CeftomaxTM – S

(Cefoperazone Sodium plus Sulbactam Sodium Injection)

COMPOSITION

CEFTOMAX - S Injection 1.5 gm

Each vial contains:
Cefoperazone Sodium equivalent to Cefoperazone IP …. 1,000 mg
Sulbactam Sodium equivalent to Sulbactam USP …. 500 mg

CEFTOMAX - S Injection 3.0 gm

Each vial contains:
Cefoperazone Sodium equivalent to Cefoperazone IP …. 2,000mg
Sulbactam Sodium equivalent to Sulbactam USP …. 1,000 mg

DOSAGE FORM
Powder for reconstitution and intravenous and intramuscular use only

DESCRIPTION
The sulbactam sodium and cefoperazone sodium combination consists of a beta-
lactamase inhibitor plus a beta-lactam.

This sulbactam /cefoperazone combination is available as a dry powder for

reconstitution in a 1:2 ratio.
PHARMACOLOGY

Pharmacodynamics
The antibacterial component of sulbactam/cefoperazone is cefoperazone, a third-
generation cephalosporin, which acts against sensitive organisms during the stage of
active multiplication by inhibiting the biosynthesis of cell wall mucopeptide. Sulbactam
does not possess any useful antibacterial activity, except against Neisseriaceae and
Acinetobacter. As sulbactam also binds with some penicillin-binding proteins, sensitive
strains are also often rendered more susceptible to sulbactam/cefoperazone than to
cefoperazone alone.

The combination of cefoperazone and sulbactam is active against all organisms

sensitive to cefoperazone. In addition, it demonstrates synergistic activity (up to 4-fold
reduction in the minimum inhibitory concentrations for the combination versus those for
each component) in a variety of organisms, most markedly the following:

● Haemophilus influenzae Bacteroides species

● Staphylococcus species Acinetobacter calcoaceticus
 ● Enterobacter aerogenes
● Escherichia coli
● Proteus mirabilis
● Klebsiella pneumoniae
● Morganella morganii
● Citrobacter freundii
● Enterobacter cloacae
● Citrobacter diversus

Sulbactam/cefoperazone is active in vitro against a wide variety of clinically

significant organisms:
Gram positive Organisms

● Staphylococcus aureus, penicillinase and non-penicillinase-producing strains

● Staphylococcus epidermidis
● Streptococcus pneumoniae (formerly Diplococcus pneumoniae)
● Streptococcus pyogenes (Group A beta-haemolytic streptococci) Streptococcus
agalactiae (Group B beta-haemolytic streptococci) Most other strains of beta-
haemolytic streptococci
● Many strains of Streptococcus faecalis (enterococcus)

Gram negative Organisms

● Escherichia coli Klebsiella species Enterobacter species

● Citrobacter species
● Haemophilus influenzae Proteus mirabilis Proteus vulgaris
● Morganella morganii (formerly Proteus morganii)
● Providencia rettgeri (formerly Proteus rettgeri)
● Providencia species
● Serratia species (including S. marcescens) Salmonella and Shigella species
● Pseudomonas aeruginosa and some other Pseudomonas species Acinetobacter
calcoaceticus
● Neisseria gonorrhoeae
● Neisseria meningitidis Bordetella pertussis
● Yersinia enterocolitica

Anaerobic Organisms

● Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides species, and

● Fusobacterium species).
● Gram-positive and gram-negative cocci (including Peptococcus,
Peptostreptococcus and Veillonella species).
 ● Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus species).

Pharmacokinetics

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose
administered as sulbactam/cefoperazone is excreted by the kidneys. Most of the
remaining dose of cefoperazone is excreted in the bile. After sulbactam/cefoperazone
administration, the mean half-life for sulbactam is about 1 hour while that for
cefoperazone is 1.7 hours. Serum concentrations have been shown to be proportional
to the dose administered. These values are consistent with previously published values
for these agents when given alone.

Mean peak sulbactam and cefoperazone concentrations after the administration of

2 g of cefoperazone/ sulbactam (1 g sulbactam, 1 g of cefoperazone) intravenously over
5 minutes were 130.2 and 236.8 mcg/mL, respectively. This reflects the larger volume
of distribution for sulbactam (Vd = 18.0–27.6 L) compared to cefoperazone (Vd = 10.2–
11.3 L).

After intramuscular administration of 1.5 g cefoperazone sulbactam (0.5 g sulbactam,

1 g cefoperazone) peak serum concentrations of sulbactam and cefoperazone are seen
from 15 minutes to 2 hours after administration. Mean peak serum concentrations were
19.0 and 64.2 mcg /mL for sulbactam and cefoperazone, respectively.

Both sulbactam and cefoperazone distribute well into a variety of tissues and fluids,
including the bile, gall bladder, skin, appendix, fallopian tubes, ovary, uterus, and others.

There is no evidence of any pharmacokinetic drug interaction between sulbactam and

cefoperazone when administered together in the form ofsulbactam/cefoperazone.

After multiple dosing, no significant changes in the pharmacokinetics of either

component of sulbactam/cefoperazone have been reported and no accumulation has
been observed when administered every 8 to 12 hours.
INDICATIONS

Monotherapy

CEFTOMAX - S Injection is indicated for the treatment of the following infections when
caused by susceptible organisms:
i. Respiratory tract infections (upper and lower)
ii. Urinary tract infections (upper and lower)
iii. Peritonitis, cholecystitis, cholangitis, and other intra-abdominal infections
iv. Septicaemia
v. Meningitis
vi. Skin and soft tissue infections
vii. Bone and joint infections
viii.Pelvic inflammatory disease, endometritis, gonorrhoea, and other infections of
the genital tract

Combination Therapy

Because of the broad spectrum of activity of sulbactam/cefoperazone, most infections

can be treated adequately with this antibiotic combination alone. However,
sulbactam/cefoperazone may also be used concomitantly with other antibiotics if such
combinations are indicated. If an aminoglycoside is used, renal function should be
monitored during the course of therapy.

DOSAGE AND ADMINISTRATION

Adults

Daily dosage recommendations for sulbactam/cefoperazone in adults are as follows:

Ratio Sulbactam/ Sulbactam Cefoperazone

Cefoperazone activity activity
(g) (g) (g)
1:2 3.0–4.5 1.0–1.5 2.0–3.0

Doses should be administered every 12 hours.

In severe or refractory infections, the daily dosage of sulbactam/cefoperazone may be

increased up to 12 g of the 1:2 ratio (i.e. 8 g cefoperazone activity).The recommended
maximum daily dosage of sulbactam is 4 g.
Renal Impairment

Dosage regimens of sulbactam/cefoperazone should be adjusted in patients with a

marked decrease in renal function (creatinine clearance of less than 30 mL/min) to
compensate for the reduced clearance of sulbactam. Patients with creatinine
clearances between 15 and 30 mL/min should receive a maximum of 1 g of sulbactam
every 12 hours (maximum daily dosage of 2 g sulbactam), while patients
with creatinine clearances of less than 15 mL/min should receive a maximum of 500 mg
of sulbactam every 12 hours (maximum daily dosage of 1 g sulbactam). The
pharmacokinetic profile of sulbactam is significantly altered by haemodialysis. The
serum half-life of cefoperazone is reduced slightly during haemodialysis. Thus, dosing
should be scheduled to follow a dialysis period.
Hepatic Impairment

Cefoperazone is extensively excreted through the bile. Dose modification may be

necessary in cases of severe biliary obstruction, severe hepatic disease or in cases
of renal dysfunction coexistent with either of those conditions. In such cases, dosage
should not exceed 2 g/day of cefoperazone without close monitoring of serum
concentrations.
Paediatric Use

Daily dosage recommendations for sulbactam/cefoperazone in children are as follows:

In serious or refractory infections, these dosages may be increased up to 240mg/kg/day

(160 mg/kg/day cefoperazone activity). Doses should be administered in two to four
equally divided doses.

Use in Neonates
For neonates in the first week of life, the drug should be given every 12 hours. The
maximum daily dosage of sulbactam in paediatrics should not exceed 80 mg/kg/day.
Intravenous Administration
Reconstitution

Sulbactam/cefoperazone is available in vials of 1.5 g and 3 g strengths, along with a

10mL ampoule of Sterile Water for Injection for reconstitution.

Total Equivalent dosage Volume of Maximum

dosage (g) of sulbactam + diluent final
cefoperazone (g) (mL) concentration
(mg/mL)

1.5 0.5+1.0 3.2 125+250

3.0 1.0+2.0 6.2 125+250

For intravenous infusion, each vial of sulbactam/cefoperazone should be

reconstituted with the appropriate amount of 5% Dextrose, 0.9% Sodium Chloride
Injection or Sterile Water for Injection, then further diluted to 20 mL with the same
solution, and followed by administration over 15 to 60 minutes. Lactated Ringer’s
Solution is a suitable vehicle for intravenous infusion, but it is not, however, for initial
reconstitution.

For intravenous injection, each vial should be reconstituted as above and administered
over a minimum of 3 minutes.

Sulbactam/cefoperazone has been shown to be compatible with Water for Injection,

5% Dextrose, normal saline, 5% Dextrose in 0.225% saline, and 5% Dextrose in normal
saline at concentrations of 10 mg cefoperazone and 5 mg sulbactam per mL and up to
250 mg cefoperazone and 125 mg sulbactam per mL.

Lactated Ringer’s Solution

Sterile Water for Injection should be used for reconstitution (see INCOMPATIBILITY,
Lactated Ringer’s Solution). A two-step dilution is required using Sterile Water for
Injection (as shown in the table above) first, which is then further diluted with Lactated
Ringer’s Solution to get a sulbactam concentration of 5 mg/mL (use 2 mL initial dilution
in 50 mL or 4 mL initial dilution in 100 mL Lactated Ringer’s Solution).

Lidocaine

Sterile Water for Injection should be used for reconstitution (see

INCOMPATIBILITY, Lidocaine). For a concentration of cefoperazone of 250 mg/mL or
larger, a two-step dilution is required using Sterile Water for Injection (shown in the table
above) first, which is then further diluted with 2% lidocaine HCl to yield solutions
containing up to 250 mg cefoperazone and 125 mg sulbactam per mL in, approximately,
a 0.5% lidocaine hydrochloride (HCl) solution.
Intramuscular Administration

Lidocaine HCl 2% is a suitable vehicle for intramuscular administration; however, it is

not for initial reconstitution.
CONTRAINDICATIONS

CEFTOMAX - S Injection is contraindicated in patients with a known allergy to

penicillins, sulbactam, cefoperazone, or any of the cephalosporins.
WARNINGS AND PRECAUTIONS

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been

reported in patients receiving beta-lactam or cephalosporin therapy. These reactions
are more apt to occur in individuals with a history of hypersensitivity reactions to
multiple allergens. If an allergic reaction occurs, the drug should be discontinued and
the appropriate therapy instituted.

Serious anaphylactic reactions require immediate emergency treatment with

epinephrine. Oxygen, intravenous steroids, and airway management, including
intubation, should be administered as indicated. As with other antibiotics, Vitamin K
deficiency has occurred in a few patients treated with cefoperazone. The mechanism is
most probably related to the suppression of gut flora, which normally synthesize this
vitamin. Those at risk include patients with poor diet, malabsorption states (e.g. cystic
fibrosis) and patients on prolonged intravenous alimentation regimens. Prothrombin
time should be monitored in these patients and in patients receiving anticoagulant
therapy, and exogenous vitamin K administered as indicated.

As with other antibiotics, overgrowth of non -susceptible organisms may occur during
the prolonged use of sulbactam/cefoperazone. Patients should be observed carefully
during the treatment. As with any potent systemic agent, it is advisable to check
periodically for organ system dysfunction during extended therapy; this includes the
renal, hepatic and haematopoietic systems. This is particularly important in neonates,
especially when premature, and other infants.

Sulbactam/cefoperazone has been effectively used in infants. It has not been

extensively studied in premature infants or neonates. Therefore, in treating premature
infants and neonates, the potential benefits and possible risks involved should be
considered before instituting therapy.
Drug Interactions

A reaction characterized by flushing, sweating, headache and tachycardia has been

reported when alcohol was ingested during and as late as the fifth day after
cefoperazone administration. A similar reaction has been reported with certain other
cephalosporins and patients should be cautioned concerning ingestion of alcoholic
beverages in conjunction with administration of sulbactam/cefoperazone. For patients
requiring artificial feeding orally or parenterally, solutions containing ethanol should be
avoided.
Renal Impairment

Please refer under DOSAGE AND ADMINISTRATION.

Hepatic Impairment

In severe hepatic dysfunction, therapeutic concentrations of cefoperazone are obtained

in the bile and only a 2- to 4-fold increase in the half-life is seen. Dose modification may
be necessary in case of severe biliary obstruction, severe hepatic disease or in

case of renal dysfunction coexistent with either of those conditions.

Pregnancy

There are 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

Caution should be exercised when sulbactam/cefoperazone is administered to a nursing

mother.

Paediatric Use

There are no significant changes in the pharmacokinetics of the components of

sulbactam/cefoperazone, compared to adult values. The mean half-life in children has
ranged from 0.91 to 1.42 hours for sulbactam and from 1.44 to 1.88 hours for
cefoperazone.

Geriatric Use

Both sulbactam and cefoperazone exhibited longer half-life, lower clearance and larger
volumes of distribution when compared to data from normal volunteers. The
pharmacokinetics of sulbactam correlated well with the degree of renal dysfunction
while for cefoperazone, there was a good correlation with the degree of hepatic
dysfunction.

UNDESIRABLE EFFECTS

Sulbactam/cefoperazone is generally well-tolerated. The majority of adverse events

are of mild or moderate severity and are tolerated with continued treatment. The most
frequent side effects observed with sulbactam/cefoperazone have been gastrointestinal.
Others include dermatologic reactions, headache, injection pain, chills, and
anaphylactoid reactions.

OVERDOSAGE

Limited information is available on the acute toxicity of cefoperazone sodium and

sulbactam sodium in humans. Overdosage of the drug would be expected to produce
manifestations that are principally extensions of the adverse reactions reported with
the drug. The fact that high cerebrospinal fluid concentrations of beta-lactam antibiotics
may cause neurological effects, including seizures, should be considered. Because
cefoperazone and sulbactam are both removed from the circulation by haemodialysis,
these procedures may enhance the elimination of the drug from the body if overdosage
occurs in patients with impaired renal function.

INCOMPATIBILITY

Aminoglycosides

Solutions of sulbactam/cefoperazone and aminoglycosides should not be directly

mixed, since there is a physical incompatibility between them. If combination therapy
with sulbactam/cefoperazone and an aminoglycoside is contemplated, this can be
accomplished by sequential intermittent intravenous infusion provided that a separate
secondary intravenous tubing is used, and that the primary intravenous tubing is
adequately irrigated with an approved diluent between doses. It is also suggested that
doses of sulbactam/cefoperazone be administered throughout the day at times as far
removed from the administration of the aminoglycoside as possible.
Lactated Ringer’s Solution

Initial reconstitution with Lactated Ringer's Solution should be avoided since this
mixture has been shown to be incompatible. However, a two-step dilution process
involving initial reconstitution in Sterile Water for Injection will result in a compatible
mixture when further diluted with Lactated Ringer's Solution.
Lidocaine

Initial reconstitution with 2% lidocaine HCl solution should be avoided since this mixture
has been shown to be incompatible. However, a two-step dilution process involving
initial reconstitution in Sterile Water for Injection will result in a compatible mixture when
further diluted with 2% lidocaine HCl solution.

STORAGE AND HANDLING INSTRUCTIONS

Before Opening

Store below 25°C. Protect from light.

Reconstituted Solution

° °
Reconstituted solution is stable for 7 days at 2–8 C and for 24 hours at 8–25 C.

PACKAGING INFORMATION
CEFTOMAX - S Injection
Vial of 20 mL, with 10 mL ampoule of Sterile Water for Injection