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ROCEPHIN IM 1 G POWDER AND SOLVENT FOR SOLUTION FOR INJECTION

Active substance(s): CEFTRIAXONE SODIUM / LIDOCAINE HYDROCHLORIDE / CEFTRIAXONE SODIUM / LIDOCAINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Rocephin IM 1 g Powder and Solvent for Solution for Injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder contains 1 g ceftriaxone as ceftriaxone sodium.
Each 1 ml of solvent contains 10 mg of lidocaine hydrochloride, corresponding to 35
mg of lidocaine hydrochloride per 3.5 ml.
Excipient with known effect:
Rocephin contains approximately 83 mg (3.6 mmol) of sodium per gram of
ceftriaxone.
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Powder and solvent for solution for injection
Powder: white to yellowish-orange crystalline powder.
Solvent: clear colourless solution.

4
4.1

CLINICAL PARTICULARS
Therapeutic indications
Rocephin is indicated for the treatment of the following infections in adults and
children including term neonates (from birth):
Bacterial Meningitis
Community acquired pneumonia
Hospital acquired pneumonia
Acute otitis media
Intra-abdominal infections
Complicated urinary tract infections (including pyelonephritis)
Infections of bones and joints
Complicated skin and soft tissue infections
Gonorrhoea
Syphilis
Bacterial endocarditis

Rocephin may be used:
For treatment of acute exacerbations of chronic obstructive pulmonary
disease in adults
For treatment of disseminated Lyme borreliosis (early (stage II) and late
(stage III)) in adults and children including neonates from 15 days of age
For Pre-operative prophylaxis of surgical site infections
In the management of neutropenic patients with fever that is suspected to be
due to a bacterial infection
In the treatment of patients with bacteraemia that occurs in association with,
or is suspected to be associated with, any of the infections listed above
Rocephin should be co-administered with other antibacterial agents whenever the
possible range of causative bacteria would not fall within its spectrum (see section
4.4).
Consideration should be given to official guidelines on the appropriate use of
antibacterial agents.

4.2

Posology and method of administration

Posology
The dose depends on the severity, susceptibility, site and type of infection and on the
age and hepato-renal function of the patient.
The doses recommended in the tables below are the generally recommended doses in
these indications. In particularly severe cases, doses at the higher end of the
recommended range should be considered.
Adults and children over 12 years of age (≥ 50 kg)
Ceftriaxone
Dosage*
1-2 g

Treatment
frequency**
Once daily

2g

Once daily

2-4 g

Once daily

Indications
Community acquired pneumonia
Acute exacerbations of chronic obstructive pulmonary
disease
Intra-abdominal infections
Complicated urinary tract infections (including
pyelonephritis)
Hospital acquired pneumonia
Complicated skin and soft tissue infections
Infections of bones and joints
Management of neutropenic patients with fever that is
suspected to be due to a bacterial infection
Bacterial endocarditis

Bacterial meningitis
* In documented bacteraemia, the higher end of the recommended dose range
should be considered.
** Twice daily (12 hourly) administration may be considered where doses greater
than 2 g daily are administered.
Indications for adults and children over 12 years of age (≥ 50 kg) that require specific
dosage schedules:
Acute otitis media
A single intramuscular dose of Rocephin 1-2 g can be given.
Limited data suggest that in cases where the patient is severely ill or previous therapy
has failed, Rocephin may be effective when given as an intramuscular dose of 1-2 g
daily for 3 days.
Pre-operative prophylaxis of surgical site infections
2 g as a single pre-operative dose.
Gonorrhoea
500 mg as a single intramuscular dose.
Syphilis
The generally recommended doses are 500 mg-1 g once daily increased to 2 g once
daily for neurosyphilis for 10-14 days. The dose recommendations in syphilis,
including neurosyphilis, are based on limited data. National or local guidance should
be taken into consideration.
Disseminated Lyme borreliosis (early [Stage II] and late [Stage III])
2 g once daily for 14-21 days. The recommended treatment durations vary and
national or local guidelines should be taken into consideration.
Paediatric population
Neonates, infants and children 15 days to 12 years of age (< 50 kg)
For children with bodyweight of 50 kg or more, the usual adult dosage should be
given.
Ceftriaxone
dosage*
50-80 mg/kg

Treatment
frequency**
Once daily

50-100 mg/kg
(Max 4 g)

Once daily

Indications
Intra-abdominal infections
Complicated urinary tract infections
(including pyelonephritis)
Community acquired pneumonia
Hospital acquired pneumonia
Complicated skin and soft tissue infections
Infections of bones and joints
Management of neutropenic patients with
fever that is suspected to be due to a bacterial
infection

80-100 mg/kg
Once daily
Bacterial meningitis
(max 4 g)
100 mg/kg (max Once daily
Bacterial endocarditis
4 g)
* In documented bacteraemia, the higher end of the recommended dose range
should be considered.
** Twice daily (12 hourly) administration may be considered where doses greater
than 2 g daily are administered.
Indications for neonates, infants and children 15 days to 12 years (< 50 kg) that
require specific dosage schedules:
Acute otitis media
For initial treatment of acute otitis media, a single intramuscular dose of Rocephin
50 mg/kg can be given. Limited data suggest that in cases where the child is severely
ill or initial therapy has failed, Rocephin may be effective when given as an
intramuscular dose of 50 mg/kg daily for 3 days.
Pre-operative prophylaxis of surgical site infections
50-80 mg/kg as a single pre-operative dose.
Syphilis
The generally recommended doses are 75-100 mg/kg (max 4 g) once daily for
10-14 days. The dose recommendations in syphilis, including neurosyphilis, are based
on very limited data. National or local guidance should be taken into consideration.
Disseminated Lyme borreliosis (early [Stage II] and late [Stage III])
50–80 mg/kg once daily for 14-21 days. The recommended treatment durations vary
and national or local guidelines should be taken into consideration.
Neonates 0-14 days
Rocephin is contraindicated in premature neonates up to a postmenstrual age of 41
weeks (gestational age + chronological age).
Ceftriaxone
dosage*
20-50 mg/kg

Treatment
frequency
Once daily

Indications

Intra-abdominal infections
Complicated skin and soft tissue infections
Complicated urinary tract infections
(including pyelonephritis)
Community acquired pneumonia
Hospital acquired pneumonia
Infections of bones and joints
Management of neutropenic patients with
fever that is suspected to be due to a bacterial
infection
50 mg/kg
Once daily
Bacterial meningitis
Bacterial endocarditis
* In documented bacteraemia, the higher end of the recommended dose range should
be
considered.

A maximum daily dose of 50 mg/kg should not be exceeded.
Indications for neonates 0-14 days that require specific dosage schedules:
Acute otitis media
For initial treatment of acute otitis media, a single intramuscular dose of Rocephin
50 mg/kg can be given.
Pre-operative prophylaxis of surgical site infections
20-50 mg/kg as a single pre-operative dose.
Syphilis
The generally recommended dose is 50 mg/kg once daily for 10-14 days. The dose
recommendations in syphilis, including neurosyphilis, are based on very limited data.
National or local guidance should be taken into consideration.
Duration of therapy
The duration of therapy varies according to the course of the disease. As with
antibiotic therapy in general, administration of ceftriaxone should be continued for
48 - 72 hours after the patient has become afebrile or evidence of bacterial eradication
has been achieved.
Older people
The dosages recommended for adults require no modification in older people
provided that renal and hepatic function is satisfactory.
Patients with hepatic impairment
Available data do not indicate the need for dose adjustment in mild or moderate liver
function impairment provided renal function is not impaired.
There are no study data in patients with severe hepatic impairment (see section 5.2).
Patients with renal impairment
In patients with impaired renal function, there is no need to reduce the dosage of
ceftriaxone provided hepatic function is not impaired. Only in cases of preterminal
renal failure (creatinine clearance < 10 ml/min) should the ceftriaxone dosage not
exceed 2 g daily.
In patients undergoing dialysis no additional supplementary dosing is required
following the dialysis. Ceftriaxone is not removed by peritoneal- or haemodialysis.
Close clinical monitoring for safety and efficacy is advised.
Patients with severe hepatic and renal impairment
In patients with both severe renal and hepatic dysfunction, close clinical monitoring
for safety and efficacy is advised.

Method of administration
Rocephin can be administered by deep intramuscular injection. Intramuscular
injections should be injected well within the bulk of a relatively large muscle and not
more than 1 g should be injected at one site.
As the solvent used is lidocaine, the resulting solution should never be administered
intravenously (see section 4.3). The information in the Summary of Product
Characteristics of lidocaine should be considered.
Ceftriaxone is contraindicated in neonates (≤ 28 days) if they require (or are expected
to require) treatment with calcium-containing intravenous solutions, including
continuous calcium-containing infusions such as parenteral nutrition, because of the
risk of precipitation of ceftriaxone-calcium (see section 4.3).
For pre-operative prophylaxis of surgical site infections, ceftriaxone should be
administered 30-90 minutes prior to surgery.
For instructions on reconstitution of the medicinal product before administration, see
section 6.6.

4.3

Contraindications

Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients
listed in section 6.1.
History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of
beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).
Ceftriaxone is contraindicated in:
Premature neonates up to a postmenstrual age of 41 weeks (gestational age +
chronological age)*
Full-term neonates (up to 28 days of age):
with hyperbilirubinaemia, 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) intravenous calcium treatment, or
calcium-containing infusions due to the risk of precipitation of a ceftriaxonecalcium salt (see sections 4.4, 4.8 and 6.2).
* In vitro studies have shown that ceftriaxone can displace bilirubin from its
serum albumin binding sites leading to a possible risk of bilirubin encephalopathy
in these patients.

Contraindications to lidocaine must be excluded before intramuscular injection of
ceftriaxone when lidocaine solution is used as a solvent (see section 4.4). See
information in the Summary of Product Characteristics of lidocaine, especially
contraindications.
Ceftriaxone solutions containing lidocaine should never be administered
intravenously.

4.4

Special warnings and precautions for use

Hypersensitivity reactions
As with all beta-lactam antibacterial agents, serious and occasionally fatal
hypersensitivity reactions have been reported (see section 4.8). In case of severe
hypersensitivity reactions, treatment with ceftriaxone must be discontinued
immediately and adequate emergency measures must be initiated. Before beginning
treatment, it should be established whether the patient has a history of severe
hypersensitivity reactions to ceftriaxone, to other cephalosporins or to any other type
of beta-lactam agent. Caution should be used if ceftriaxone is given to patients with a
history of non-severe hypersensitivity to other beta-lactam agents.
Severe cutaneous adverse reactions (Stevens Johnson syndrome or Lyell’s
syndrome/toxic epidermal necrolysis) have been reported; however, the frequency of
these events is not known (see section 4.8).
Interaction with calcium containing products
Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in
premature and full-term neonates 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 neonates, treated with
ceftriaxone and calcium-containing solutions or any other calcium-containing
products. In vitro studies demonstrated that neonates have an increased risk of
precipitation of ceftriaxone-calcium compared to other age groups.
In patients of any age ceftriaxone must not be mixed or administered simultaneously
with any calcium-containing intravenous solutions, even via different infusion lines or
at different infusion sites. However, in patients older than 28 days of age ceftriaxone
and calcium-containing 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 salt-solution to avoid
precipitation. In patients requiring continuous infusion with calcium-containing total
parenteral nutrition (TPN) solutions, healthcare professionals may wish to consider
the use of alternative antibacterial treatments which do not carry a similar risk of
precipitation. If the use of ceftriaxone is considered necessary in patients requiring
continuous nutrition, TPN solutions and ceftriaxone 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 and
the infusion lines flushed between solutions (see sections 4.3, 4.8, 5.2 and 6.2).
Paediatric population
Safety and effectiveness of Rocephin in neonates, infants and children have been
established for the dosages described under Posology and Method of Administration
(see section 4.2). Studies have shown that ceftriaxone, like some other cephalosporins,
can displace bilirubin from serum albumin.

Rocephin is contraindicated in premature and full-term neonates at risk of developing
bilirubin encephalopathy (see section 4.3).
Immune mediated haemolytic anaemia
An immune mediated haemolytic anaemia has been observed in patients receiving
cephalosporin class antibacterials including Rocephin (see section 4.8). Severe cases
of haemolytic anaemia, including fatalities, have been reported during Rocephin
treatment in both adults and children.
If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporinassociated anaemia should be considered and ceftriaxone discontinued until the
aetiology is determined.
Long term treatment
During prolonged treatment complete blood count should be performed at regular
intervals.
Colitis/Overgrowth of non-susceptible microorganisms
Antibacterial agent-associated colitis and pseudo-membranous colitis have been
reported with nearly all antibacterial agents, including ceftriaxone, and may range in
severity from mild to life-threatening. Therefore, it is important to consider this
diagnosis in patients who present with diarrhoea during or subsequent to the
administration of ceftriaxone (see section 4.8). Discontinuation of therapy with
ceftriaxone and the administration of specific treatment for Clostridium difficile
should be considered. Medicinal products that inhibit peristalsis should not be given.
Superinfections with non-susceptible micro-organisms may occur as with other
antibacterial agents.
Severe renal and hepatic insufficiency
In severe renal and hepatic insufficiency, close clinical monitoring for safety and
efficacy is advised (see section 4.2).
Interference with serological testing
Interference with Coombs tests may occur, as Rocephin may lead to false-positive test
results. Rocephin can also lead to false-positive test results for galactosaemia (see
section 4.8).
Non-enzymatic methods for the glucose determination in urine may give falsepositive results. Urine glucose determination during therapy with Rocephin should be
done enzymatically (see section 4.8).
The presence of ceftriaxone may falsely lower estimated blood glucose values
obtained with some blood glucose monitoring systems. Please refer to instructions for
use for each system. Alternative testing methods should be used if necessary.

Sodium
Each gram of Rocephin contains 3.6 mmol sodium. This should be taken into
consideration in patients on a controlled sodium diet.
Antibacterial spectrum
Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable
for use as a single agent for the treatment of some types of infections unless the
pathogen has already been confirmed (see section 4.2). In polymicrobial infections,
where suspected pathogens include organisms resistant to ceftriaxone, administration
of an additional antibiotic should be considered.
Use of lidocaine
In case a lidocaine solution is used as a solvent, ceftriaxone solutions must only be
used for intramuscular injection. Contraindications to lidocaine, warnings and other
relevant information as detailed in the Summary of Product Characteristics of
lidocaine must be considered before use (see section 4.3). The lidocaine solution
should never be administered intravenously.
Biliary lithiasis
When shadows are observed on sonograms, consideration should be given to the
possibility of precipitates of calcium ceftriaxone. Shadows, which have been mistaken
for gallstones, have been detected on sonograms of the gallbladder and have been
observed more frequently at ceftriaxone doses of 1 g per day and above. Caution
should be particularly considered in the paediatric population. Such precipitates
disappear after discontinuation of ceftriaxone therapy. Rarely precipitates of calcium
ceftriaxone have been associated with symptoms. In symptomatic cases, conservative
nonsurgical management is recommended and discontinuation of ceftriaxone
treatment should be considered by the physician based on specific benefit risk
assessment (see section 4.8).
Biliary stasis
Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in
patients treated with Rocephin (see section 4.8). 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 of Rocephin-related biliary
precipitation cannot be ruled out.
Renal lithiasis
Cases of renal lithiasis have been reported, which is reversible upon discontinuation
of ceftriaxone (see section 4.8). In symptomatic cases, sonography should be
performed. Use in patients with history of renal lithiasis or with hypercalciuria should
be considered by the physician based on specific benefit risk assessment.
4.5

Interaction with other medicinal products and other forms of interaction

Calcium-containing diluents, such as Ringer’s solution or Hartmann’s solution,
should not be used to reconstitute Rocephin vials or to further dilute a reconstituted
vial for intravenous administration because a precipitate can form. Precipitation of
ceftriaxone-calcium can also occur when ceftriaxone is mixed with calciumcontaining solutions in the same intravenous administration line. Ceftriaxone must not
be administered simultaneously with calcium-containing intravenous solutions,
including continuous calcium-containing infusions such as parenteral nutrition via a
Y-site. However, in patients other than neonates, ceftriaxone 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 (see sections 4.2, 4.3, 4.4, 4.8
and 6.2).
Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and
the risk of bleeding. It is recommended that the International Normalised Ratio (INR)
is monitored frequently and the posology of the anti-vitamin K drug adjusted
accordingly, both during and after treatment with ceftriaxone (see section 4.8).
There is conflicting evidence regarding a potential increase in renal toxicity of
aminoglycosides when used with cephalosporins. The recommended monitoring of
aminoglycoside levels (and renal function) in clinical practice should be closely
adhered to in such cases.
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.
There have been no reports of an interaction between ceftriaxone and oral calciumcontaining products or interaction between intramuscular ceftriaxone and calciumcontaining products (intravenous or oral).
In patients treated with ceftriaxone, the Coombs' test may lead to false-positive test
results.
Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia.
Likewise, non-enzymatic methods for glucose determination in urine may yield falsepositive results. For this reason, glucose level determination in urine during therapy
with ceftriaxone should be carried out enzymatically.
No impairment of renal function has been observed after concurrent administration of
large doses of ceftriaxone and potent diuretics (e.g. furosemide).
Simultaneous administration of probenecid does not reduce the elimination of
ceftriaxone.
4.6

Fertility, pregnancy and lactation

Pregnancy

Ceftriaxone crosses the placental barrier. There are limited amounts of data from the
use of ceftriaxone in pregnant women. Animal studies do not indicate direct or
indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal
development (see section 5.3). Ceftriaxone should only be administered during
pregnancy and in particular in the first trimester of pregnancy if the benefit outweighs
the risk.
Breastfeeding
Ceftriaxone is excreted into human milk in low concentrations but at therapeutic
doses of ceftriaxone no effects on the breastfed infants are anticipated. However, a
risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded.
The possibility of sensitisation should be taken into account. A decision must be made
whether to discontinue breast-feeding or to discontinue/abstain from ceftriaxone
therapy, taking into account the benefit of breast feeding for the child and the benefit
of therapy for the woman.
Fertility
Reproductive studies have shown no evidence of adverse effects on male or female
fertility.
4.7

Effects on ability to drive and use machines
During treatment with ceftriaxone, undesirable effects may occur (e.g. dizziness),
which may influence the ability to drive and use machines (see section 4.8). Patients
should be cautious when driving or operating machinery.

4.8

Undesirable effects

The most frequently reported adverse reactions for ceftriaxone are eosinophilia,
leucopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased.
Data to determine the frequency of ceftriaxone ADRs was derived from clinical trials.
The following convention has been used for the classification of frequency:
Very common (≥ 1/10)
Common (≥ 1/100 - < 1/10)
Uncommon (≥ 1/1000 - < 1/100)
Rare (≥ 1/10000 - < 1/1000)
Not known (cannot be estimated from the available data)
Uncommon

Rare

Not Known a

Genital fungal
infection

Pseudomembranous
colitisb

Superinfectionb

System Organ
Class
Infections and
infestations

Common

Blood and
lymphatic
system
disorders
Immune
system
disorders

Eosinophilia
Granulocytopenia
Leucopenia
Anaemia
Thrombocytopenia Coagulopathy

Nervous
system
disorders
Ear and
labyrinth
disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal Diarrhoeab
disorders
Loose stools
Hepatobiliary
disorders

Hepatic enzyme
increased

Haemolytic
anaemiab
Agranulocytosis
Anaphylactic
shock
Anaphylactic
reaction
Anaphylactoid
reaction
Hypersensitivityb
Convulsion

Headache
Dizziness

Vertigo

Bronchospasm

Nausea
Vomiting

Pancreatitisb
Stomatitis
Glossitis
Gall bladder
precipitationb
Kernicterus

System Organ
Class
Skin and
subcutaneous
tissue disorders

Common

Uncommon

Rare

Not Known a

Rash

Pruritus

Urticaria

Stevens Johnson
Syndromeb
Toxic epidermal
necrolysisb
Erythema
multiforme
Acute
generalised
exanthematous
pustulosis
Oliguria
Renal
precipitation
(reversible)

Renal and
urinary
disorders
General
disorders and
administration
site conditions
Investigations

a

b

Haematuria
Glycosuria

Phlebitis
Oedema
Injection site pain Chills
Pyrexia
Blood creatinine
increased

Coombs test
false positiveb
Galactosaemia
test false
positiveb
Non enzymatic
methods for
glucose
determination
false positiveb
Based on post-marketing reports. Since these reactions are reported voluntarily
from a population of uncertain size, it is not possible to reliably estimate their
frequency which is therefore categorised as not known.
See section 4.4

Description of selected adverse reactions
Infections and infestations
Reports of diarrhoea following the use of ceftriaxone may be associated with
Clostridium difficile. Appropriate fluid and electrolyte management should be
instituted (see section 4.4).
Ceftriaxone-calcium salt precipitation
Rarely, severe, and in some cases, fatal, adverse reactions have been reported in preterm and full-term neonates (aged < 28 days) who had been treated with intravenous
ceftriaxone and calcium. Precipitations of ceftriaxone-calcium salt have been
observed in lung and kidneys post-mortem. The high risk of precipitation in neonates
is a result of their low blood volume and the longer half-life of ceftriaxone compared
with adults (see sections 4.3, 4.4, and 5.2).

Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in
children treated with high doses (e.g. ≥ 80 mg/kg/day or total doses exceeding 10
grams) and who have other risk factors (e.g. dehydration, confinement to bed). This
event may be asymptomatic or symptomatic, and may lead to ureteric obstruction and
postrenal acute renal failure, but is usually reversible upon discontinuation of
ceftriaxone (see section 4.4).
Precipitation of ceftriaxone calcium salt in the gallbladder has been observed,
primarily in patients treated with doses higher than the recommended standard dose.
In children, prospective studies have shown a variable incidence of precipitation with
intravenous application - above 30 % in some studies. The incidence appears to be
lower with slow infusion (20 - 30 minutes). This effect is usually asymptomatic, but
the precipitations have been accompanied by clinical symptoms such as pain, nausea
and vomiting in rare cases. Symptomatic treatment is recommended in these cases.
Precipitation is usually reversible upon discontinuation of ceftriaxone (see section
4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose

In overdose, the symptoms of nausea, vomiting and diarrhoea can occur. Ceftriaxone
concentrations cannot be reduced by haemodialysis or peritoneal dialysis. There is no
specific antidote. Treatment of overdose should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Third-generation
cephalosporins, ATC code: J01DD04.
Mode of action
Ceftriaxone inhibits bacterial cell wall synthesis following attachment to penicillin
binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan)
biosynthesis, which leads to bacterial cell lysis and death.
Resistance
Bacterial resistance to ceftriaxone may be due to one or more of the following
mechanisms:






hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases
(ESBLs), carbapenemases and Amp C enzymes that may be induced or stably
derepressed in certain aerobic Gram-negative bacterial species.
reduced affinity of penicillin-binding proteins for ceftriaxone.
outer membrane impermeability in Gram-negative organisms.
bacterial efflux pumps.

Susceptibility testing breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European
Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
Dilution Test
(MIC, mg/L)
Pathogen
Susceptible
Resistant
Enterobacteriaceae
≤1
>2
Staphylococcus spp.
a.
a.
Streptococcus spp.
b.
b.
(Groups A, B, C and G)
Streptococcus pneumoniae
≤ 0.5c.
>2
Viridans group Streptococci ≤0.5
>0.5
Haemophilus influenzae
≤ 0.12c.
> 0.12
Moraxella catarrhalis
≤1
>2
Neisseria gonorrhoeae
≤ 0.12
> 0.12
Neisseria meningitidis
≤ 0.12 c.
> 0.12
Non-species related
≤ 1d.
>2
a. Susceptibility inferred from cefoxitin susceptibility.
b. Susceptibility inferred from penicillin susceptibility.
c. Isolates with a ceftriaxone MIC above the susceptible breakpoint are rare and, if
found, should be re-tested and, if confirmed, should be sent to a reference
laboratory.
d. Breakpoints apply to a daily intravenous dose of 1 g x 1 and a high dose of at least
2 g x 1.
Clinical efficacy against specific pathogens
The prevalence of acquired resistance may vary geographically and with time for
selected species and local information on resistance is desirable, particularly when
treating severe infections. As necessary, expert advice should be sought when the
local prevalence of resistance is such that the utility of ceftriaxone in at least some
types of infections is questionable.

Commonly susceptible species
Gram-positive aerobes
Staphylococcus aureus (methicillin-susceptible)£
Staphylococci coagulase-negative (methicillin-susceptible)£
Streptococcus pyogenes (Group A)
Streptococcus agalactiae (Group B)
Streptococcus pneumoniae
Viridans Group Streptococci
Gram-negative aerobes
Borrelia burgdorferi
Haemophilus influenzae
Haemophilus parainfluenzae
Moraxella catarrhalis
Neisseria gonorrhoea
Neisseria meningitidis
Proteus mirabilis
Providencia spp.
Treponema pallidum
Species for which acquired resistance may be a problem
Gram-positive aerobes
Staphylococcus epidermidis+
Staphylococcus haemolyticus+
Staphylococcus hominis+
Gram-negative aerobes
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli%
Klebsiella pneumoniae%
Klebsiella oxytoca%
Morganella morganii
Proteus vulgaris
Serratia marcescens
Anaerobes
Bacteroides spp.
Fusobacterium spp.
Peptostreptococcus spp.
Clostridium perfringens

Inherently resistant organisms
Gram-positive aerobes
Enterococcus spp.
Listeria monocytogenes
Gram-negative aerobes
Acinetobacter baumannii
Pseudomonas aeruginosa
Stenotrophomonas maltophilia
Anaerobes
Clostridium difficile
Others:
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.
Legionella spp.
Ureaplasma urealyticum
£ All methicillin-resistant staphylococci are resistant to ceftriaxone.
+
Resistance rates >50% in at least one region
%
ESBL producing strains are always resistant

5.2

Pharmacokinetic properties

Absorption
Following intramuscular injection, mean peak plasma ceftriaxone levels are
approximately half those observed after intravenous administration of an equivalent
dose. The maximum plasma concentration after a single intramuscular dose of 1 g is
about 81 mg/l and is reached in 2 - 3 hours after administration.
The area under the plasma concentration-time curve after intramuscular
administration is equivalent to that after intravenous administration of an equivalent
dose.
Distribution
The volume of distribution of ceftriaxone is 7 – 12 l. Concentrations well above the
minimal inhibitory concentrations of most relevant pathogens are detectable in tissue
including lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone,
and in cerebrospinal, pleural, prostatic and synovial fluids. An 8 - 15 % increase in
mean peak plasma concentration (Cmax) is seen on repeated administration; steady

state is reached in most cases within 48 - 72 hours depending on the route of
administration.
Penetration into particular tissues
Ceftriaxone penetrates the meninges. Penetration is greatest when the meninges are
inflamed. Mean peak ceftriaxone concentrations in CSF in patients with bacterial
meningitis are reported to be up to 25 % of plasma levels compared to 2 % of plasma
levels in patients with uninflamed meninges. Peak ceftriaxone concentrations in CSF
are reached approximately 4-6 hours after intravenous injection. Ceftriaxone crosses
the placental barrier and is excreted in the breast milk at low concentrations (see
section 4.6).
Protein binding
Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at
plasma concentrations below 100 mg/l. Binding is saturable and the bound portion
decreases with rising concentration (up to 85 % at a plasma concentration of
300 mg/l).
Biotransformation
Ceftriaxone is not metabolised systemically; but is converted to inactive metabolites
by the gut flora.
Elimination
Plasma clearance of total ceftriaxone (bound and unbound) is 10 - 22 ml/min. Renal
clearance is 5 - 12 ml/min. 50 - 60 % of ceftriaxone is excreted unchanged in the
urine, primarily by glomerular filtration, while 40 - 50 % is excreted unchanged in the
bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.
Patients with renal or hepatic impairment
In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are
only minimally altered with the half-life slightly increased (less than two fold), even
in patients with severely impaired renal function.
The relatively modest increase in half-life in renal impairment is explained by a
compensatory increase in non-renal clearance, resulting from a decrease in protein
binding and corresponding increase in non-renal clearance of total ceftriaxone.
In patients with hepatic impairment, the elimination half-life of ceftriaxone is not
increased, due to a compensatory increase in renal clearance. This is also due to an
increase in plasma free fraction of ceftriaxone contributing to the observed
paradoxical increase in total drug clearance, with an increase in volume of distribution
paralleling that of total clearance.
Older people

In older people aged over 75 years the average elimination half-life is usually two to
three times that of young adults.
Paediatric population
The half-life of ceftriaxone is prolonged in neonates. From birth to 14 days of age, the
levels of free ceftriaxone may be further increased by factors such as reduced
glomerular filtration and altered protein binding. During childhood, the half-life is
lower than in neonates or adults.
The plasma clearance and volume of distribution of total ceftriaxone are greater in
neonates, infants and children than in adults.
Linearity/non-linearity
The pharmacokinetics of ceftriaxone are non-linear and all basic pharmacokinetic
parameters, except the elimination half-life, are dose dependent if based on total drug
concentrations, increasing less than proportionally with dose. Non-linearity is due to
saturation of plasma protein binding and is therefore observed for total plasma
ceftriaxone but not for free (unbound) ceftriaxone.
Pharmacokinetic/pharmacodynamic relationship
As with other beta-lactams, the pharmacokinetic-pharmacodynamic index
demonstrating the best correlation with in vivo efficacy is the percentage of the dosing
interval that the unbound concentration remains above the minimum inhibitory
concentration (MIC) of ceftriaxone for individual target species (i.e. %T > MIC).

5.3

Preclinical safety data

There is evidence from animal studies that high doses of ceftriaxone calcium salt led
to formation of concrements and precipitates in the gallbladder of dogs and monkeys,
which proved to be reversible. Animal studies produced no evidence of toxicity to
reproduction and genotoxicity. Carcinogenicity studies on ceftriaxone were not
conducted.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Solvent: water for injections.
6.2
Incompatibilities
Based on literature reports, ceftriaxone is not compatible with amsacrine,
vancomycin, fluconazole and aminoglycosides.

Solutions containing ceftriaxone should not be mixed with or added to other agents
except those mentioned in section 6.6. In particular diluents containing calcium, (e.g.
Ringer’s solution, Hartmann’s solution) should not be used to reconstitute ceftriaxone
vials or to further dilute a reconstituted vial for intravenous administration because a
precipitate can form. Ceftriaxone must not be mixed or administered simultaneously
with calcium containing solutions including total parenteral nutrition (see section 4.2,
4.3, 4.4 and 4.8).
If combination of another antibiotic with Rocephin is intended in the treatment,
administration should not occur in the same syringe or in the same infusion solution.
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.
6.3

Shelf life

Unopened vials or ampoules:
Powder for solution for injection: 3 years
Solvent for solution for injection: 5 years
Chemical and physical in-use stability of the reconstituted product has been
demonstrated for at least 6 hours at or below 25°C or 24 hours at 2-8°C.
From a microbiological point of view, the product should be used immediately. If not
used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C,
unless preparation of the solution has taken place in controlled and validated aseptic
conditions.
6.4

Special precautions for storage

Do not store above 30°C, keep vials in the outer carton in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5

Nature and contents of container

Type 1 Ph. Eur 15 ml glass vial with fluorobutyl rubber stopper and aluminium cap,
containing a sterile powder, equivalent to 1 g ceftriaxone, and one colourless type 1
glass ampoule with 3.5 ml of a solution which contains 10 mg lidocaine hydrochloride
per ml.
Pack size of 1 or 5 vial(s) and 1 or 5 ampoule(s).

6.6

Special precautions for disposal

Preparation of solutions for injection:
The use of freshly prepared solutions is recommended. For storage conditions of the
reconstituted medicinal product, see section 6.3.

Rocephin should not be mixed in the same syringe with any drug other than 1%
Lidocaine Hydrochloride solution (for intramuscular injection only).
Solutions are light yellow to brownish yellow.
For IM injection, 1 g Rocephin is dissolved in 3.5 ml of the provided solution, which
contains 10 mg lidocaine hydrochloride per ml water for injections. Subsequently this
solution is administered via a deep intramuscular injection.
Dosages greater than 1 g should be divided and injected at more than one site.
See also the information in section 6.2.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Roche Products Ltd
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00031/0841

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
02/08/2016

10

DATE OF REVISION OF THE TEXT
24/05/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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