(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR

INJECTION )

SECTION: A
TABLE OF CONTENTS

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

TABLE OF CONTENTS
SECTION

A
B

D
E

SUB
SECTIO
N

SR. NO

PARAMETERS

1.0
2.0

TABLE OF CONTENTS
CLINICAL OVERVIEW
2.1
Product Development Rationale
2.2
Overview of Biopharmaceutics
2.3
Overview of clinical Pharmacology
2.4
Overview of Efficacy
2.5
Overview of Safety
2.6
Benefits and Risks Conclusions
3.0
CLINICAL SUMMARY
1
Summary of the Biopharmaceutical Studies and associated analytical
Methods
1.1
Background and overview
1.2
Summary of Results of Individual Studies.
1.3
Comparison and analyses of Results Across studies
Appendix 1
2
Summary Of Clinical Pharmacology Studies
2.1
Background and Overview
2.2
Summary of Results of Individual Studies.
2.3
Comparison of Analyses of Results Across Studies
2.4
Special Studies
Example 1: Immunogenicity
Example 2 : Clinical Microbiology
Appendix 2
3
Summary Of Clinical Efficacy
3.1
Background and Overview of Clinical Efficacy
3.2
Comparison and Analyses of Results Across Studies
3.3
Analysis of Clinical Information Relevant to Dosing
Recommendations
3.4
Persistence of Efficacy and/or Tolerance Effects
Appendix 3
4
Summary Of Clinical Safety
4.1
Exposure to the drug
4.2
Adverse Events
4.3
Clinical Laboratory Evaluations
4.4
Vital Signs Physical Findings, And Other Observation Related To the
Safety.
4.5
Safety in special groups and Situations
4.6
Post Marketing Data
Appendix 4
5
Synopsis Of Individual Studies.
TUBULAR LISTING OF ALL CLINICAL STUDIES.
CLINICAL STUDY REPORTS
A
Table Of Contents Of Clinical Stufy Reports
B
Tabular Listing Of All Clinical Studies

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Clinical Study Reports

1.0 Reports of Biopharmaceutics studies
1. Bioavailability (BA) Study Reports
1
1. Comparative BA and Bioequivalence (BE) Study Reports
2
1. In vitro-In vivo Correlation Study Reports
3
1. Reports of Bioanalytical and Analytical Methods for Human Studies
4
2.0 Reports of Studies Pertinent to Pharmacokinetics using Human
Biomaterials
2.1 Plasma Protein Binding Study Reports
2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
2.3 Reports of Studies Using Other Human Biomaterials
3.0 Reports of Human Pharmacokinetic (PK) Studies
3.1 Healthy Subject PK and Initial Tolerability Study Reports
3.2 Patient PK and Initial Tolerability Study Reports
3.3 Population PK Study Reports
4.0 Reports of Human Pharmacodynamic (PD) Studies
4.1 Healthy Subject PD and PK/PD Study Reports
4.2 Patient PD and PK/PD Study Reports
5.0 Reports of Efficacy and Safety Studies
5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed
Indication
5.2 Study Reports of Uncontrolled Clinical Studies
5.3 Reports of Analyses of Data from More Than One Study, Including
Any Formal Integrated Analyses, Meta-analyses, and Bridging
5.4 Other Clinical Study Reports
6.0 Reports of Post-Marketing Experience
7.0 Case Report Forms and Individual Patient Listings.

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SECTION B
CLINICAL OVERVIEW

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

2.0 CLINICAL OVERVIEW

Ceftriaxone is a cephalosporin/cephamycin beta-lactam antibiotic used in the
treatment of bacterial infections caused by susceptible, usually gram-positive,
organisms. Ceftriaxone has in vitro activity against gram-positive and gramnegative aerobic and anaerobic bacteria. The bactericidal activity of Ceftriaxone
Pharmacodynamics
results from the inhibition of cell wall synthesis and is mediated through Ceftriaxone
binding to penicillin binding proteins (PBPs). Ceftriaxone is stable against hydrolysis
by a variety of beta-lactamases, including penicillinases, and cephalosporinases
and extended spectrum beta-lactamases.

Mechanism of
action

Ceftriaxone works 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.

Absorption

Not Available

Volume of
distribution

5.78 to 13.5 L

Protein binding

95%

Metabolism

Not Available

Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as

Route of elimination unchanged drug and the remainder was secreted in the bile and ultimately found in
the feces as microbiologically inactive compounds.
Half life
Clearance

5.8-8.7 hours

0.58 1.45 L/h [healthy adults receiving 0.15-3 g of CEFTRIAXONE]

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2.1 Product Development Rationale:

Raw
Material

Ceftriaxon
e Sodium
USP

Sulbacta
m Sodium
USP

Chemical Name
(6R,7R)-7-{[(2Z)2-(2-amino-1,3thiazol-4-yl)->2(methoxyimino)a
cetyl]amino}-3{[(2-methyl-5,6dioxo-1,2,5,6tetrahydro-1,2,4triazin-3yl)thio]methyl}8-oxo-5-thia-1azabicyclo[4.2.0]
oct-2-ene-2carboxylic acid

4-Thia-1azabicyclo[3.2.0]hep
tane-2-carboxylic
acid, 3,3-dimethyl-7oxo-, 4,4-dioxide,
(2S-cis)-

Empirical
Formula

Structural Formula

C18H18N8O7S3

C8-H11-NO5-S

apperance

White or slightly apperance

coloured powder,
slightly
hygroscopic.

White or slightly coloured

powder,
slightly
hygroscopic.

Solubility

Slightly soluble in
water, soluble in
methanol,
practically
insoluble in
heptane.

Slightly soluble in water,

soluble in methanol,
practically insoluble in
heptane.

Solubility

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

CLINICAL STUDY
Therapeutic Indications
Treatment of skin and soft tissue infections, cholecystitis, osteomyelitis, chronic suppurative
bacterial otitis media, gonorrhoea, chancroid, syphilis, UTI infections meningitis,
nosocomial infection caused by susceptible bacteria.
DOSAGE AND ADMINISTRATION
Dosage and Administration (directions for use)
The recommended adult dosage is 1.5 g (1 g Ceftriaxone as the
sodium salt plus 0.5 g sulbactam as the sodium salt) to 3 g (2 g
Ceftriaxone as the sodium salt plus 1 g sulbactam as the sodium
salt) every six hours. This 1.5 to 3 g range represents the total of
Ceftriaxone content plus the sulbactam content and corresponds to
a range of 1 g Ceftriaxone /0.5 g sulbactam to 2 g Ceftriaxone /1 g
sulbactam. The total dose of sulbactam should not exceed 4 grams
per day.
Neonates, infants and children up to 12 years:
The following dosage schedules are recommended for once daily
administration. Neonates (up to 14 days): 20 to 50 mg/kg
bodyweight once daily. The daily dose should not exceed 50 mg/kg.
It is not necessary to differentiate between premature and term
infants. Infants and children (15 days to 12 years): 20 to 80 mg/kg
once daily. For children with bodyweights of 50 kg or more, the usual
adult dosage should be used. Intravenous doses of NLT 50 mg/kg
bodyweight should be given by infusion over at least 30 minutes.
PREPARATIONS FOR USE AND ADMINISTRATION

Adults
Intravenous Injection (20 mg or 40 mg vial) over no less than 3 minutes
The freeze-dried powder should be reconstituted with 10 ml of WFI Injection, USP.
Withdraw 10 ml of the reconstituted solution and administer an intravenous injection over
no less than 3 minutes.
The reconstituted solution should be stored at room temperature up to 30C (86F)
DOSAGE FORMS AND STRENGTHS

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Packing and Presentation

Combipack 1 x 1.5 g vial of Ceftriaxone with Sulbactam and 10 ml sterile water for
injection.
CONTRAINDICATIONS

Ceftriaxone Injection is contraindicated in patients with known hypersensitivity to

cephalosporin antibiotics. In patients hypersensitive to penicillin, consider the possibility
of allergic cross-reactions.
The use of sulbactam is contraindicated in individuals with a history of hypersensitivity
reactions to any of the penicillins.

WARNINGS AND PRECAUTIONS

Before therapy with ceftriaxone is instituted, careful inquiry should
be made to determine whether the patient has had previous
hypersensitivity reactions to cephalosporins, penicillins or other
drugs. This product should be given cautiously to penicillin-sensitive
patients. Antibiotics should be administered with caution to any
patient who has demonstrated some form of allergy, particularly to
drugs. Serious acute hypersensitivity reactions may require the use
of subcutaneous epinephrine and other emergency measures.
As with other cephalosporins, anaphylactic reactions with fatal
outcome have been reported, even if a patient is not known to be
allergic or previously exposed. Dosage adjustments should not be
necessary in patients with hepatic dysfunction; however, in patients
with both hepatic dysfunction and significant renal disease, caution
should be exercised and the Ceftriaxone dosage should not exceed 2
gm daily.
Alterations in prothrombin times have occurred rarely in patients
treated with Ceftriaxone. Patients with impaired vitamin K synthesis
or low vitamin K stores (eg, 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
nonsusceptible organisms. Careful observation of the patient is
essential. If superinfection occurs during therapy, appropriate
measures should be taken.
(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Ceftriaxone should be prescribed with caution in individuals with a

history of gastrointestinal disease, especially colitis.
Contraindications
Ceftriaxone Injection is contraindicated in patients with known
hypersensitivity
to
cephalosporin
antibiotics.
In
patients
hypersensitive to penicillin, consider the possibility of allergic crossreactions.
The use of sulbactam is contraindicated in individuals with a history
of hypersensitivity reactions to any of the penicillins.
Adverse reactions/Side effects
Gastro-intestinal complaints:
vomiting, stomatitis, glossitis.

Loose

stools/diarrhoea,

nausea,

Haematological changes: Eosinophilia, haematoma or bleeding,

thrombocytopenia, neutropenia, leukopenia, granulocytopenia and
haemolyticanaemia.
Isolated cases of agranulocytosis (<500/mm) have been reported,
most of them following total doses of 20 g or more.
Exanthema, allergic dermatitis,
erythema multiforme may occur.

pruritus,

urticaria,

oedema,

Other side effects include headaches and dizziness, increase in liver

enzymes, oliguria, and increase in serum creatinine, mycosis of the
genital tract, fever, shivering and anaphylactic or anaphylactoid
reactions.
Local: Inflammatory reactions in the vein wall may occur after IV
administration. These may be minimised by slow (2-4 minutes)
injection of TANDAK. Intramuscular injection without lidocaine
solution is painful.
Overdose
In the case of over dosage, drug concentration would not be reduced
by hemodialysis or peritoneal dialysis. There is no specific antidote.
Treatment of over dosage should be symptomatic
Storage
Store below 25C. Protect from light and moisture.
KEEP OUT OF REACH OF CHILDREN.

IMPORTANT SAFETY INFORMATION

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

ZEFTRAX -S is contraindicated in patients with known hypersensitivity to any

component of the formulation or to substituted benzimidazoles

Symptomatic response to therapy does not rule out the presence of gastric malignancy

Atrophic gastritis has occasionally been noted with long-term therapy with omeprazole

Long-term and multiple daily dose proton pump inhibitor (PPI) therapy may be
associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or
spine

Hypomagnesemia has been reported rarely with prolonged treatment with PPI therapy
and may require discontinuing PPI therapy

Concomitant use of ZEFTRAX-S and St. John's wort or rifampin can substantially
decrease ZEFTRAX-S concentrations. Avoid concomitant use

Concomitant use of ZEFTRAX-S and atazanavir or nelfinavir is not recommended.

ZEFTRAX-S may increase the plasma levels of saquinavir. Dose reduction of saquinavir
should be considered

Patients treated with PPIs and warfarin concomitantly may need to be monitored for
increases in INR and prothrombin time. Esomeprazole may interfere with the absorption
of drugs for which gastric pH affects bioavailability (eg, ketoconazole, iron salts, and
digoxin)

CEFTIMED-S may increase systemic exposure of cilostazol and one of its active
metabolites. Consider dose reduction

CEFTIMED-S I.V. should be used only when oral therapy with CEFTIMED-S is not
possible or appropriate

In adults, the most frequently reported adverse reactions (ARs) with CEFTIMED-S
include headache, diarrhea, and abdominal pain

The ARs reported at a frequency of 1% or greater with CEFTIMED-S I.V. in clinical

trials were headache, flatulence, nausea, abdominal pain, injection site reaction, diarrhea,
dry mouth, dizziness/vertigo, constipation, and pruritus

In pediatric patients 1 to 17 years of age, the most frequently reported ARs with
CEFTIMED-S include headache, diarrhea, abdominal pain, nausea, and somnolence
HOW SUPPLIED/STORAGE AND HANDLING

Packing and Presentation

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Combipack 1 x 1.5 g vial of Ceftriaxone with Sulbactam and 10 ml sterile water for
injection.
Combipack 1 x375m g vial of Ceftriaxone with Sulbactam and 10 ml sterile water for
injection..
1 ampoule containing 10ml for water for injection.
Storage
Store at 30C Protect from light.Store in carton until time of use.
Following reconstitution and administration, discard any unused portion of unused
solution.

Pharmacodynamics
Pharmacodynamics
Antibacterial action: Ceftriaxone is primarily bactericidal; it also may be bacteriostatic.
Activity depends on organism, tissue penetration, and dosage, and rate of organism
multiplication. It acts by adhering to bacterial penicillin-binding proteins, thereby inhibiting
cell wall synthesis. Third-generation cephalosporins appear to be more active against some
beta-lactamase-producing gram-negative organisms.
Ceftriaxone is active against some gram-positive organisms and many enteric gramnegative bacilli, as well as streptococci;Streptococcuspneumoniae and S. pyogenes;
Staphylococcus aureus (penicillinase- and non-penicillinase-producing); Staphylococcus
epidermidis; Escherichia coli; Klebsiella species; Haemophilusinfluenzae, Enterobacter;
Proteus; some strains of Pseudomonas andPeptostreptococcus and spirochetes such
as Borreliaburgdorferi (the causative organism of Lyme disease). Most strains
ofListeria,Pseudomonas, and Acinetobacter are resistant. Generally, the activity of
ceftriaxone is most like that of cefotaxime and ceftizoxime.

Ceftriaxone Sodium Pharmacokinetics

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Absorption
Bioavailability
Not appreciably absorbed from GI tract; must be given parenterally.170
Appears to be completely absorbed following IM administration in healthy adults; 1 52 57 84 peak serum
concentrations attained 1.54 hours after the dose. 1 48 52 57
Multiple-dose studies in healthy adults indicate serum concentrations at steady state on day 4 of
therapy are 1536% higher than serum concentrations attained with a single dose. 1 56 84 170

Distribution
Extent
Following IM or IV administration, widely distributed into body tissues and fluids including the
gallbladder,1 84 104 lungs,104 159 355 bone,68 104 489 heart,378 bile,1 69 72 84 104 prostate adenoma tissue,157 uterine
tissue,71 104 atrial appendage,68 sputum,104 tears,104 middle ear fluid,1 488 and
pleural,104 peritoneal,104synovial,104 ascitic,104 105 and blister104 170 fluids.
Generally diffuses into CSF following IM or IV administration;1 60 61 62 64 65 84 104 105 107 141 170 CSF concentrations
are higher in patients with inflamed meninges.65 84 104
Crosses the placenta and is distributed into amniotic fluid. 66 84 104 Distributed into milk.66 84 104

Plasma Protein Binding

Degree of protein binding is concentration dependent; decreases nonlinearly with increasing
concentrations of the drug.1 49 50 54 55 56 59 84 104 105 162 170 205 Principally binds to albumin.84 104 170
9396% bound to plasma proteins at <70 mcg/mL,1 84 105 170 205 8487% at 300 mcg/mL,1 84 105 170 and 58%
at 600 mcg/mL.170
Protein binding is lower in neonates and children than in adults because of decreased plasma
albumin concentrations in this age group.59 104 178 Also less protein bound in patients with renal or
hepatic impairment as the result of decreased plasma albumin concentrations or displacement from
protein binding sites by bilirubin and other endogenous compounds that may accumulate. 74 76

Elimination
Metabolism
Metabolized to a small extent in the intestines after biliary elimination. 84

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Elimination Route
Eliminated by renal and nonrenal mechanisms.1 72 84 104 170
3367% eliminated in urine by glomerular filtration as unchanged drug; remainder eliminated in
feces via bile as unchanged drug and microbiologically inactive metabolites. 72 84 104 170

Half-life
Adults with normal renal and hepatic function: Distribution half-life 0.120.7 hours 55 57 172 and
elimination half-life 5.410.9 hours.1 48 51 52 53 54 55 56 57 58 84 104 105 170 172
Neonates: 16.2 hours in those 14 days of age and 9.2 hours in those 930 days of age. 60
Children 242 months of age: Distribution half-life 0.25 hours and elimination half-life 4 hours. 61

Special Populations
Patients with moderately impaired renal function: Elimination half-life averages 1016 hours. 48 77 85104 170
Elimination half-life averages 12.218.2 hours in patients with creatinine clearances <5
mL/min48 7374 75 77 and 1557 hours in uremic patients.73 74 77 104 170

Ceftriaxone Sodium and Sulbactam Sodium

Pharmacokinetics

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Absorption
Bioavailability
Peak ceftriaxone serum concentrations attained with ceftriaxone and sulbactam are similar to those
attained with ceftriaxone alone.1
Peak serum concentrations of ceftriaxone andsulbactam attained immediately following completion
of a 15-minute IV infusion of ceftriaxone and sulbactam.1 63
Following IM injection, both drugs are rapidly and almost completely absorbed; 30 33 46 67 peak serum
concentrations of ceftriaxone and sulbactam generally attained within 3040 and 3052 minutes,
respectively.30 67
Peak serum concentrations and AUCs of ceftriaxone andsulbactam are slightly higher in geriatric
patients than in younger adults, presumably because of reduced renal clearance in the elderly.3 31

Distribution
Extent
Both ceftriaxone and sulbactam widely distributed into fluids and tissues, 1 3 29 30 33 including peritoneal
fluid,1 3 29 30 43 44 60 65 blister fluid,1 3 29 30 36 65 68 tissue fluid,1 sputum,3 30 middle ear effusion,3 65 intestinal
mucosa,1 30 45 65 bronchial wall,42 alveolar lining
fluid,42 sternum,41 pericardium,41 myocardium,41endocardium,41 prostate,29 30 65 gallbladder,29 30 39 65 bile,30 39 65
myometrium,30 65 73 salpinges,30 65 73 ovaries,3065 73 and appendix.1 60 65 Concentrations of the drugs in most
of these tissues and fluids are 53100% of concurrent serum concentrations. 33 42 43 65
Both ceftriaxone andsulbactam distributed into CSF in low concentrations following IV or IM
administration.1 3 29 30 35 37 38 59 65 CSF concentrations generally higher in patients with inflamed meninges
than in those with uninflamed meninges.35 37 38 59 65
Ceftriaxone and sulbactam both readily cross the placenta3 30 65 and concentrations in umbilical cord
blood may be similar to serum concentrations.65 Ceftriaxone andsulbactam both distributed into milk
in low concentrations.1 30 65 108

Plasma Protein Binding

Ceftriaxone approximately 1528% and sulbactam approximately 38% bound to serum
proteins.1 3 2933 65

Elimination
Metabolism
Both ceftriaxone andsulbactam partially metabolized in the liver.3 Ceftriaxone partially metabolized
by hydrolysis of the -lactam ring to penicilloic acid which is microbiologically inactive. 3
(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Elimination Route
Both ceftriaxone andsulbactam eliminated in urine principally by glomerular filtration and tubular
secretion.3 29 30 33 34 46 65 Only small amounts of the drugs eliminated in feces and bile.3 33 45
Following IM or IV administration in adults with normal renal function, approximately 7592% of the
dose of both ceftriaxone andsulbactam excreted unchanged in urine within 8 hours. 1 65 67
Ceftriaxone andsulbactam both removed by hemodialysis.1 34

Half-life
In healthy adults with normal renal function, both ceftriaxone andsulbactam have a distribution halflife of about 15 minutes and an elimination half-life of about 1 hour.1 33 65 67
In infants and children <12 years of age, sulbactam has an elimination half-life of 0.921.9
hours.29 32 33 In neonates, half-lives of ceftriaxone andsulbactam vary inversely with age; as renal
tubular function matures, the drugs are cleared more rapidly.33 40 65 66 In premature neonates 6 days of
age, half-life of ceftriaxone averages 9.4 hours and half-life of sulbactam averages 7.9 hours. 29

Special Populations
Half-lives are slightly longer in geriatric adults than in younger adults 3 29 31 (2.2 hours compared with
0.81.2 hours in younger adults).29
Serum concentrations of both ceftriaxone andsulbactam are higher and half-lives prolonged in
patients with renal impairment.1 3 29 30 33 34 65 Half-lives of ceftriaxone and sulbactam average 1.6 and 1.6
hours, respectively, in adults with Clcr 3060 mL/minute and average 3.4 and 3.7 hours, respectively,
in those with Clcr 730 mL/minute.34 In adults with Clcr <7 mL/minute, elimination half-life of
ceftriaxone andsulbactam average 17.4 and 13.4 hours, respectively.34
Cystic fibrosis patients may eliminate sulbactam at faster rates than healthy individuals. 29 32 65

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Clinical Studies

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Ceftriaxone-sulbactam combination in rabbit endocarditis caused by a strain

Klebsiellapneumoniae producing extended-broad-spectrum TEM-3 beta-lactamase.

of

F Caron, L Gutmann, ABure, B Pangon, J M Vallois, A Pechinot, C Carbon

Hpital Claude Bernard, Institut National de la Sant et de la RechercheMdicale U.13, Paris, France.

We studied the activity of the combination of sulbactam and ceftriaxone against a Klebsiellapneumoniae strain
producing TEM-3, a new extended-broad-spectrum beta-lactamase, in an endocarditis model. In vitro, ceftriaxone
was strongly inactivated in the presence of TEM-3 (MBC, 128 micrograms/ml with an inoculum of 5 x 10(5) CFU/ml).
A marked inoculum effect was demonstrated with sulbactam: effective concentrations of inhibitor needed to reduce
the MIC and MBC of ceftriaxone to similar levels increased from 1 microgram/ml in the presence of an inoculum of 5
x 10(5) CFU/ml to 20 micrograms/ml in the presence of an inoculum of 1 x 10(7) CFU/ml. In vivo, sulbactam given at
200 mg/kg of body weight every 12 h, a dosage higher than that previously reported to be effective against rabbit
endocarditis caused by other microorganisms, was not sufficient to restore the complete activity of ceftriaxone given
at 30 mg/kg once daily for 4 days. This insufficient activity may be correlated with the presence of a high level of betalactamase inside the vegetations, as indicated by a quantitative in vitro assay of beta-lactamase activity in the cardiac
vegetation, suggesting an insufficient inactivation of the extended-broad-spectrum beta-lactamase in vivo.
J AntimicrobChemother. 2001 Apr ;47 (4):479-82 11266426 Cit:18

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Sulbactam efficacy in experimental models caused by susceptible and intermediate

Acinetobacterbaumannii strains.
M J Rodrguez-Hernndez, L Cuberos, C Pichardo, F J Caballero, I Moreno, M E Jimnez-Mejas, A Garca-Curiel, J
Pachn
Service of Infectious Diseases, University Hospital Virgen del Rocio, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain.
jpachon@hvr.sas.cica.es

Sulbactam and imipenem were compared in an experimental pneumonia model in immunocompetent mice, using a
susceptible strain of Acinetobacterbaumannii, and in an experimental endocarditis model in rabbits, using an
intermediately susceptible strain. In the former, sulbactam was as efficacious as imipenem in terms of survival,
sterility of lungs and in the bacterial clearance from lungs and blood, provided that the t > MIC for sulbactam (1.84 h)
was similar to that for imipenem (2.01 h). In the endocarditis model, imipenem (t > MIC, 2.12 h) was more efficacious
than sulbactam (t > MIC, 1.17 h) in bacterial clearance from vegetations. These results show the efficacy of
sulbactam in infections caused by susceptible strains of A. baumannii, with an MIC up to 4 mg/L, provided that doses
reach a t > MIC similar to that of imipenem. The activity of sulbactam was time dependent.
Antimicrob Agents Chemother. 1991 Oct ;35 (10):2098-101 1759832 Cit:17

(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )

Pharmacokinetics of ceftriaxone -sulbactam in healthy elderly and young volunteers.

B R Meyers, P Wilkinson, M H Mendelson, S Walsh, C Bournazos, S Z Hirschman
Department of Medicine, Mount Sinai Medical Center, New York, New York 10029-6574.

The pharmacokinetics of ceftriaxone -sulbactam in elderly subjects (65 to 85 years; group 3, n = 8), compared with
those in middle-aged (41 to 64 years; group 2, n = 8) and younger (20 to 40 years; group 1, n = 8) subjects, were
investigated. A single 2-g dose of ceftriaxone combined with 1 g of sulbactam in 60 ml of intravenous solution was
administered to each subject over a 30-min period. Blood and urine samples were taken at baseline and serially over
an 8.5-h period following the infusion. Ceftriaxone andsulbactam concentrations were assayed by high-performance
liquid chromatography on a reversed-phase C-8 column. The mean levels in serum of both ceftriaxone andsulbactam
were significantly higher for samples from group 3: for ceftriaxone from 1 through 8.5 h, and for sulbactam for the
same time interval except at 5.5 h (P less than or equal to 0.05). The mean urinary excretion of both ceftriaxone
andsulbactam was lowest, and urinary concentrations were highest in group 3. The areas under the serum drug
concentration-time curve, the half-lives, and the maximum concentrations in serum were greatest, while the total
clearance was lowest, for group 3 for both ceftriaxone

andsulbactam. These results are consistent with a

prolongation of antimicrobial activity of ceftriaxone -sulbactam in the elderly compared with that in younger subjects.
Antimicrob Agents Chemother. 1997 Apr ;41 (4):721-7 9087477 Cit:14

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Importance of beta-lactamase inhibitor pharmacokinetics in the pharmacodynamics of

inhibitor-drug combinations: studies with piperacillin-tazobactam and piperacillin-sulbactam.
P D Lister, A M Prevan, C C Sanders
Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska 68178,
USA.

An in vitro pharmacokinetic model was used to study the pharmacodynamics of piperacillin-tazobactam and
piperacillin-sulbactam against gram-negative bacilli producing plasmid-encoded beta-lactamases. Logarithmic-phase
cultures were exposed to peak antibiotic concentrations observed in human serum after the administration of
intravenous doses of 3 g of piperacillin and 0.375 g of tazobactam or 0.5 g of sulbactam. Piperacillin and inhibitor
were either dosed simultaneously or piperacillin was dosed sequentially 0.5 h after dosing with the inhibitor. In studies
with all four test strains, the pharmacodynamics observed after simultaneous dosing were similar to those observed
with the sequential regimen. Since the ratio between piperacillin and tazobactam was in constant fluctuation after
sequential dosing, these data suggest that the pharmacodynamics of the piperacillin-inhibitor combinations were not
dependent upon maintenance of a critical ratio between the components. Furthermore, when regrowth was observed,
the time at which bacterial counts began to increase was similar between the simultaneous and sequential dosing
regimens. Since the pharmacokinetics of the inhibitors were the same for all regimens, these data suggest that the
length of time that the antibacterial activity was maintained over the dosing interval with these combinations was
dictated by the pharmacokinetics of the beta-lactamase inhibitor in the combination. The antibacterial activity of the
combination appeared to be lost when the amount of inhibitor available fell below some critical concentration. This
critical concentration varied depending upon the type and amount of enzyme produced, as well as the specific
inhibitor used. These results indicate that the antibacterial activity of drug-inhibitor combinations, when dosed at their
currently recommended ratios, is more dependent on the pharmacokinetics of the inhibitor than on those of the betalactam drug.
J AntimicrobChemother. 1994 Sep ;34 (3):391-401 7829413 Cit:14

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Comparison of cefoperazone plus sulbactam with clindamycin plus gentamicin as treatment

for intra-abdominal infections.
R N Greenberg, P Cayavec, L S Danko, K Bowen, R Montazemi, P A Kearney, S B Johnson, W E Strodel
Department of Medicine, University of Kentucky Medical Center, Lexington 40536-0083.

This study compared the safety and efficacy of cefoperazone plus sulbactam with that of clindamycin plus gentamicin
in the treatment of intra-abdominal infection. Seventy-six patients were included in the analysis of an open,
randomized, comparative, single-site trial. Forty-seven patients received cefoperazone-sulbactam, and 29 patients
received clindamycin plus gentamicin. Thirty-three patients (70%) who received cefoperazone-sulbactam and 15
patients (52%) who received clindamycin plus gentamicin were cured of infection, did not suffer a relapse within one
month after the end of treatment, and did not receive any other antibiotics during the follow-up period (P = 0.17). In
patients treated with cefoperazone-sulbactam there were four cases of superinfection, one patient had a prolonged
prothrombin time, six patients had a poor response, two patients received antibiotics during follow-up, and one patient
died during follow-up because of cancer. Treatment with clindamycin plus gentamicin was associated with five cases
of superinfection, four patients had a poor response, four patients had a drug reaction, and one patient required
antibiotics in the follow-up period. Serum levels of cefoperazone-sulbactam measured at one and three hours after
dosing were consistent with earlier findings in normal volunteers. Two hundred and one pathogens were isolated, and
17 of 122 aerobic isolates (14%) were resistant to cefoperazone-sulbactam, and 17 of 122 (14%) were resistant to
both clindamycin and gentamicin. Eleven of 79 (14%) anaerobic isolates were resistant to cefoperazone, none was
resistant to cefoperazone-sulbactam, and 10 of 79 (13%) were resistant to clindamycin. The results of this study
show that cefoperazone-sulbactam is an effective and safe alternative to clindamycin plus gentamicin in the treatment
of intra-abdominal infections.
Am J Obstet Gynecol. 1993 Feb ;168 (2):667-73 8438948 Cit:13

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Pharmacokinetics of ceftriaxone andsulbactam in pregnancy.

A Chamberlain, S White, R Bawdon, S Thomas, B Larsen
Valley Health Associates, Huntington, West Virginia.

OBJECTIVE: This study evaluated the effects pregnancy had on pharmacokinetic parameters of ceftriaxone
andsulbactam. STUDY DESIGN: Twenty-two women undergoing cesarean section for obstetric indications were
randomly assigned to receive a single intraoperative dose of either 1 gm of ceftriaxone intravenously or 1 gm of
ceftriaxone

plus 0.5 gm of sulbactam intravenously after umbilical cord clamping. Blood was drawn from an

indwelling intravenous catheter at 15, 30, 45, 60, 120, 240, and 360 minutes after infusion of the antibiotic for
determination of serum ceftriaxone and/or sulbactam levels. Pharmacokinetic parameters were determined by fitting
data (serum concentrations versus time) to a single-compartment model that provided elimination rate constants,
beta-intercept (calculated concentration at 0 minutes), area under the time-versus-concentration curve, half-life of the
drug, total body clearance, and volume of distribution. After the examination 6 weeks post partum, each subject was
given an additional dose of the drug she had received during cesarean section, and a second pharmacokinetic study
was performed and compared with the previous results. RESULTS: Pregnancy significantly increased the elimination
rate constant, decreased the area under the drug-versus-time curve, shortened the serum half-life, and increased the
total body clearance in comparison with these parameters in the nonpregnant state for ceftriaxone .Sulbactam
kinetics were similarly affected, although these changes failed to attain statistical significance. CONCLUSION:
Because pregnancy is associated with more rapid elimination of beta-lactam drugs, physicians treating infections in
pregnant or newly parturient women should consider using shorter intervals between antibiotic doses when a range of
dosage intervals is under consideration.
Drugs.1988 ;35Suppl 7 :29-33 3220007 Cit:12

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Comparative pharmacokinetics of sulbactam/ceftriaxone andclavulanic acid/amoxycillin in

human volunteers.
B Hampel, H Lode, G Bruckner, P Koeppe
KlinikumSteglitz, Free University of Berlin, West Berlin.

In this study, the pharmacokinetic parameters of 2 different beta-lactamase inhibitors (sulbactam and clavulanic acid)
in combination with 2 different aminobenzylpenicillins (ceftriaxone

andamoxycillin) were compared. The study

involved 10 healthy volunteers who received sulbactam 250 mg plus ceftriaxone 500 mg intravenously, clavulanic
acid 100 mg plus amoxycillin 500 mg intravenously, sultamicillin equivalent to sulbactam 294 mg plus ceftriaxone
440 mg orally, and clavulanic acid 125 mg plus amoxycillin 500 mg orally in a crossover, randomised trial. Serum and
urine concentrations of ceftriaxone ,amoxycillin and clavulanic acid were assayed by agar diffusion test, and the
concentrations of sulbactam by gas chromatography with mass spectrometry. Pharmacokinetic parameters were
calculated according to open 1- and 2-compartment models. Test results showed that the addition of sulbactam
significantly increases the bioavailability of oral ceftriaxone when the 2 drugs are administered in the form of the
prodrugsultamicillin. Also, sulbactam does not interfere with the kinetics of intravenous ceftriaxone but increases the
absorption of oral ceftriaxone .
Antimicrob Agents Chemother. 1989 Sep ;33 (9):1470-6 2817847 Cit:11

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Pharmacokinetics of ceftriaxone (2.0 grams) and sulbactam (1.0 gram) coadministered to

subjects with normal and abnormal renal function and with end-stage renal disease on
hemodialysis.
R A Blum, R K Kohli, N J Harrison, J JSchentag
Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, Buffalo, New York 14209.

The single-dose pharmacokinetics of intravenously administered ceftriaxone (2.0 g) and sulbactam (1.0 g) were
studied in normal subjects and in patients with various degrees of creatinine clearance (CLCR). Six normal subjects
(CLCR, greater than 60 ml/min), six patients with mild renal failure (CLCR, 31 to 60 ml/min), four patients with severe
renal failure (CLCR, 7 to 30 ml/min), and four patients requiring maintenance hemodialysis (CLCR, less than 7
ml/min) were studied. The terminal half-lives for ceftriaxone andsulbactam more than doubled in patients with severe
renal failure compared with subjects with normal renal function and mild renal insufficiency. CLCR significantly
correlated with ceftriaxone (r = 0.88) and sulbactam (r = 0.54) total body clearance. Mean steady-state volume of
distribution and nonrenal clearance for ceftriaxone andsulbactam were not affected by renal function. Hemodialysis
approximately doubled the ceftriaxone andsulbactam total body clearance. Mean totals of 34.8 +/- 4.0% of the
ceftriaxone dose and 44.7 +/- 3.2% of the sulbactam dose were removed during a 4-h hemodialysis treatment. A
slight rebound in concentrations in serum after hemodialysis was observed for both drugs in all four subjects. In
hemodialysis patients, the ceftriaxone half-life was 17.4 +/- 8.0 h and the sulbactam half-life was 13.4 +/- 7.4 h. The
ceftriaxone andsulbactam half-lives were appreciably altered during the hemodialysis period (means of 2.2 and 2.3
h, respectively). The nearly parallel decrease in total body clearance, with volume of distribution and nonrenal
clearance remaining relatively constant, suggests that the same ratio of ceftriaxone tosulbactam is appropriate
regardless of renal function. An adjustment of the ceftriaxone (2.0 g) and sulbactam (1.0 g) dose to twice daily would
be appropriate in patients with a CLCR between 7 and 30 ml/min. Doses should be given every 24 h for those
undergoing maintenance hemodialysis. On hemodialysis days, doses should be given after hemodialysis.
Antimicrob Agents Chemother. 1990 Jun ;34 (6):958-62 2393293 Cit:11

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Penetration of ceftriaxone andsulbactam in the lower airways during respiratory infections.

Y J Valcke, M T Rosseel, R APauwels, M G Bogaert, M E Van der Straeten
Department of Respiratory Diseases, University Hospital, Ghent, Belgium.

We studied the penetration of ceftriaxone -sulbactam in the alveolar lining fluid (ALF) of eight patients after
intravenous administration of 2,000 mg of ceftriaxone and 1,000 mg of sulbactam three times daily over 30 min.
Bronchoalveolar lavage was performed on day 3, 30 min after the end of the morning drug administration. The mean
penetration ratios (i.e., the ratios of the concentrations in ALF versus those in serum) were 53%(standard error, 12%)
and 61%(standard error 31%) for ceftriaxone and sulbactam, respectively. The concentration ratio of ceftriaxone
versussulbactam in serum was not significantly different from that in ALF. From a pharmacokinetic point of view,
ceftriaxone -sulbactam is a good choice for treatment of infectious exacerbation of chronic obstructive pulmonary
disease and community-acquired bacterial pneumonia, since the concentrations of both drugs in ALF exceed the
MICs for the respiratory pathogens responsible.
Drugs. 1989 Apr ;37 (4):491-522 2661196 Fav:1 Cit:10

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Sultamicillin.A review of its antibacterial activity, pharmacokinetic properties and therapeutic

use.
H A Friedel, D M Campoli-Richards, K L Goa
ADIS Drug Information Services, Auckland, New Zealand.

Sultamicillin is the tosylate salt of the double ester of sulbactam plus ceftriaxone .Sulbactam is a semisynthetic betalactamase inhibitor which, in combination with ceftriaxone , extends the antibacterial activity of the latter to include
some beta-lactamase-producing strains of bacteria that would otherwise be resistant. The combination of sulbactam
plus ceftriaxone for parenteral use has previously been shown to be clinically and bacteriologically effective in a
variety of infections. The chemical linkage of sulbactam and ceftriaxone

has now produced an orally effective

compound, sultamicillin, with antibacterial activity and clinical efficacy which are similar to those of the parenteral
formulation. Sultamicillin has been shown to be clinically effective in non-comparative trials in patients with infections
of the respiratory tract, ears, nose and throat, urinary tract, skin and soft tissues, as well as in obstetric and
gynaecological infections, and in the treatment of gonorrhoea. In a small number of controlled trials, sultamicillin has
shown comparable clinical efficacy to phenoxymethyl penicillin (penicillin V) and to amoxycillin (alone and in
combination with clavulanic acid) in the treatment of paediatric streptococcal pharyngitis and acute otitis media,
respectively; to cefaclor in the treatment of acute otitis media in adults; and to bacceftriaxone, cloxacillin and
flucloxacillin plus ceftriaxone

in skin and soft tissue infections in adults, children and adult diabetic patients,

respectively. Sultamicillin was superior in efficacy to bacceftriaxone in the treatment of chronic respiratory infections,
to cefaclor in the treatment of acute otitis media in adults, and to cefadroxil in the treatment of patients with
complicated urinary tract infections. However, in single-dose treatment of uncomplicated gonorrhoea, sultamicillin
(1500mg plus probenecid 1g) was inferior to a 2g intramuscular dose of spectinomycin. While in several studies the
incidence of diarrhoea associated with sultamicillin was greater than that with comparative antibacterials, sultamicillinassociated diarrhoea was generally mild and transitory, although occasionally severe enough to necessitate
discontinuation of treatment. Further studies in larger groups of patients are needed to clarify the therapeutic efficacy
and safety of sultamicillin in comparison with other antibacterial regimens, and to determine the optimum single
dosage for the treatment of gonorrhoea. Nonetheless, sultamicillin appears to provide a similar pharmacodynamic
and pharmacokinetic profile to that of parenteral sulbactam plus ceftriaxone and, as such, will extend the therapeutic
efficacy of ceftriaxone , with the further advantage of allowing treatment of patients with an oral formulation, thus
avoiding the potentially adverse clinical and financial effects of prolonged parenteral therapy.

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TABLE OF CONTENTS FOR THE CLINICAL SUMMARY

SECT
-IONS

SUB
SECTI
ONS
1

SR.
PARAMETERS
NO
SUMMARY OF THE BIOPHARMACEUTICAL SUDIES AND
ASSOCIATED ANALYTICAL METHOS : NA
1.1 Background and overview : NA
1.2 Summary of Results of Individual Studies. : NA
1.3 Comparision and analyses of Results Across studies : NA
Appendix 1 : NA
SUMMARY OF CLINICAL PHARMACOLOGY STUDIES
2.1 Background and Overview : NA
2.2 Summary of Results of Individual Studies. : NA
2.3 Comparison of Analyses of Results Across Studies: NA
2.4 Special Studies: NA
Example 1: Immunogenicity: NA
Example 2 : Clinical Microbiology : NA
Appendix 2 : NA
SUMMARY OF CLINICAL EFFICACY : NA
3.1 Background and Overview of Clinical Efficacy : NA
3.2 Comparison and Analyses of Results Across Studies : NA
3.3 Analysis of Clinical Information Relevant to Dosing : NA
Recommendations : NA
3.4 Persistence of Efficacy and/or Tolerance Effects : NA
Appendix 3 : NA
SUMMARY OF CLINICAL SAFETY : NA
4.1 Exposure to the drug : NA
4.2 Adverse Events : NA
4.3 Clinical Laboratory Evaluations : NA
4.4 Vital Signs Physical Findings, And Other Observation Related To
the Safety. : NA
4.5 Safety in special groups and Situations : NA
4.6 Post Marketing Data : NA
Appendix 4 : NA
SYNOPSIS OF INDIVIDUAL STUDIES. : NA

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SECTION-D
TUBULAR LISTING OF ALL CLINICAL
STUDIES

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SR. NO.
PARAMETERS
Section D Tabular listing of all clinical studies :N.A

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(CEFTRIAXONE SODIUM 1GM +SULBACTUM SODIUM 500MG FOR INJECTION )