ELORES is indicated for the treatment of the following indications:
· Lower Respiratory tract infections
· Urinary Tract Infections(complicated and uncomplicated)
· Sepsis
· Bacterial meningitis
· Infections of bones or joints
· Infections of skin or soft tissues
· Surgical prophylaxis

ELORES may be administered by deep intramuscular injection, slow intravenous injection, or as a slow
intravenous infusion, after reconstitution of the solution according to the directions.
Diluents containing calcium, (e.g. Ringer's solution or Hartmann's solution), should not be used to
reconstitute Ceftriaxone/sulbactam 1.5g/vial powder for solution for injection/infusion or to further dilute a
reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium
can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration
line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered
simultaneously.
Dosage and mode of administration should be determined by the severity of the infection, susceptibility of
the causative organism and the patient's condition. Under most circumstances a once-daily dose - or, in the
specified indications, a single dose - will give satisfactory therapeutic results.

Adults and children 12 years and over
Standard therapeutic dosage: 1.5g once daily.
Severe infections: 3-6g daily, normally as a single dose every 24 hours.
The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general,

administration of ELORES should be continued for a minimum of 48 to 72 hours after the patient has
become afebrile or evidence of bacterial eradication has been obtained.
Elderly
These dosages do not require modification in elderly patients provided that renal and hepatic function are
satisfactory (see below).
Neonates, infants and children up to 12 years
The following dosage schedules are recommended for once daily administration:
Neonates
A daily dose of 30 - 75mg/kg body weight, not to exceed 75mg/kg. In the neonate, the intravenous dose
should be given over 60 minutes to reduce the displacement of bilirubin from albumin, thereby reducing the
potential risk of bilirubin encephalopathy (see section 4.4).
Infants and children of up to 12 years
Standard therapeutic dosage: 30 - 75mg/kg body weight once daily.
In severe infections up to 120mg/kg body weight daily may be given. For children with body weights of
50kg or more, the usual adult dosage should be used. Doses of 75mg/kg or over should be given by slow
intravenous infusion over at least 30 minutes. Doses greater than 120mg/kg body weight should be avoided
because of the increased risk of biliary precipitates.
Renal and hepatic impairment
In patients with impaired renal function, there is no need to reduce the dosage of ELORES provided liver
function is intact. Only in cases of pre-terminal renal failure (creatinine clearance < 10ml per minute) should
the daily dosage be limited to 3g or less.
In patients with liver damage there is no need for the dosage to be reduced provided renal function is intact.
In severe renal impairment accompanied by hepatic insufficiency, the plasma concentration of ELORES
should be determined at regular intervals and dosage adjusted.
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.

ELORES is contraindicated in patients with known hypersensitivity to beta-lactam antibiotics. In patients hypersensitive to penicillin, the possibility of allergic cross-reactions should be borne in mind. Hyperbilirubinaemic newborns and preterm newborns should not be treated with ceftriaxone. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients. Premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life). Full-term newborns (up to 28 days of age) • with jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired • if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium.

As with other cephalosporins, anaphylactic reactions with fatal outcome were also reported, even if a patient
is not known to be allergic or previously exposed.(see section 4.2).

Before therapy with ELORES is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, any other cephalosporin, or to any penicillin or other beta-lactam drug. ELORES is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other beta-lactam drug (see Section 4.3). ELORES should be given with caution to patients who have had any other type of hypersensitivity
reaction to a penicillin or any other beta-lactam drug.

ELORES should be given with caution to patients who have other allergic diatheses.
Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term
newborns aged less than 1 month have been described. At least one of them had received ceftriaxone and
calcium at different times and through different intravenous lines. In the available scientific data, there are no
reports of confirmed intravascular precipitations in patients, other than newborns, treated with ceftriaxone
and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated
that newborns have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.

In patients of any age ELORES must not be mixed or administered simultaneously with any calciumcontaining
IV solutions, even via different infusion lines or at different infusion sites. However, in patients
older than 28 days of age Ceftriaxone/sulbactam, powder for solution for injection/infusion and calciumcontaining
solutions may be administered sequentially one after another if infusion lines at different sites are
used, or if the infusion lines are replaced or thoroughly flushed between infusions with physiological saltsolution
to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN
solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which
do not carry a similar risk of precipitation. If use of ELORES nutrition, TPN solutions and ELORES can be
administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of
TPN solution could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion
lines between solutions.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial
agents, including ELORES, and may range in severity from mild diarrhoea to fatal colitis. Treatment with
antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing
strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to
antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with
diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to
occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be
discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of
C. difficile, and surgical evaluation should be instituted as clinically indicated.

Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.
An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class
antibacterials including ELORES. Severe cases of haemolytic anaemia, including fatalities, have been
reported during treatment in both adults and children. If a patient develops anaemia while on ceftriaxone, the
diagnosis of a cephalosporin associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined.

Antibiotic-associated diarrhoea, colitis and pseudomembranous colitis have all been reported with the use of
Ceftriaxone/sulbactam. These diagnoses should be considered in any patient who develops diarrhoea during
or shortly after treatment. Ceftriaxone/sulbactam 1.5g/vial powder for solution for injection/infusion should
be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted.

ELORES should be used with caution in individuals with a previous history of gastro-intestinal disease, particularly colitis.

As with other cephalosporins, prolonged use of ceftriaxone may result in the overgrowth of non-susceptible
organisms, such as enterococci and Candida spp.

In severe renal and hepatic insufficiency, dosage should be reduced according to given recommendations(see section 4.2).

ELORES may precipitate in the gallbladder and then be detectable as shadows on ultrasound (see section 4.8). This can happen in patients of any age, but is more likely in infants and small children who are usually
given a larger dose of ELORES on a body weight basis. In children, doses greater than 120mg/kg body
weight should be avoided because of the increased risk of biliary precipitates. There is no clear evidence of
gallstones or of acute cholecystitis developing in children or infants treated with ELORES. As the condition
appears to be transient and reversible upon discontinuation, therapeutic procedures are not normally
indicated.

Shadows, which have been mistaken for gallstones are however, precipitates of calcium ceftriaxone which
disappear on completion or discontinuation of ELORES therapy. Rarely have these findings been associated
with symptoms. In symptomatic cases, conservative nonsurgical management is recommended.

Discontinuation of ELORES treatment in symptomatic cases should be at the discretion of the physician.

Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with
antibodies directed against the drug to produce a positive Coombs' test and occasionally a rather mild
haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated
with ELORES. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding
major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of ELORES - related
biliary precipitation can not be ruled out.

Safety and effectiveness of ELORES in neonates, infants and children have been established for the dosages
described under Dosage and administration. Studies have shown that ceftriaxone, like some other
cephalosporins, can displace bilirubin from serum albumin.

During prolonged treatment a complete blood count should be performed at regular intervals.

No impairment of renal function has so far been observed after concurrent administration of large doses of
ELORES and potent diuretics (e.g. furosemide).

No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during
simultaneous administration with ELORES.

No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the
administration of ELORES. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with
possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of
ELORES is not altered by probenecid.

In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and
ceftriaxone. The clinical relevance of this finding is unknown, but caution is advised if concurrent
administration of ceftriaxone with chloramphenicol is proposed.

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute
ELORES vials or to further dilute a reconstituted vial for IV administration because a precipitate can form.
Precipitation of ceftriaxone-calcium can also occur when ELORES is mixed with calcium-containing
solutions in the same IV administration line. ELORES must not be administered simultaneously with
calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral
nutrition via a Y-site. However, in patients other than neonates, ELORES and calcium-containing solutions
may be administered sequentially, of one another, if the infusion lines are thoroughly flushed between
infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood
demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium.

Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and
aminoglycosides.

In patients treated with ELORES, the Coombs' test may rarely become false-positive. ELORES, like other
antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination
during therapy with ELORES should be done enzymatically.

Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable
to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following
treatment.

Pregnancy
Sulbactam and Ceftriaxone cross the placental barrier. There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
 

Lactation
Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass
poorly into breast milk of nursing mothers, caution should be exercised when sulbactam/ceftriaxone is
administered to a nursing mother.

Since Ceftriaxone/sulbactam sometimes induces dizziness the ability to drive and use machines can be impaired.

ELORES is generally well tolerated. The majority of adverse events are of mild or moderate severity and
are tolerated with continued treatment. In pooled clinical trial data from comparative studies in
approximately 654 patients out of which 325 were treated with Ceftriaxone/sulbactam and the following was
observed:
Gastrointestinal: As with other antibiotics, the most frequent side effects observed with
ceftriaxone/sulbactam have been gastrointestinal (7.08%). Diarrhea/loose stools have been reported most
frequently followed by nausea and vomiting.

General disorders and administration site conditions: The reactions observed with Ceftriaxone/Sulbactam in
15.08% of volunteers. Pain, swelling or itching at site, phlebitis, edema have been reported more common in
the patient treated with Ceftriaxone/Sulcabtam.

Nervous system disorders: The most common side effects observed with ceftriaxone/sulbactam have been
Headache and Dizziness. In the comparative clinical data, 4.31% patients observed nervous system disorders.

Local Reactions:
· Ceftriaxone/sulbactam is well tolerated following intramuscular administration. Occasionally,
transient pain may follow administration by this route. As with other cephalosporins and penicillins,
when ceftriaxone/sulbactam is administered by an intravenous catheter some patients may develop
phlebitis at the infusion site.

Other Adverse Reactions:
Based on ceftriaxone nature following adverse reactions may also occur:

Hepatic: Elevations of SGOT/SGPT.
Hematological: Eosinophilia, thrombocytopenia, leukopenia, granulocytopenia, hematoma or bleeding. Hemolytic anemia is observed less frequently. Agranulocytosis (< 500/mm3) may occur occasionally at a total cumulative dose exceeding 20 g.

Skin reactions: Exanthema, allergic dermatitis, pruritis, urticaria, edema, erythema multiforme.

Based on ceftriaxone nature other side effects such as headache, dizziness, increase in serum creatinine,
mycosis of the genital tract, oliguria, fever, and shivering may occur.

Local Reactions:
Based on ceftriaxone nature following local reactions may also occur:

• Pain, induration, and tenderness may be encountered in a small number of patients.
• Inflammatory reactions in the vein wall may also occur after IV administration. These may be minimized by slow injection, given over 2 to 5 minutes.

In the case of overdose nausea, vomiting, diarrhoea, can occur. ELORES concentration can not be reduced
by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

ATC classification
Pharmacotherapeutic group: cephalosporins and related substances, ATC code: J01DD54
 

Mode of action
Ceftriaxone acts by inhibiting the mucopeptide synthesis in the bacterial cell wall. The beta-lactam moiety of
ceftriaxone binds to carboxypeptidases, endopeptidases, and transpeptidases in the bacterial cytoplasmic
membrane. These enzymes are involved in cell-wall synthesis and cell division. By binding to these
enzymes, ceftriaxone results in the formation of of defective cell walls and cell death. Sulbactam is a
molecule that is given in combination with beta lactam antibiotics to inhibit beta lactamase, an enzyme
produced by bacteria that destroys the antibiotics. Sulbactam is an irreversible inhibitor of beta-lactamase; it
binds the enzyme and does not allow it to interact with the antibiotic.

Thus, fixed dose combination ceftriaxone/sulbactam, powder for solution for injection/infusion i.e.
ceftriaxone and sulbactam serves as an effective measure to combat a specific resistance mechanism of betalatamase
producing organisms, in addition to that it also provides synergy against wide range of bacteria.
This kind of combination therapy is useful against life threatening infections in hospitalized and out patients.
 

Rationale behind combination
Ceftriaxone and sulbactam is a synergistic antimicrobial combination with marked in-vitro antibacterial
activity against a broad spectrum of organisms. Sulbactam not only potentiates the antibacterial activity of
beta-lactams but also exhibits a moderate antibacterial activity. By forming a protein complex with betalactamases,
sulbactam irreversibly blocks their destructive hydrolytic activity. Thus, sulbactam addition
extends the spectrum of activity of ceftriaxone. As sulbactam also binds with some penicillin binding
proteins, sensitive strains are often rendered more susceptible to the ceftriaxone/sulbactam, powder for
solution for injection/infusion combination than ceftriaxone alone. In bacterial strains that produce either low
amounts of beta-lactamase, or none at all, a synergistic effect is observed when sulbactam is associated with
beta-lactam antibiotic that has a complementary affinity for the target sites.

The presence of the inactive ingredient EDTA in the combination provides the following benefits;

1. Alters the porosity of bacterial cell membrane and enhances the penetration of ceftriaxone into bacteria making ceftriaxone effective at less concentrations.
2. Breaks biofilm and makes ceftriaxone+sulbactam effective even in infections with biofilm.
3. EDTA makes ceftriaxone effective in Metallo-beta-lactamase ESBL strains.
4. Prevention of resistance development.

Breakpoints:
Values that indicate the Resistant (R), Intermediate (I), and Sensitive (S) in selected organism

S. aureus/MTCC737	≤13	14-23	≥24
S. epidermis/MTCC435	≤13	14-20	≥21
B. subtilis/ATCC736	≤13	14-20	≥21
C. braakii/MTCC2690	≤14	14-20	≥21
P. vulgaris/ MTCC426	≤14	15-20	≥21
M. morganii/ MTCC662	≤14	15-17	≥18
P. aeruginosa/ MTCC1688	≤13	14-20	≥21
K. pneumoniae/ 10031 (ATCC)	≤13	14-18	≥19
E.coli/1687	≤13	14-23	≥24
A. baumanii/ MTCC1425	≤14	15-20	≥21

Microbiology:
Ceftriaxone has bactericidal activity that results from the inhibition of bacterial cell wall synthesis. It is
effective against Gram-negative and Gram-positive bacterias.
Commonly susceptible species:
Gram positive aerobes: Staphylococcus aureus*(MSSA) , Streptococcus agalactiae , Streptococcus bovis ,
Streptococcus pyogenes* , Streptococcus pneumoniae* ,
Gram-positive anaerobes : Peptococcus niger , Peptostreptococcus spp. ,
Gram-negative aerobes : Citrobacter koseri,1 Escherichia coli*1, Haemophilus influenzae* , Haemophilus
parainfluenzae* , Klebsiella pneumoniae*1, Klebsiella oxytoca*1, Moraxella catarrhalis* , Morganella
morganii11 , Neisseria meningitidis* , Proteus mirabilis*1, Proteus vulgaris1 , Providencia spp.1 , Salmonella
spp.1 , Serratia spp.1 , Shigella spp.
Species for which acquired resistance may be a problem :
Gram-positive aerobes : Staphylococcus epidermidis*$ (MSSE)
Gram-negative aerobes : Citrobacter freundii1 , Enterobacter spp.1 ,3, Pseudomonas aeruginosa 2$
Inherently resistant species :
Gram-positive aerobes: Enterococcus faecalis , Enterococcus faecium , Listeria monocytogenes,
Staphylococcus aureus MRSA , Staphylococcus epidermidis MRSE , Gram-positive anaerobes: Clostridium
difficile , Gram-negative aerobes :Acinetobacter spp. , Achromobacter spp.
Aeromonas spp. , Alcaligenes spp. , Flavobacterium spp. , Legionella gormanii ,
Gram-negative anaerobes : Bacteroides spp.
Others : Chlamydia spp. , Chlamydophila spp. , Mycobacterium spp. , Mycoplasma spp.
Rickettsia spp. , Ureaplasma urealyticum
_{* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications
$ Species with natural intermediate susceptibility
1 Some strains produce inducible or stably derepressed chromosomally-encoded cephalosporinases and ESBLs (extended spectrum
beta-lactamases) and thus are clinically resistant to cephalosporins.
2 In suspected or proven Pseudomonas infection combination with an aminoglycoside is necessary.
3 Clinical efficacy has been demonstrated for susceptible isolates of Enterobacter cloacae and Enterobacter aerogenes in approved
clinical indications.}

Clinical efficacy and safety
In one of the phase III study conducted on ELORES the clinical efficacy and safety end points were obtained
by collating the data of 204 urinary tract infection subjects, 93 lower respiratory tract infection subjects, 93
Otitis media subjects, 75 Bone and Joint Infection subjects, 95 Surgical Prophylaxis patients, 34 bacterial
Septicemia Subjects and 60 patients of Skin and Skin structure infection.

Efficacy: Among the total subjects screened for bone and joint infection, 32 (91.43%) subjects who received
ELORES had shown complete clinical cure in terms of total relief and no-disease symptoms when compared
to only 15 (34.09%) subjects in the Ceftriaxone group.

Among the total subjects screened for bacterial septicemia, 18(100%) subjects who received ELORES had
shown complete clinical cure in terms of total relief and no-disease symptoms when compared to only 1
(6.25%) subjects in the Ceftriaxone group. There were no subjects with treatment failure in the ELORES
group as well as in the Ceftriaxone group.

Among the total subjects screened for LRTI, 42 (91.30%) subjects who received ELORES had shown
complete clinical cure in terms of total relief and no-disease symptoms when compared to only 15(34.09%)
subjects in the Ceftriaxone group. However ELORES group did not show any response to the treatment
compared to 7 (15.91%) subjects in the Ceftriaxone group.

Among the total subjects screened for surgical prophylaxis, 45 (91.84%) subjects who received ELORES
had shown complete clinical cure in terms of total relief and no-disease symptoms when compared to 13
(30.95%) subjects in the Ceftriaxone group. No ELORES group showed failure of response to the treatment
compared to 16 (38.10%) subjects in the Ceftriaxone group.

Among the total subjects screened for skin and skin structure infection, 17 (68.00%) subjects who received
ELORES had shown complete clinical cure in terms of total relief and no-disease symptoms when compared
to 2 (7.14%) subjects in the Ceftriaxone group. However ELORES group did not show any failure response
to the treatment compared to 10 (35.71%) subjects in the Ceftriaxone group.

Among the total subjects screened for UTI, 80 (84.21%) of them who received ELORES had shown
complete clinical cure in terms of total relief and no-disease symptoms when compared to 35 (32.46%)
subjects in the Ceftriaxone group. There was no failure in the ELORES group subjects when compared to
ceftriaxone it had 6 (16.7%) failure response.

Among the total subjects screened for Chronic suppurative otitis media, 35 (90.00%) subjects who received
ELORES had shown complete clinical cure in terms of total relief and no-disease symptoms when compared
to 11 (32.57%) subjects in the Ceftriaxone group. Treatment failures were more in ceftriaxone group
compared to ELORES group.

Safety: In both the treatment arms some of the adverse events were observed. In Otitis media of 46
randomized (100%) subjects in ELORES group, 3 subjects (6.52%) developed AEs related to gastrointestinal
disorders (Nausea, Diarrhoea), 8 subjects (17.39%) related to general disorders and administration site
conditions (Pain at Site, Pruritis) and 4 subjects (8.70%) developed AEs related to nervous system disorders
(Headache, Dizziness). Whereas of 47 randomized (100%) subjects in Ceftriaxone group, 4 subjects (8.51%)
developed AE related to general disorders and administration site conditions (Pain at Site).

In bacterial septicemia, among 18 randomized subjects in ELORES group, 6 subjects (33.33%) developed
AEs related to gastrointestinal disorders (Nausea, Vomiting), 1 event (5.56%) related to general disorders and
administration site conditions (Pain at Site) and 2 subjects (11.11%) developed AEs related to nervous
system disorders (Headache, Dizziness). Whereas, among 16 randomized subjects of ceftriaxone group, 2
subjects (12.50%) developed AE related to ear and labyrinth disorders (Vertigo), 5 subjects (31.25%)
developed AEs related gastrointestinal disorders (Nausea, Vomiting), 5 (31.25%) related to general disorders
and administration site conditions (Pain at Site), 3 subject’s (18.75%) related to nervous system disorders
(Headache, Dizziness).

In bone and joint infection, among 37 randomized subjects in ELORES group, 5 subjects developed AEs
(14.29%) related to gastrointestinal disorders (Nausea, Vomiting), 9 (25.71%) event were related to general
disorders and administration site conditions (Localized Pain, Pain at Site, Swelling at Inject Site, Itching) and
1 subject developed AE (2.86%) related to nervous system disorders (Headache). Whereas in Ceftriaxone
group, among 40 randomized subjects, 2 (5%) subject developed AEs related to gastrointestinal disorders
(Nausea, Vomiting), 15 subjects (37.50%) AE were related to general disorders and administration site
conditions (Localized Pain, Pain at Site, Swelling at Inject Site, Itching, Localized Edema), 3 (7.50%) related
to nervous system disorders (Headache, Dizziness), and 4 subject’s (10%) AEs were related to ear and
labyrinth disorders (Vertigo).

In ELORES group of skin and skin structure infections, of 28 (100%) randomized subjects, 1 subject’s
(3.57%) AE related to general disorders and administration site conditions (Pain at Site) and 2 subjects
(7.14%) developed AEs related to nervous system disorders (Dizziness). Whereas of 32 (100%) randomized
subjects in Ceftriaxone group, 2 subjects (6.25%) developed AEs related to gastrointestinal disorders
(Nausea), 3 subjects (9.37%) related to general disorders and administration site conditions (Pain at Site), 4
subjects (12.5%) related to nervous system disorders (Headache, Dizziness) and 1 subject (3.12%) related to
vascular disorders (Hypotension).

In surgical prophylaxis, among 50 randomized (100%) subjects in ELORES group, 3 subjects (6.00%)
developed AEs related to gastrointestinal disorders (Nausea, Vomiting), 13 subjects (26.00%) related to
general disorders and administration site conditions (Pain at Site, Rahses). Whereas of 45 randomized
(100%) subjects in Ceftriaxone group, 20 subjects (44.44%) developed AEs related to general disorders and
administration site conditions (Pain at Site, Erythema at injection site, Fever, Phlebitis), 1 subject (2.22%)
related to nervous system disorders (Dizziness).

In ELORES group of lower respiratory tract infections, of 46 randomized (100%) subjects, 3 subjects
(6.52%) developed AEs related to gastrointestinal disorders (Nausea, Vomiting), 1 event was (2.17%) related
to general disorders and administration site conditions (Pain at Site) and 3 subjects (6.52%) developed AEs
related to nervous system disorders (Headache, Dizziness). In Ceftriaxone group of lower respiratory tract
infections, of 47 (100%) randomized subjects, 1 subject (2.13%) developed AEs related to ear and labyrinth
disorders (Vertigo), 4 subjects (6.38%) developed AEs related gastrointestinal disorders (Nausea, Vomiting),
8 subjects (17.02%) related to general disorders and administration site conditions (Pain at Site, Edema,
Erythema, Phlebitis), 2 subjects (4.26%) related to nervous system disorders (Headache).

In UTI of 102 randomized subjects in ELORES group, 3 subjects (2.94%) developed AEs related to
gastrointestinal disorders (Nausea, Vomiting), 16 subjects (15.69%) related to general disorders and
administration site conditions (Pain at Site, Fever, Edema, Erythema at injection site, Skin rash) and 2
subjects (1.96%) developed AEs related to nervous system disorders (Dizziness). Whereas of 102
randomized subjects in ceftriaxone group, 7 subjects (6.86%) developed AEs related gastrointestinal
disorders (Nausea, Vomiting), 27 subjects (26.47%) related to general disorders and administration site
conditions (Pain at Site, Fever, Edema, Erythema at injection site, Skin rash, Itching at injection site), 3
subjects (2.94%) related to nervous system disorders (Headache, Dizziness).

General Introduction

ELORES is a combination product of ceftriaxone, sulbactam and EDTA. Serum concentrations are
proportional to the dose administered. The pharmacokinetic properties are detailed below:

General characteristics
Absorption: Ceftriaxone and Sulbactam is completely bioavailable following intramuscular administration.
The maximum plasma concentration of ceftriaxone after a single IV dose of 1.5 g is about 148.762 μg/ml
(SD ± 14.826) and is reached in 0.563 hours (SD ± 0.169) after the dose, while that of sulbactam sodium is 19.287 (SD± 5.685 μg/ml) and is reached approximately in 0.521 hour (SD ± 0.102) in healthy volunteers.

Distribution: Ceftriaxone distributes well in various compartments and also passes the placental barrier. The
mean volume of distribution in healthy adults is 0.13 l/kg. Ceftriaxone is reversibly bound to albumin. The
binding is 95 % at plasma concentrations less than 100 mg/l with the binding percentage decreasing as the
concentration increases (to 85 % at ceftriaxone plasma concentrations of 300 μg/ml). The ceftiaxone is
distributed in 5.2 hours approximately in blood stream, while sulbactam reaches its half life in 0.94 hours .
Sulbactam has been found to be approximately 38% reversibly bound to human serum protein.

Serum levels:
Following the intravenous infusion of 1.5 g of ELORES for 30 minutes, mean values (±SD) of Cmax for
Ceftriaxone, treatment were 152.06 ± 6.65 μg/ml and Sulbactam treatment were 21.32 ± 1.80 μg/ml.
 

Metabolism: Ceftriaxone does not undergo systemic metabolism but it is broken down in the small intestine
by bacterial action.
Sulbactam is not metabolised, but is excreted primarily in the urine (glomerular filtration and tubular
secretion) with a small amount being recovered in bile and faeces.

Elimination: Over a 0.15 to 3 g dose range, the values of elimination half-life range from 6 to 9 hours, total
plasma clearance from 0.6–1.4 l/h and renal clearance from 0.3–0.7 l/h.
50–60 % of ceftriaxone is eliminated as an unchanged active substance in the urine whilst the remainder is
excreted via the bile into the faeces as microbiologically inactive metabolites.
Over a 0.15 to 3 gm dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours .
Ceftriaxone concentrates in the urine. The urine concentrations are 5–10 times higher than those found in the plasma.

Ceftriaxone cannot be removed by dialysis. This applies to both haemodialysis and peritoneal dialysis.
Urinary excretion is via glomerular filtration. No tubular secretion takes place. For this reason, no increase in
the serum levels is to be expected in coincident administration of probenecid and is actually - even at higher
dosage e.g. with 1-2 g probenecid - not found.

Approximately 75 to 85% of sulbactam are excreted unchanged in the urine during the first 8 hours after
administration to individuals with normal renal function. Somewhat higher and more prolonged serum levels
of ampicillin and sulbactam can be achieved with the concurrent administration of probenecid.

Linearity/nonlinearity:
Non-Linearity:
The pharmacokinetics of ceftriaxone are non-linear with respect to the dose. This non-linearity is explained
by a concentration dependent decrease of binding to plasma proteins which leads to a respective increase in
distribution and elimination.
With the exception of elimination half-life, all pharmacokinetic parameters are dose-dependent. Repeat
dosing of 0.5 to 2 g results in 15 % –36 % accumulation above single dose values . When multiple doses of
sulbactam 0.5g were administered 6-hourly for 3 days to healthy volunteers no significant accumulation was seen.

After high doses of ceftriaxone diarrhoea, formation of biliary caliculi in the gallbladder and nephropathy were observed in monkeys and dogs

Di sodium edetate Ph. Eur.

Solutions containing ceftriaxone/sulbactam should not be mixed with or added to solutions containing other
agents. In particular, diluents containing calcium, (e.g. Ringer's solution, Hartmann's solution) should not be
used to reconstitute ceftriaxone/sulbactam vials or to further dilute a reconstituted vial for IV administration
because a precipitate can form. Ceftriaxone/sulbactam must not be mixed or administered simultaneously
with calcium-containing solutions. Based on literature reports, ceftriaxone/sulbactam is not compatible with
amsacrine, vancomycin, fluconazole, aminoglycosides and labetalol.

2 years from the date of manufacture. For shelf life of diluted product see section 6.6.

ELORES is to be stored at controlled room temperature or store below 30°C and protected from light.
For shelf life of diluted product see section 6.6.

30 ml type I tubular glass vial with 20 mm grey butyl rubber stoppers and sealed with 20mm flip off red aluminum seals.

Preparation of solutions for injection and infusion
ELORES upon dilution with following diluted solution remain stable for the following time periods :

Reconstitution
ELORES comes in a unit carton pack containing one vial of dry powder for injection along with package
insert. Reconstitute ELORES with the WFI and agitate the vial gently until the powder dissolves completely
and administer immediately. Use injection only if the solution is clear and free from particulate matter.

Following are the recommendation for diluting the solution

Product name	Supplied in vial	Vol of WFI required to prepare the solution for IV use	Maximum final concentration in mg/ml ceftriaxone/sulbactam
ELORES	30 ml	10 ml	100+50

 

ELORES sterile powder should be stored at room temperature 77±41°F (25 °C±5 °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.

ELORES has been shown to be compatible with 0.9% Sodium Chloride, 5.0% Dextrose, 10.0% Dextrose,
0.9% Sodium Chloride Injection + 5% Dextrose, 0.32% sodium lactate, 5% Sodium Bicarbonate & 10%
Mannitol.

The use of freshly prepared solutions is recommended. These maintain potency for at least 6 hours at or
below 25°C except 10.0% Dextrose or 24 hours at 2-8°C. Protect from light.

Any unused product or waste material should be disposed of in accordance with local requirements.