Long-acting, broad-spectrum cephalosporin antibiotic for parenteral use

COMPOSITION:
Ryxon Injection 500mg Ryxon Injection 1g
Each vial contains: Each vial contains:
Ceftriaxone USP500mg Ceftriaxone USP 1g
(as Ceftriaxone Sodium) (as Ceftriaxone Sodium)

PROPERTIES, EFFECTS
Microbiology
The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone exerts in-vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ceftriaxone is highly stable to most b-lactamases, both penicillinases and cephalosporinases, of gram-positive and gram-negative bacteria. Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections (see Indications):

GRAM-POSITIVE AEROBES:
Staphylococcus aureus (including penicillinase-producing strains)
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus group A (Str. pyogenes)
Streptococcus group B (Str. agalactiae)
Streptococcus viridans
Streptococcus bovis

NOTE:
Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. Most strains of Enterococci (e.g. Streptococcus faecalis) are resistant.

GRAM-NEGATIVE AEROBES:
Aeromonas spp.
Alcaligenes spp.
Branhamella catarrhalis (b-lactamase negative and positive)
Citrobacter spp.
Enterobacter spp. (some strains are resistant)
Escherichia coli
Haemophilus ducreyi
Haemophilus influenzae (including penicillinase-producing strains)
Haemophilus parainfluenzae
Klebsiella spp. (including Kl. pneumoniae)
Moraxella spp.
Morganella morganii
Neisseria gonorrhoeae (including penicillinase-producing strains)
Neisseria meningitidis
Plesiomonas shigelloides
Proteus mirabilis
Proteus vulgaris
Providencia spp.
Pseudomonas aeruginosa (some strains are resistant)
Salmonella spp. (including S. typhi)
Serratia spp. (including S. marcescens)
Shigella spp.
Vibrio spp. (including V. cholerae)
Yersinia spp. (including Y. enterocolitica)
Note: Many strains of the above microorganisms that are multiply resistant to other antibiotics, e.g. penicillins, older cephalosporins and aminoglycosides, are susceptible to ceftriaxone.
Treponema pallidum is sensitive in-vitro and in animal experiments. Clinical investigations indicate that primary and secondary syphilis respond well to ceftriaxone therapy.

ANAEROBIC ORGANISMS
Bacteroides spp. (including some strains of B. fragilis)
Clostridium spp. (except Cl. difficile)
Fusobacterium spp. (except F. mortiferum and F. varium)
Peptococcus spp.
Peptostreptococcus spp.
Note:
Many strains of b-lactamase-producing Bacteroides spp. (notably B. fragilis) are resistant.
Susceptibility to ceftriaxone can be determined by the disk diffusion test or by the agar or broth dilution test using standardized techniques for susceptibility testing such as those recommended by the National Committee for Clinical

Laboratory Standards (NCCLS). The NCCLS issued the following interpretative breakpoints for ceftriaxone:

Susceptible Moderately Resistant
Susceptible
Dilution test, inhibitory concentrations in mg/l < 8 16-32 > 64

Diffusion test (disk with 30 µg ceftriaxone)
inhibition zone diameter in mm > 21 20-14 < 13

Microorganisms should be tested with the ceftriaxone disk since it has been shown by in-vitro-tests to be active against certain strains resistant to cephalosporin class disks.
Where NCCLS recommendations are not in daily use, alternative, well standardized susceptibility interpretative guidelines such as those issued by DIN, ICS and others may be substituted.

PHARMACOKINETICS
Ceftriaxone is characterized by an unusually long elimination half-life of approximately eight hours in healthy adults. The area under the plasma concentration time curves after IV and IM administration is identical. This means that the bioavailability of ceftriaxone administered IM is 100%.
On intravenous administration, ceftriaxone diffuses rapidly into the interstitial fluid, where bactericidal concentration against susceptible organisms are maintained for 24 hours (see figure).
Concentration after 1 g Ryxon (mg/l)

ELIMINATION
The elimination half-life in healthy adults is about eight hours. In infants aged less than eight days and in persons over 75 years of age, the average elimination half-life is about twice as long.
In adults, 50-60% of ceftriaxone is excreted unchanged by the kidneys, while 40-50% is excreted unchanged in the bile. The intestinal flora transforms ceftriaxone into inactive metabolites. In neonates, renal elimination accounts for about 70% of the dose. In patients with renal impairment or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.

PROTEIN BINDING
Ceftriaxone is reversibly bound to albumin, and the binding decreases with the increase in the concentration, e.g. from 95% binding at plasma concentrations of < 100 mg/l to 85% binding at 300 mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.

PENETRATION INTO THE CEREBROSPINAL FLUID
Ceftriaxone penetrates the inflamed meninges of infants and children. The average extent of diffusion in the cerebrospinal fluid in bacterial meningitis is 17% of the plasma concentration, i.e. approximately four times that in aseptic meningitis. Ceftriaxone concentration of >1.4 mg/l have been found in the CSF 24 hours after IV injection of Ryxon in doses of 50-100 mg/kg. In adult meningitis patients, administration of 50 mg/kg leads within 2-24 hours to CSF concentrations several times higher than the minimum inhibitory concentrations required for the most common causative organisms of meningitis.

INDICATION
Infections caused by pathogens sensitive to Ryxon, e.g.:

• Sepsis;
  
• Meningitis;
  
• Abdominal infections (peritonitis, infections of the biliary and gastrointestinal tracts);
  
• Infections of the bones, joints, soft tissue, skin and of wounds;
  
• Infections in patients with impaired defence mechanisms;
  
• Renal and urinary tract infections;
  
• Respiratory tract infections, particularly pneumonia, and ear, nose and throat Infections;
  
• Genital infections, including gonorrhea.
  
• perioperative prophylaxis of infections.

STANDARD DOSAGE
Adults and children over twelve years: The usual dosage is 1-2 g of Ryxon administered once daily (every 24 hours). In severe cases or in infections caused by moderately sensitive organisms, the dosage may be raised to 4 g, administered once daily.
Neonates, infants and children up to twelve years:
The following dosage schedules are recommended for once daily administration:
Neonates (up to two weeks): A daily dose of 20-50 mg/kg bodyweight, not to exceed 50 mg/kg, on account of the immaturity of the infant's enzyme systems. It is not necessary to differentiate between premature and infants born at term.
Infants and children (three weeks to twelve years): A daily dose of 20-80 mg/kg.
For children with body-weights of 50 kg or more, the usual adult dosage should be used.
Intravenous doses of 50 mg or more per kg should be given by infusion over at least 30 minutes.
Elderly patients: The dosages recommended for adults require on modification in the case of geriatric patients.
Duration of therapy:
The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of Ryxon should be continued for a minimum of 48-72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.
Combination therapy :
Synergy between Ryxon and aminoglycosides has been demonstrated with many gram-negative bacilli under experimental conditions. Although enhanced activity of such combinations is not always predictable, it should be considered in severe, life-threatening infections due to microorganisms such as Pseudomonas aeruginosa. Because of physical incompatibility the two drugs must be administered separately at the recommended dosages.

SPECIAL DOSAGE INSTRUCTIONS
Meningitis
In bacterial meningitis in infants and children, treatment begins with doses of 100 mg/kg (not to exceed 4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dosage can be reduced accordingly. The best results have been found with the following duration of therapy:

Neisseria meningitidis: 4 days Streptococcus pneumoniae 7 days
Haemophilus influenzae: 6 days Susceptible Enterobacteriaceae 10-14 days

GONORRHEA
For the treatment of gonorrhea (penicillinase-producing and nonpenicillinase-producing strains), a single IM dose of 250 mg Ryxon is recommended.
PRE-OPERATIVE PROPHYLAXIS
To prevent postoperative infections in contaminated or potentially contaminated surgery, the recommended approach depending on the risk of infection-is a single dose of 1-2 g Ryxon administered 30-90 minutes prior to surgery. In colorectal surgery, concurrent (but separate) administration of Ryxon and a 5-nitroimidazole, e.g. ornidazole, has proven effective.

IMPAIRED RENAL AND HEPATIC FUNCTION
In patients with impaired renal function, there is no need to reduce the dosage of Ryxon provided hepatic function is intact. Only in cases of preterminal renal failure (creatinine clearance <10 ml/min) should the Ryxon dosage not exceed 2 g daily. In patients with liver damage, there is no need for the dosage to be reduced provided renal function is intact. In cases of concomitant severe renal and hepatic dysfunction, the plasma concentrations of ceftriaxone should be determined at regular intervals.
In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.

DIRECTIONS FOR USE
Reconstituted solutions retain their physical and chemical stability for six hours at room temperature (or 24 hours at 5C). As a general rule, however the solutions should be used immediately after preparation. They range in colour from pale yellow to amber, depending on the concentration and the length of storage. This characteristic of the active ingredient is of no significance for the efficacy or tolerance of the drug.
INTRAMUSCULAR INJECTION
For IM injection, Ryxon 500 mg is dissolved in 2 ml, and Ryxon 1 g in 3.5 ml, of 1% lidocaine solution and administered by deep intragluteal injection. It is recommended that not more than 1 g be injected on either side.
The lidocaine solution must never be administered intravenously.
INTRAVENOUS INJECTION
For IV injection, Ryxon 500 mg is dissolved in 5 ml, and Ryxon 1 g in 10 ml, of sterile water for injections, and then administered by IV injection lasting two to four minutes.
RESTRICTIONS ON USE
Ryxon is contraindicated in patients with known hypersensitivity to the cephalosporin class of antibiotics. In patients hypersensitive
to penicillin, the possibility of allergic cross-reactions should be borne in mind.
Although the relevent preclinical investigations revealed neither mutagenic nor teratogenic effects, Ryxon should not be used in pregnancy (particularly in the first trimester) unless absolutely indicated.

PRECAUTIONS
As with other cephalosporins, anaphylactic shock cannot be ruled out even if a thorough patient history is taken. Anaphylactic shock requires immediate countermeasures such as intravenous epinephrine followed by a glucocorticoid.
In rare cases, shadows suggesting sludge have been detected by sonograms of the gallbladder. This condition was reversible on discontinuation or completion of Ryxon therapy. Even if such findings are associated with pain, conservative, non surgical management is recommended.
In-vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Caution should be exercised when considering Ryxon for hyperbilirubinemic neonates, especially prematures.
During prolonged treatment the blood picture should be checked at regular intervals.

UNDESIRABLE EFFECTS
Ryxon is generally well tolerated. During the use of Ryxon the following side effects, which were reversible either spontaneously or after withdrawal of the drug, have been observed:
SYSTEMIC SIDE EFFECTS
Gastrointestinal complaints (about 2% of cases): loose stools or diarrhea, nausea, vomiting, stomatitis and glossitis.
Hematological changes (about 2%): eosinophilia, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia.
Skin reactions (about 1%): exanthema, allergic dermatitis, pruritus, urticaria, edema, erythema multiforme.
OTHER, RARE SIDE EFFECTS:
headache and dizziness, increase in liver enzymes, gallbladder sludge, oliguria, increase in serum creatinine, mycosis of the genital tract, shivering and anaphylactic or anaphylactoid reactions.
Pseudomembranous enterocolitis and coagulation disorders have been reported as very rare side effects.
LOCAL SIDE EFFECTS
In rare cases, phlebitic reactions occurred after IV administration. These may be prevented by slow (two to four minutes) injection of the substance.
intramuscular injection without lidocaine solution is painful.
INTERACTIONS
No impairment of renal function has so far been observed after concurrent administration of large doses of Ryxon and potent diuretics (e.g. Furosemide). There is no evidence that Ryxon increases renal toxicity of aminoglycosides. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Ryxon. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of Ryxon is not altered by probenecid.

STORAGE
Store at room temperature below 25oC.

PRESENTATION
Packs for injection containing 1 vial with dry substance equivalent to 500 mg or 1 g ceftriaxone, with 5 ml or 10 ml ampoule of sterile water for Injection.