibiotic therapy. If C. difficile diarrhea is suspected or confirmed, current non-C.difficile antibiotic therapy may need to be withdrawn. Appropriate treatment with fluid and electrolyte proteins antibiotic therapy against C. difficile surgical treatment should be prescribed according to clinical indications. Drugs inhibiting intestinal peristalsis should not be used.

Superinfections

As with treatment with other antibacterial drugs, superinfections can develop.

Changes in prothrombin time

Rare cases of changes in prothrombin time have been described in patients treated with Rocephin®. Patients with vitamin K insufficiency (impaired vitamin K synthesis) may require monitoring of prothrombin time during therapy and administration of vitamin K (10 mg/week) if prothrombin time increases before or during therapy.

The formation of ceftriaxone calcium salt precipitates

Fatal reactions have been described as a result of deposits of ceftriaxone-calcium precipitates in the lungs and kidneys of newborns. Theoretically there is a possibility of interaction of ceftriaxone with calcium-containing solutions for intravenous administration also in other age groups of patients; therefore ceftriaxone should not be mixed with calcium-containing solutions (including for parenteral nutrition) and also administered simultaneously, including through separate infusion accesses at different sites.

Theoretically, based on the calculation of 5 half-lives of ceftriaxone, the interval between the administration of ceftriaxone and calcium-containing solutions should be at least 48 hours. There are no data on possible interaction of ceftriaxone with calcium-containing drugs for oral administration and ceftriaxone for intramuscular administration with calcium-containing drugs (intravenous or for oral administration).

After administration of ceftriaxone usually in doses exceeding the standard recommended ones (1 g per day or more) an ultrasound examination of the gallbladder revealed precipitates of the calcium salt of ceftriaxone, formation of which is most likely in pediatric patients. Precipitates rarely produce any symptoms and disappear after completion or discontinuation of therapy with Rocephin®.

If l and phenomena are associated with clinical symptoms, conservative nonsurgical treatment is recommended and the decision to discontinue is left to the discretion of the treating physician and must be based on an individualized benefit-risk assessment.

While there is evidence of intravascular precipitate formation only in neonates when using ceftriaxone and calcium-containing infusion solutions or any other calcium-containing drug, Rozefin® should not be mixed or administered simultaneously in children and adult patients with calcium-containing infusion solutions even using different venous accesses (see Sections “Contraindications”. “Interactions with other medications” subsection “Post-registration monitoring”).

Pancreatitis

Rare cases of pancreatitis have been described in patients treated with Rocephin®, possibly due to biliary obstruction. Most of these patients already had risk factors for biliary tract congestion, such as previous therapy, severe disease, and complete parenteral nutrition. At the same time the trigger role of biliary precipitates formed under the influence of Rocephin® in the biliary tract in the development of pancreatitis cannot be excluded.

Performance in children

The safety and efficacy of Rocephin® in newborn infants and young children has been determined for the doses described under the section “Dosage and administration”. Studies have shown that, like other cephalosporins, ceftriaxone can displace bilirubin from serum albumin binding. Rocephin® should not be used in newborns, especially premature infants with risk of bilirubin encephalopathy (see section “Contraindications”).

Long-term treatment

Long-term treatment should include regular monitoring of peripheral blood counts and liver and kidney function tests.

Blood count monitoring

In long-term treatment, regular complete blood counts should be performed.

Serologic studies

False-positive results of the Coombs test for galactosemia in the determination of glucose in the urine may be noted during treatment with ceftriaxone (glucosuria is recommended to be determined by enzymatic method only).

There is no evidence of an effect of the drug on driving vehicles and operating machinery. However, during therapy with Rocephin® care should be taken while driving vehicles and operating machinery because of the possibility of dizziness and other adverse reactions which may interfere with the ability to control vehicles and machinery.

Contraindications

Side effects

Clinical trial experience

Skin: rash (1.3%), exanthema, allergic dermatitis and pruritus (0.1-1%); urticaria (post-registration reports), individual cases of severe skin adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell syndrome/toxic epidermal necrolysis).

Blood disorders: Anemia (0.1-1%), autoimmune hemolytic anemia and serum sickness (< 0.1%), immune hemolytic anemia (post-registration reports), granulocytopenia (post-registration reports), isolated cases of agranulocytosis (< 500/mm3, most after 10 days of treatment and after using total doses of 20 g or more).

Hepatic disorders: jaundice, ultrasound shadows (in asymptomatic patients and patients with a clinical picture) indicating deposits in the gallbladder, biliary sludge (< 0.1%).

Urogenital system disorders: candidiasis and vaginitis (0.1-1%), oliguria and nephrolithiasis (post-registration reports).

Gastrointestinal disorders: diarrhea (3.3%), nausea, vomiting, dysgeusia (taste disorder) and stomach pain (0.1-1%), abdominal pain, colitis, flatulence, dyspepsia, pseudomembranous colitis and stomatitis (< 0.1%), glossitis (post-registration reports).

Nervous system disorders: dizziness and headache (0.1-1%), ataxia and paresthesias (< 0.1%).

Other adverse reactions: fever, chills, sweating, malaise, burning tongue, redness, swelling, and anaphylactic shock (0.1-1%); bronchospasm, palpitations, and epistaxis (< 0.1%); pharyngeal/throat edema (post-registration reports).

Injection site reactions: pain (9.4%; pain with an I/M injection is usually mild and less frequent when ceftriaxone is injected in sterile 1% lidocaine solution), thickening and soreness (1-2%), phlebic reactions (0.1-1%), thrombophlebitis (< 0.1%).

Changes in laboratory parameters: Eosinophilia (4.6%), thrombocytosis (5.1%), leukopenia (2%), neutropenia, lymphopenia, thrombocytopenia, increase or decrease in hematocrit, prolongation of SP and decrease in Hb (0.1-1%), leukocytosis, lymphocytosis, monocytosis, basophilia and decrease in SP (< 0.1%), increased AST level (4%, more common in patients under one year of age), ALT (4.8%, more common in patients under one year of age and over 50 years), increased ALP activity (1%); increased bilirubin levels (0.1-1%), increased urea nitrogen levels (1.1%, more common in patients under one year of age and older than 50 years), increased creatinine levels, erythrocyturia, proteinuria, and presence of cylinders in urine (0.1-1%), glucosuria (< 0.1%).

Post-registration follow-up experience

A small number of deaths have been reported in which crystalline material was found at autopsy in the lungs and kidneys (in neonates receiving ceftriaxone and calcium-containing solutions). In some of these cases, the same IV infusion line was used for both ceftriaxone and calcium-containing fluids, and in some cases there was sediment in the IV infusion line. At least one fatality was reported in a neonate who received ceftriaxone and calcium-containing solutions at different points in time in different IV lines; no crystalline material was observed at autopsy in this neonate. There were no similar reports of other patients (other than neonates).

Overdose

Symptoms: echoacoustic obscurations indicating a kidney sediment formed by calcium precipitate of ceftriaxone in the urine were observed in one patient who received ceftriaxone at a dose of 10 g/day (2.5 times the maximum recommended dose). No other cases of ceftriaxone overdose have been reported.

Treatment: There is no information about the symptoms or treatment of ceftriaxone overdose. Excessive serum ceftriaxone concentration cannot be reduced by hemodialysis or peritoneal dialysis. Treatment must be symptomatic.

Similarities