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Oryx®
Rx only
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Oryx®
(Ceftriaxone Sodium) injection and other antibacterial drugs, Oryx® injection should be used
only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Description
Oryx® is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or
intramuscular administration. Ceftriaxone Sodium is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)
glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, 72 -(Z)-(O-methyloxime), disodium salt,
sesquaterhydrate. The empirical formula of Ceftriaxone Sodium is C18H16N8Na2O7S3. 3.5
H2O. It has a calculated molecular weight of 661.59 and the following structural formula:
Oryx® is a white to yellowish-orange crystalline powder which is readily soluble in water,
sparingly soluble in methanol and very slightly soluble in ethanol. The pH of a 1% aqueous
solution is approximately 6.7. The color of Oryx® solutions ranges from light yellow to amber,
depending on the length of storage, concentration and diluent used. Oryx® contains
approximately 83 mg (3.6 mEq) of sodium per gram of Ceftriaxone activity.
Composition
Oryx® 250 mg IM/IV Injection: Each vial contains dry substance equivalent to 250 mg
Ceftriaxone (as sterile Ceftriaxone Sodium USP) accompanied by a solvent ampoule of 2 ml
Lidocaine HCI USP 1% Injection for IM injection or 5 ml Water for Injection USP for IV
injection.
Oryx® 500 mg IM/IV Injection: Each vial contains dry substance equivalent to 500 mg
Ceftriaxone (as sterile Ceftriaxone Sodium USP) accompanied by a solvent ampoule of 2 ml
Lidocaine HCI USP 1% Injection for IM injection or 5 ml Water for Injection USP for IV
injection.
Oryx® 1 g IM/IV Injection: Each vial contains dry substance equivalent to 1 g Ceftriaxone (as
sterile Ceftriaxone Sodium USP) accompanied by a solvent ampoule of 3.5 ml Lidocaine HCI
USP 1% Injection for IM injection or 10 ml Water for Injection USP for IV injection.
Oryx® 2 g IV Injection: Each vial contains dry substance equivalent to 2 g Ceftriaxone (as
sterile Ceftriaxone Sodium USP) and each of two ampoules contains 10 ml Water for Injection
USP for IV injection.
Microbiology
The bactericidal activity of Ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone
has a high degree of stability in the presence of beta-lactamases, both penicillinases and
cephalosporinases, of gram-negative and gram-positive bacteria. Ceftriaxone is usually active
against most strains of the following microorganisms, both in vitro and in clinical infections.
Aerobic gram - negative microorganisms: Acinetobacter calcoaceticus, Enterobacter
aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae (including
ampicillin-resistant and beta-lactamase producing strains), Haemophilus parainfluenzae,
Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis (including beta-lactamase
producing strains), Morganella morganii, Neisseria gonorrhoeae (including penicillinase- and
nonpenicillinase - producing strains), Neisseria meningitides, Proteus mirabilis, Proteus
vulgaris, Serratia marcescens. Ceftriaxone is also active against many strains of Pseudomonas
aeruginosa. Note: Many strains of the above organisms that are multiply resistant to other
antibiotics, e.g., penicillins, cephalosporins, and aminoglycosides are susceptible to Ceftriaxone.
Aerobic gram - positive microorganisms: Staphylococcus aureus (including penicillinaseproducing strains), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus
pyogenes, Viridans group streptococci. Note: Methicillin-resistant staphylococci are resistant to
cephalosporins, including Ceftriaxone. Most strains of Group D streptococci and enterococci, eg.
Enterococcus (Streptococcus) faecalis are resistant. Anaerobic microorganisms: Bacteroides
fragilis, Clostridium species, Peptostreptococcus species. Note: Most strains of Clostridium
difficile are resistant.
Pharmacokinetic
The pharmacokinetics of Ceftriaxone are nonlinear and all basic pharmacokinetic parameters,
except the elimination half life, are dose dependent if based on total drug concentrations.
Absorption: The maximum plasma concentration after a single IM dose of 1 g is about 81 mg/L
and is reached in 2-3 hours after administration. The area under the plasma concentration-time
curve after IM administration is equivalent to that after IV administration of an equivalent dose,
indicating 100% bioavailability of intramuscularly administered Ceftriaxone. Distribution: The
volume of distribution of Ceftriaxone is 7-12 L. Ceftriaxone has shown excellent tissue and body
fluid penetration after a dose of 1-2 g; concentrations well above the minimal inhibitory
concentrations of most pathogens responsible for infections are detectable for more than 24
hours in over 60 tissues or body fluids including lung, heart, biliary tract/liver, tonsil, middle ear
and nasal mucosa, bone as well as cerebrospinal, pleural, prostatic and synovial fluids. On
intravenous administration, Ceftriaxone diffuses rapidly into the interstitial fluid, where
bactericidal concentrations against susceptible organisms are maintained for 24 hours. Protein
binding: Ceftriaxone is reversibly bound to albumin, and the binding decreases with the increase
in 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. Metabolism: Ceftriaxone is not
metabolized systemically; but is converted to inactive metabolites by the gut flora. Elimination:
Total plasma clearance is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of Ceftriaxone
is excreted unchanged in the urine, while 40-50% is excreted unchanged in the bile. The
elimination half-life in adults is about 8 hours.
Indication and Use
Oryx® is indicated for the treatment of the following infections when caused by susceptible
organisms: Lower respiratory tract infections, Acute bacterial otitis media, Skin and skinstructure infections, Urinary tract infections (complicated and uncomplicated), Uncomplicated
gonorrhea (cervical/urethral and rectal), Pelvic inflammatory disease, Bacterial septicemia, Bone
and joint infections, Intra-abdominal infections, Meningitis and in Surgical prophylaxis.
Dosage and Administration
Oryx® can be administered either intravenously or intramuscularly. Dosage and mode of
administration should be determined by severity of infection, susceptibility of causative
organisms and the patient's condition. Under most circumstances, once-daily dose or in the
specified indications, a single dose will give satisfactory therapeutic results. Adults and
children over 12 years: The usual dosage is 1-2 g of Oryx® once daily (every 24 hours). In
severe cases or in infections caused by moderately sensitive organisms, the dosage may be raised
to 4 g once daily. Neonates, infants and children up to 12 years: The following dosage
schedules are recommended for once daily administration. Neonates (up to 14 days): 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 term infants.
Infants and children (15 days to 12 years): A daily dose of 20-80 mg/kg. For children with
bodyweights of 50 kg or more, the usual adult dosage should be used. Intravenous doses of > 50
mg/kg body weight should be given by infusion over at least 30 minutes. Elderly patients: The
dosages recommended for adults require no modification in case of geriatric patients. Duration
of therapy: Oryx® therapy should be continued for at least 2 days after the signs and symptoms
of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated
infections, longer therapy may be required. When treating infections caused by Streptococcus
pyogenes, therapy should be continued for at least 10 days. Combination therapy: Synergy
between Ceftriaxone 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 and 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. 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. Best results have been found with the following duration
of therapy: Neisseria meningitidis-4 days, Haemophilus influenzae-6 days, Streptococcus
pneumoniae-7 days, Susceptible Enterobacteriaceae-10 to 14 days. Gonorrhoea (penicillinase producing and nonpenicillinase - producing strains): a single IM dose of 250 mg Oryx® is
recommended. Perioperative prophylaxis: A single dose of 1-2 g depending on the risk of
infection of 30-90 minutes prior to surgery. In colorectal surgery, administration of Oryx® with
or without a 5-nitroimidazole, e.g. Ornidazole, has been proven effective. Impaired renal and
hepatic function: In patients with impaired renal function, there is no need to reduce the dosage
of Oryx® provided hepatic function is intact. Only in cases of preterminal renal failure
(creatinine clearance <10 ml/min) should the Oryx® 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 patients with both severe renal and hepatic dysfunction, the plasma concentrations of
Ceftriaxone should be determined at regular intervals and, if necessary, the dose should be
adjusted. In patients undergoing dialysis, no additional supplementary dosing is required
following the dialysis. Plasma concentrations should, however, be monitored, to determine
whether dosage adjustments are necessary, since the elimination rate in these patients may be
altered.
Directions for use
Intramuscular Injection: For IM injection, Oryx® 250 mg or Oryx® 500 mg is dissolved in 2
ml and Oryx® 1 g in 3.5 ml of Lidocaine HCl 1% solution and administered by deep intragluteal
injection. It is recommended that not more than 1 g be injected at one site. The Lidocaine
solution must never be administered intravenously. Intravenous Injection: For IV injection,
Oryx® 250 mg or Oryx® 500 mg is dissolved in 5 ml, Oryx® 1 g in 10 ml and Oryx® 2 g in 20
ml of Water for Injection. The injection should be administered over 2-4 minutes, directly into
the vein or via the tubing of an intravenous infusion.
Contraindication
Ceftriaxone is contraindicated in patients with known allergy to the cephalosporin class of
antibiotics. In patients hypersensitive to penicillin, the possibility of allergic cross-reactions
should be borne in mind.
Use in Pregnancy and Lactation
Pregnancy: The safety of Ceftriaxone in the treatment of infections during pregnancy has not
been established. Ceftriaxone should only be used during pregnancy if the likely benefit
outweighs the potential risk to the fetus and/or the mother. Lactation: Ceftriaxone is excreted in
breast milk at low concentrations. Therefore, caution should be exercised when Ceftriaxone is
administered to a nursing mother.
Side Effect
Ceftriaxone is generally well-tolerated. During the treatment, 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 diarrhoea,
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 minimized by slow (two to four minutes) injection. Intramuscular
injection without Lidocaine solution is painful.
Precaution
Ceftriaxone is excreted via both biliary and renal route. Therefore, patients with renal failure
normally require no adjustment in dosage when usual doses of Ceftriaxone is administered but
concentrations of drug in the serum should be monitored periodically. If evidence of
accumulation exists, dosage should be decreased accordingly. Although transient elevations in
BUN (Blood Urea Nitrogen) and serum creatinine have been observed at recommended dosage
nephrotoxic potential of Ceftriaxone is similar to that of other cephalosporins. Dosage
adjustments should not be necessary in patients with hepatic dysfunction; however, in patients
with both hepatic dysfunction and significant renal disease, Ceftriaxone dosage should not
exceed 2 gm daily without close monitoring of serum concentrations. Alternations in
prothrombin times have occurred rarely in patients treated with Ceftriaxone. Patients with
impaired vitamin-K synthesis or low vitamin-K stores (e.g. chronic hepatic disease and
malnutrition) may require monitoring of prothrombin time during Ceftriaxone treatment.
Vitamin-K (administration 10 mg weekly) may be necessary if the prothrombin time is
prolonged before or during therapy. Prolonged use of Ceftriaxone may result in overgrowth of
non-susceptible organisms. Careful observation of the patient is essential. If superinfection
occurs during therapy, appropriate measures should be taken. Ceftriaxone should be prescribed
with caution in individuals with a history of gastrointestinal disease, especially colitis.
Warning
Before therapy with Ceftriaxone is instituted, careful inquiry should be made to determine
whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and
other drugs. This product should be given cautiously to penicillin hypersensitive patients. Serious
acute hypersensitivity reactions may require the use of subcutaneous epinephrine and other
emergency measures. Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including Ceftriaxone and may range in severity from mild to life-threatening. Therefore,
it is important to consider this diagnosis in patients who develop diarrhoea subsequent to the
administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora
of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by
Clostridium difficile is one primary cause of antibiotic-associated colitis.
Drug Interaction
No impairment of renal function has so far been observed after concurrent administration of
large doses of Ceftriaxone and potent diuretics (e.g. Furosemide). There is no evidence that
Ceftriaxone increases renal toxicity of aminoglycosides. No effect similar to that of Disulfiram
has been demonstrated after ingestion of alcohol subsequent to the administration of Ceftriaxone.
Ceftriaxone does not contain N-methylthiotetrazole moiety associated with possible ethanol
intolerance and bleeding problems of certain other cephalosporins. The elimination of
Ceftriaxone is not altered by Probenecid.
Stability and Storage Recommendation
Ceftriaxone sterile powder should be stored at room temperature (25°C to 30°C) or below and
protected from light. After reconstitution, protection from normal light is not necessary. The
color of solutions ranges from light yellow to amber, depending on the length of storage,
concentration and diluent used. Reconstituted solutions retain their physical and chemical
stability for 6 hours at room temperature and for 24 hours at 5°C. As a general rule, however the
solutions should be used immediately after preparation.
Packaging Quantity
Oryx® Injection is supplied as a sterile crystalline powder in glass vials.
Oryx® 250 mg IV Injection : Pack of 1 vial containing 250 mg Ceftriaxone (as sterile
Ceftriaxone Sodium USP) accompanied by one ampoule of 5 ml Water for Injection USP for IV
injection, a sterile disposable syringe (5 ml) with a baby needle, a butterfly needle, an alcohol
prep pad and a strip bandage.
Oryx® 250 mg IM Injection : Pack of 1 vial containing 250 mg Ceftriaxone (as sterile
Ceftriaxone Sodium USP) accompanied by one ampoule of 2 ml Lidocaine HCI USP 1%
Injection for IM injection, a sterile disposable syringe (5 ml) with a baby needle, an alcohol prep
pad and a strip bandage.
Oryx® 500 mg IV Injection : Pack of 1 vial containing 500 mg Ceftriaxone (as sterile
Ceftriaxone Sodium USP) accompanied by one ampoule of 5 ml Water for Injection USP for IV
injection, a sterile disposable syringe (5 ml) with a baby needle, a butterfly needle, an alcohol
prep pad and a strip bandage.
Oryx® 500 mg IM Injection : Pack of 1 vial containing 500 mg Ceftriaxone (as sterile
Ceftriaxone Sodium USP) accompanied by one ampoule of 2 ml Lidocaine HCI USP 1%
Injection for IM injection, a sterile disposable syringe (5 ml) with a baby needle, an alcohol prep
pad and a strip bandage.
Oryx® 1 g IV Injection (Single pack) : Pack of 1 vial containing 1 g Ceftriaxone (as sterile
Ceftriaxone Sodium USP) accompanied by one ampoule of 10 ml Water for Injection USP for
IV injection, a sterile disposable syringe (10 ml) with an extra needle, a butterfly needle, an
alcohol prep pad and a strip bandage.
Oryx® 1 g IV Injection (Five packs): Each box contains 5 blister packs. Each blister pack
contains 1 vial containing 1 g Ceftriaxone (as sterile Ceftriaxone Sodium USP) and one ampoule
of 10 ml Water for Injection USP for IV injection.
Oryx® 1 g IM Injection : Pack of 1 vial containing 1 g Ceftriaxone (as sterile Ceftriaxone
Sodium USP) accompanied by one ampoule of 3.5 ml Lidocaine HCI USP 1% Injection for IM
injection, a sterile disposable syringe (5 ml), an alcohol prep pad and a strip bandage.
Oryx® 2 g IV Injection : Pack of 1 vial containing 2 g Ceftriaxone (as sterile Ceftriaxone
Sodium USP) and each of two ampoules contains 10 ml Water for Injection USP for IV
injection, a sterile disposable syringe (20 ml), a butterfly needle, an alcohol prep pad and a strip
bandage.