Ceftriaxone-AFT

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Ceftriaxone sodium 2.1586 g equivalent to ceftriaxone 2 g
Available from:
AFT Pharmaceuticals Ltd
INN (International Name):
Ceftriaxone sodium 2.1586 g (equivalent to ceftriaxone 2 g)
Dosage:
2 g
Pharmaceutical form:
Powder for injection
Composition:
Active: Ceftriaxone sodium 2.1586 g equivalent to ceftriaxone 2 g
Units in package:
Vial, glass, Type 1 with rubber stopper (qilu), 1 dose unit
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Qilu Antibiotics Pharmaceutical Co Ltd
Therapeutic indications:
Infections caused by pathogens sensitive to Ceftriaxone e.g.: · sepsis; · meningitis; · abdominal infections (peritonitis, infections of the biliary and gastrointestinal tracts); · infections of the bones, joints, soft tissue, skin and of wounds; · infections in patients with impaired defence mechanisms; · renal and urinary tract infections; · respiratory tract infections, particularly pneumonia, and ear, nose and throat infections; · genital infections, including gonorrhoea. · perioperative prophylaxis of infections.
Product summary:
Package - Contents - Shelf Life: Vial, glass, Type II with rubber stopper (qilu) - 1 dose units - 36 months from date of manufacture stored at or below 25°C protect from light 24 hours reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Vial, glass, Type 1 with rubber stopper (qilu) - 1 dose units - 36 months from date of manufacture stored at or below 25°C protect from light 24 hours reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Vial, glass, Type II with rubber stopper (qilu) - 5 dose units - 36 months from date of manufacture stored at or below 25°C protect from light 24 hours reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Vial, glass, Type 1 with rubber stopper (qilu) - 5 dose units - 36 months from date of manufacture stored at or below 25°C protect from light 24 hours reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Vial, glass, Type II with rubber stopper (qilu) - 10 dose units - 36 months from date of manufacture stored at or below 25°C protect from light 24 hours reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Vial, glass, Type 1 with rubber stopper (qilu) - 10 dose units - 36 months from date of manufacture stored at or below 25°C protect from light 24 hours reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) protect from light
Authorization number:
TT50-6314/1b
Authorization date:
2010-09-14

Page 1 of 15

NEW ZEALAND DATA SHEET

1.

CEFTRIAXONE-AFT powder for injection

Ceftriaxone-AFT 500 mg powder for injection.

Ceftriaxone-AFT 1 g powder for injection.

Ceftriaxone-AFT 2 g powder for injection.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Ceftriaxone-AFT 500 mg: each vial contains 500 mg ceftriaxone (as sodium).

Ceftriaxone-AFT 1 g: each vial contains 1 g ceftriaxone (as sodium).

Ceftriaxone-AFT 2 g: each vial contains 2 g ceftriaxone (as sodium).

Excipients with known effect:

Each gram of ceftriaxone contains approximately 83 mg (3.6 mmol) of sodium.

3.

PHARMACEUTICAL FORM

Powder for injection.

White to pale yellow powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Infections caused by pathogens sensitive to ceftriaxone e.g.:

sepsis;

meningitis;

abdominal infections (peritonitis, infections of the biliary and gastrointestinal tracts);

infections of the bones, joints, soft tissue, skin and of wounds;

infections in patients with impaired defence mechanisms;

renal and urinary tract infections;

respiratory tract infections, particularly pneumonia, and ear, nose and throat infections;

genital infections, including gonorrhea;

perioperative prophylaxis of infections.

4.2

Dose and method of administration

Dose

Adults and children over twelve years

The usual dosage is 1-2 g of ceftriaxone administered once daily (every 24 hours). In severe cases or in

Page 2 of 15

infections caused by moderately sensitive organisms, the dosage may be raised to 4 g, administered

once daily.

Elderly patients

The dosages recommended for adults require no modification in the case of geriatric patients.

Paediatric population

The following dosage schedules are recommended for once daily administration:

Neonates (up to 14 days): A daily dose of 20-50 mg/kg bodyweight, not to exceed 50 mg/kg, on account

of the immaturity of the infant’s enzyme systems. It is not necessary to differentiate between premature

and infants born at term.

Infants and children (15 days to twelve years): A daily dose of 20-80 mg/kg.

NOTE: For children with bodyweights of 50 kg or more, the usual adult dosage should be used.

Intravenous doses of 50 mg or more per kg should be given by infusion over at least 30 minutes.

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 a minimum of 48 to 72 hours after the

patient has become afebrile or evidence of bacterial eradication has been obtained.

Combination therapy

Synergy between ceftriaxone and aminoglycosides has been demonstrated with many Gram-negative

bacteria under experimental conditions. Although enhanced activity of such combinations is not always

predictable, it should be considered in severe, life-threatening infections due to microorganisms such

Pseudomonas

aeruginosa.

Because

physical

incompatibility

medicines

must

administered separately at the recommended dosages.

Special dosage instructions

Meningitis

In bacterial meningitis in infants and children, treatment begins with doses of 100 mg/kg (not to exceed

4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined,

the dosage can be reduced accordingly. Effective results have been found with the following duration

of therapy:

Neisseria meningitides

4 days

Haemophilus influenza

6 days

Streptococcus pneumoniae

7 days

Gonorrhoea

For the treatment of gonorrhoea (penicillinase-producing and nonpenicillinase-producing strains), a

single IM dose of 250 mg ceftriaxone is recommended.

Page 3 of 15

Perioperative prophylaxis

prevent

postoperative

infections

contaminated

potentially

contaminated

surgery,

recommended approach – depending on the risk of infection – is a single dose of 1 – 2 g ceftriaxone

administered

30-90

minutes

prior

surgery.

colorectal

surgery,

concurrent

(but

separate)

administration of ceftriaxone with or without a 5-nitroimidazole, e.g. ornidazole, has proven effective.

Impaired renal and hepatic function

In patients with impaired renal function, there is no need to reduce the dosage of ceftriaxone provided

hepatic function is intact. Only in cases of preterminal renal failure (creatinine clearance <10 mL/min)

should the ceftriaxone dosage not exceed 2 g daily. In patients with liver damage, there is no need for

the dosage to be reduced provided renal function is intact. In cases of concomitant severe renal and

hepatic dysfunction, the plasma concentrations of ceftriaxone should be determined at regular intervals

and if necessary the dose adjusted.

In patients undergoing dialysis no additional supplementary dosing is required following the dialysis.

Plasma concentrations should be monitored, however, to determine whether dosage adjustments are

necessary, since the elimination rate in these patients may be reduced.

Method of administration

As a general rule, the solution should be used immediately after preparation. Reconstituted solutions

retain their physical and chemical stability for six hours at room temperature or 24 hours under

refrigeration (2-8 °C). The solutions range in colour from pale yellow to amber, depending on the

concentration and the length of storage. This characteristic of the active ingredient is of no significance

for the efficacy or tolerance of the drug.

Do NOT use diluents containing calcium, e.g. Ringer’s solution or Hartmann’s solution, to reconstitute

ceftriaxone. Particulate formation can result.

Ceftriaxone and calcium-containing solutions, including continuous calcium-containing infusions such

as parenteral nutrition, should not be mixed or co-administered to any patient irrespective of age, even

via different infusion lines at different sites.

Calcium-containing solutions or products must not be administered with 48 hours of last administration

of ceftriaxone.

For instructions on reconstitution of the medicine before administration, see section 6.6.

Intramuscular injection

For IM injection, Ceftriaxone-AFT 1 g is dissolved in 3.5 mL of 1% lidocaine hydrochloride solution

and injected well within the body of a relatively large muscle. It is recommended that not more than 1 g

to be injected at one site.

The lidocaine solution must never be administered intravenously.

Page 4 of 15

Intravenous injection

For IV injection, Ceftriaxone-AFT 500 mg is dissolved in 5 mL, or Ceftriaxone-AFT 1 g in 10 mL, of

sterile water for injections. The intravenous administration should be given over two to four minutes.

Intravenous infusion

The infusion should last at least 30 minutes.

For IV infusion, 2 g ceftriaxone are dissolved in 40 mL of one of the following calcium-free infusion

solutions: sodium chloride 0.9%, sodium chloride 0.45% + dextrose 2.5%, dextrose 5%, dextrose 10%,

dextran 6% in dextrose 5%, hydroxyethyl starch 6-10% infusions, sterile water for injections.

Ceftriaxone solutions should not be mixed with or piggybacked into solutions containing other

antimicrobial

drugs or into diluent solutions

other than those listed above, owing

possible

incompatibility.

4.3

Contraindications

Ceftriaxone is contraindicated in patients with known hypersensitivity to the active substance or to any

of the excipients listed in section 6.1.

Ceftriaxone is contraindicated in patients who have had previous experience of a major allergy or

anaphylaxis to cephalosporin or penicillin.

Ceftriaxone is contraindicated in hyperbilirubinemic neonates, especially prematures.

In vitro

studies

have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin

encephalopathy can possibly develop in these patients.

Ceftriaxone must not be co-administered with calcium-containing IV solutions, including continuous

calcium-containing infusions such as parental nutrition, in neonates because of the risk of precipitation

of ceftriaxone-calcium salt. Cases of fatal reactions with ceftriaxone-calcium precipitates in lung and

kidneys in neonate have been described. In some cases the infusion lines and the times of administration

of ceftriaxone and calcium-containing solutions differed.

4.4

Special warnings and precautions for use

Hypersensitivity reactions may occur in susceptible individuals.

As with other cephalosporins, anaphylactic shock cannot be ruled out even if a thorough patient history

is taken. Anaphylactic shock requires immediate countermeasures.

Hepatitis and hepatocellular injury

Cases of hepatitis and hepatocellular injury with or without jaundice have been observed during

ceftriaxone therapy and may occur early in the treatment period and independently of cholelithiasis.

Page 5 of 15

Patients should be advised to report immediately any symptoms suggestive of liver injury.

Antibiotic associated pseudomembranous colitis

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including

ceftriaxone. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of

the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients

who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks

after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone.

However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent

effective against C. difficile should be considered. Fluids, electrolytes and protein replacement should

be provided when indicated.

Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil), may prolong

and/or worsen the condition and should not be used.

Other causes of colitis should be considered.

Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent

to the administration of antibacterial agents.

Superinfections with non-susceptible microorganisms may occur as with other antibacterial agents.

Immune mediated haemolytic anaemia

Immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class

antibacterials. Severe cases of haemolytic anaemia, including fatalities, have been reported during

treatment in both adults and children. If a patient develops anaemia while on ceftriaxone, the diagnosis

of a cephalosporin-associated anaemia should be considered and ceftriaxone discontinued until the

aetiology is determined.

Alterations in clotting time

Alterations in prothrombin times have occurred rarely in patients treated with ceftriaxone. Patients with

impaired vitamin K synthesis or low vitamin K stores (e.g. chronic hepatic disease and malnutrition)

may require monitoring of prothrombin time during ceftriaxone treatment. Vitamin K administration

(10 millgram weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

During prolonged treatment the blood profile should be checked at regular intervals.

Interactions with calcium-containing products

There are no reports to date of intravascular or pulmonary precipitations in patients, other than neonates,

treated with ceftriaxone and calcium-containing IV solutions. However, the theoretical possibility exists

for an interaction between ceftriaxone and calcium-containing IV solutions in patients other than

neonates. Therefore, ceftriaxone and calcium-containing solutions, including continuous calcium-

containing infusions such as parenteral nutrition, should not be mixed or co-administered to any patient

Page 6 of 15

irrespective of age, even via different infusion lines at different sites.

As a further theoretical consideration and based on 5 half-lives of ceftriaxone, calcium- containing IV

solutions and ceftriaxone should not be administered within 48 hours of each other, in any patient.

No data are available on the potential interaction between ceftriaxone and oral calcium-containing

products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).

Others

Ceftriaxone should be given with caution to patients who have experienced symptoms of allergy

associated with a cephalosporin or penicillin.

Pseudomembranous colitis and delaying peristalsis-Pseudomembranous colitis has been reported with

virtually all broad-spectrum antibiotics. It is important to consider this diagnosis in patients who

develop diarrhoea in association with the use of ceftriaxone. Drugs which delay peristalsis may prolong

and/or worsen the condition and should not be used.

Prolonged prothrombin time may occur in patients receiving protracted antimicrobial therapy.

Shadows which have been mistaken for gallstones have been detected on sonograms of the gallbladder,

usually following doses higher than the standard recommended dose. These shadows are, however,

precipitates of calcium ceftriaxone which disappear on completion or discontinuation of ceftriaxone

therapy.

Rarely

have

these

findings

been

associated

with

symptoms.

asymptomatic

cases

discontinuation of treatment is not recommended as the condition is reversible after completion of the

treatment.

symptomatic

cases,

conservative

non-surgical

management

recommended.

Discontinuation of ceftriaxone treatment in symptomatic cases should be at the discretion of the

clinician.

Pancreatitis, possibly of biliary obstruction aetiology, has been rarely reported in patients treated with

ceftriaxone. 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 co-factor role of ceftriaxone-

related biliary precipitation cannot be discounted.

Safety and effectiveness of ceftriaxone in neonates, infants and children have been established for the

dosages described in section 4.2.

In vitro

studies have shown that ceftriaxone, like some other

cephalosporins, can displace bilirubin from serum albumin. Caution should be exercised when

considering ceftriaxone for hyperbilirubinaemic neonates, especially prematures. Ceftriaxone should

not be used in neonates (especially prematures) at risk of developing bilirubin encephalopathy.

4.5

Interaction with other medicines and other forms of interaction

No impairment of renal function has so far been observed after concurrent administration of large

doses of ceftriaxone and potent diuretics (e.g. frusemide).

Page 7 of 15

There is no evidence that ceftriaxone increases renal toxicity of aminoglycosides.

No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent

to the administration of ceftriaxone. Ceftriaxone does not contain an N-methylthiotetrazole moiety

associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins.

The elimination of ceftriaxone is not altered by probenecid.

In an

in vitro

study antagonistic effects have been observed with the combination of chloramphenicol

and ceftriaxone.

In patients treated with ceftriaxone the Coombs’ test may rarely become false-positive. Ceftriaxone,

like other antibiotics, may result in false-positive tests for galactosaemia.

Nonenzymatic methods for the glucose determination in urine may give false-positive results. For this

reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically.

4.6

Fertility, pregnancy and lactation

Pregnancy

Category B1

Ceftriaxone crosses the placental barrier. Safety in human pregnancy has not been established.

Reproductive toxicity studies have been performed in mice and rats at doses up to 20 times the human

dose of 2 g/d (586 mg/kg/d in rats), and have not shown evidence of embryotoxocity, foetotoxicity,

teratogenicity or adverse effects on male or female fertility, birth or peri- and postnatal development.

In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the

human dose (84 mg/kg/d in monkeys).

Breast-feeding

As ceftriaxone is secreted in the breast milk at low concentrations, caution is advised in nursing

mothers.

4.7

Effects on ability to drive and use machines

During treatment

with

ceftriaxone

undesirable effects may

occur

(e.g.

dizziness),

which

influence the ability to drive and use machines. Patients should be cautious when driving or operating

machinery.

4.8

Undesirable effects

Ceftriaxone is generally well tolerated. During the use of ceftriaxone, the following side effects, which

were reversible either spontaneously or after withdrawal of the medicine, have been observed:

Page 8 of 15

Systemic side effects

Gastrointestinal complaints (about 2% of cases): loose stools or diarrhoea, nausea, vomiting, stomatitis

and glossitis.

Haematological changes (about 2%): eosinophilia, leukopenia, granulocytopenia, haemolytic anaemia,

thrombocytopenia.

Skin reactions (about 1%): exanthema, allergic dermatitis, pruritus, urticaria, oedema, erythema

multiforme.

Other, rare side effects: headache and dizziness, increase in liver enzymes, jaundice and hepatitis,

symptomatic precipitation of the calcium salt of ceftriaxone in the gallbladder, oliguria, increase in

serum creatinine, mycosis of the genital tract, shivering and anaphylactic or anaphylactoid reactions

and secondary infection.

Pseudomembranous enterocolitis and coagulation disorders have been reported as very rare side effects.

Pancreatitis and Steven Johnson Syndrome have also been reported as very rare side effects.

Very rare cases of renal precipitation have been reported, mostly in children aged 3 years or older, who

have been treated with high doses (> 80 mg/kg/day) or total doses of greater than 10 g and presenting

other risk factors (e.g. fluid restrictions, confinement to bed, etc.). This may be symptomatic or

asymptomatic, may lead to renal insufficiency and is reversible with discontinuation of ceftriaxone.

Fatal reactions with calcium-ceftriaxone precipitates in lungs and kidney in neonates and premature

infants have been described. In some cases the infusion lines and times of administration of ceftriaxone

calcium

containing

solutions

differed.

Ceftriaxone

must

been

mixed

administered

simultaneously with calcium containing solutions or products even via different infusion lines.

Local side effects

Phlebitis at the site of injection and cutaneous vasculitis may occur. These may be minimized by slow

(two to four minutes) injection of the substance.

Intramuscular injection without lidocaine solution is painful.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to

report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

In the case of overdosage, drug concentration would not be reduced by haemodialysis or peritoneal

Page 9 of 15

dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic.

For advice on the management of overdose please contact the National Poisons Centre on 0800 POISON

(0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, third-generation cephalosporins, ATC

code: J01DD04.

Mechanism of action

Ceftriaxone

long

acting,

broad-spectrum

cephalosporin

antibiotic

parenteral

use.

bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone exerts

in

vitro

activity against a wide range of Gram-negative and Gram-positive microorganisms. Ceftriaxone

is highly stable to most beta-lactamases, both penicillinases and cephalosporinases, of Gram-positive

and Gram-negative bacteria.

Ceftriaxone is usually active against the following microorganisms

in vitro

and in clinical infections

(see section 4.1):

Gram-positive aerobes:

Staphylococcus aureus

(methicillin-sensitive)

Staphylococci

coagulase-negative

Streptococcus pyogenes

(β-hemolytic, group A)

Streptococcus agalactiae

(β-hemolytic, group B)

Streptococci

β-hemolytic (non-group A or B)

Streptococcus

viridans

Streptococcus pneumoniae

NOTE:

Methicillin-resistant

Staphylococcus

spp. are resistant to cephalosporins, including ceftriaxone. In

general,

Enterococcus faecalis

Enterococcus faecium

Listeria monocytogenes

are resistant.

Gram-negative aerobes:

Acinetobacter lwoffi

Acinetobacter anitratus

(mostly

A. baumanii

Aeromonas hydrophila

Alcaligenes faecalis

Alcaligenes odorans

Alcaligenes

-like bacteria

Borrelia burgdorferi

Page 10 of 15

Capnocytophaga

spp.

Citrobacter diversus

(including

C. amalonaticus

Citrobacter freundii

Escherichia coli

Enterobacter aerogenes

Enterobacter cloacae

Enterobacter

spp. (other)

Haemophilus ducreyi

Haemophilus influenza

Haemophilus parainfluenzae

Hafnia alvei

Klebsiella oxytoca

Klebsiella pneumoniae

Moraxella catarrhalis

(former

Branhamella catarrhalis

Moraxella osloensis

Moraxella

spp. (other)

Morganella morganii

Neisseria gonorrhoeae

Neisseria meningitides

Pasteurella multocida

Plesiomonas shigelloides

Proteus penneri

Proteus mirabilis

Proteus vulgaris

Pseudomonas fluorescens

Psudomonas

spp. (other)*

Providentia rettgeri

Providentia

spp. (other)

Salmonella typhi

Salmonella

spp. (non-typhoid)

Serratia marcescens

Serratia

spp. (other)

Shigella

spp.

Vibrio

spp.

Yersinia enterocolitica

Yersinia

spp. (other)

*Some isolates of these species are resistant to ceftriaxone, mainly due to the production of the

chromosomally encoded β-lactamase.

**Some isolates of these species are resistant due to production of extended spectrum plasmid mediated

β-lactamase.

Page 11 of 15

NOTE:

Many strains of the above microorganisms that are multiple resistant to other antibiotics, e.g. amino-

and ureido-penicillins, older cephalosporins and aminoglycosides, are susceptible to ceftriaxone.

Treponema pallidum

is sensitive

in vitro

and in animal experiments. Clinical investigations indicate

that primary and secondary syphilis respond well to ceftriaxone therapy. With a few exceptions, clinical

P. aeruginosa

isolates are resistant to ceftriaxone.

Anaerobic organisms:

Bacteroides

spp. (bile-sensitive)*

Clostridium

spp. (excluding the

C. difficle

Fusobacterium nucleatum

Fusobacterium

spp. (other)

Gaffkia anaerobica

(former

Peptococcus

Peptostreptococcus

spp.

*Some isolates of these species are resistant to ceftriaxone due to β-lactamase-production.

NOTE:

Many strains of β-lactamase-producing

Bacteroides

spp. (notably

B. fragilis

) are resistant.

Clostridium difficile

is resistant.

Susceptibility to ceftriaxone can be determined by the disk diffusion test or by the agar or broth dilution

test using standardised techniques for susceptibility testing such as those recommended by the National

Committee for Clinical Laboratory Standards (NCCLS). The NCCLS issued interpretative breakpoints

for ceftriaxone are:

Susceptible

Moderately susceptible

Resistant

Dilution test, inhibitory concentrations in mg/L

≤ 8

16-32

≥ 32

Diffusion test (disk with 30 μg ceftriaxone),

inhibition zone diameter in mm

≥ 21

20-14

≤ 13

Microorganisms should be tested with the ceftriaxone disk since it has been shown by

in vitro

tests to

be active against certain strains resistant to cephalosporin class disks.

Where NCCLS recommendations are not in daily use, alternative, well standardised, susceptibility

interpretative guidelines such as those issued by DIN, ICS and others may be substituted.

5.2

Pharmacokinetic properties

The pharmacokinetics of ceftriaxone are nonlinear and all basic pharmacokinetic parameters, except

the elimination half-life, are dose dependent if based on total drug concentrations. An overall mean and

the range of means from studies have been presented for the primary pharmacokinetic parameters of

ceftriaxone administered in the dose range 150 mg – 3 g.

Page 12 of 15

Absorption

The maximum plasma concentration after a single IM dose of 1 g is about 81 mg/L and is reached in 2-

hours

after

administration.

area

under

plasma

concentration-time

curve

after

administration is equivalent to that after IV administration of an equivalent dose, indicating 100%

bioavailability of intramuscularly administered ceftriaxone.

Distribution

The volume of distribution of ceftriaxone is 7-12 L. Ceftriaxone has shown excellent tissue and body

fluid penetration after a dose of 1-2 g; concentrations well above the minimal inhibitory concentrations

of most pathogens responsible for infection are detectable for more than 24 hours in over 60 tissues or

body fluids including lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone as well

as cerebrospinal, pleural, prostatic and synovial fluids.

Following intravenous administration, ceftriaxone diffuses rapidly into the interstitial fluid, sustaining

bactericidal concentrations against susceptible organisms for 24 hours.

Protein binding

Ceftriaxone is reversibly bound to albumin, and the binding decreases with the increase in the

concentration, e.g. from 95% binding at plasma concentrations of <100 mg/L to 85% binding at

300 mg/L. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is

correspondingly higher than in plasma.

Penetration into particular tissues

Ceftriaxone

penetrates

inflamed

meninges

neonates,

infants

children.

Ceftriaxone

concentration are >1.4 mg/L in the CSF 24 hours after IV injection of Ceftriaxone in doses of 50 – 100

mg per kg (neonates and infants, respectively). Peak concentration in CSF is reached about 4 hours after

IV injection and gives an average value of 18 mg/L. The average extent of diffusion into the

cerebrospinal fluid during bacterial meningitis is 17% of the plasma concentration and 4% in patients

with aseptic meningitis. In adult meningitis patients, administration of 50 mg per kg leads within 2 –

24 hours to CSF concentrations several times higher than the minimum inhibitory concentrations

required for the most common causative organisms of meningitis.

Ceftriaxone crosses the placental barrier and is secreted in the breast milk at low concentrations.

Metabolism

Ceftriaxone is not metabolized systemically; only the intestinal flora transforms the agent into inactive

metabolites.

Elimination

The total plasma clearance is 10 – 22 mL/min. Renal clearance is 5 – 12 mL/min. 50-60% of ceftriaxone

is excreted unchanged in the urine, while 40-50% is excreted unchanged in the bile. The elimination

half-life in adults is about eight hours.

Page 13 of 15

Special populations

Neonates and elderly patients

In neonates, urinary recovery accounts for about 70% of the dose. In infants aged less than eight days

and in elderly persons aged over 75 years, the average elimination half-life is usually 2 to 3 times that

in the young adult group.

Renal or hepatic dysfunction

In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally

altered and the elimination half-life is only slightly increased. If kidney function alone is impaired,

biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is

increased.

5.3

Preclinical safety data

Repeated dose administrations in animals revealed the known and reversible side effect of parenterally

administered third-generation cephalosporins at high doses (e.g. alteration of laboratory parameters,

enteric disturbances and a certain degree of nephrotoxocity). A specific side effect of ceftriaxone is the

formation of biliary calculi in the gallbladder of dogs, and to a minor extent in monkeys. Ceftriaxone

had no effect on reproductive parameters, and was found to have neither mutagenic nor antigenic

activity.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

None.

6.2

Incompatibilities

This medicine must not be mixed with other medicines except those mentioned in section 6.6.

Ceftriaxone should not be added to solutions containing calcium such as Hartmann’s solution and

Ringer’s solution. Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin

and fluconazole and aminoglycosides.

6.3

Shelf life

Powder: 36 months.

Reconstituted solution: 24 hours when stored in a refrigerator (2 – 8°C). Do not freeze. Protect from

light.

6.4

Special precautions for storage

Page 14 of 15

Store below 25°C. Protect from light.

For storage conditions after reconstitution of the medicine, see section 6.3.

6.5

Nature and contents of container

Ceftriaxone-AFT is supplied in glass vials closed with a rubber stopper and a flip-off cap, in pack sizes

of 1, 5 or 10 vials.

6.6

Special precautions for disposal and other handling

Ceftriaxone powder must be reconstituted prior to use.

As a general rule, the solution should be used immediately after preparation. Reconstituted solutions

retain their physical and chemical stability for six hours at room temperature or 24 hours under

refrigeration (2-8 °C).

The solutions range in colour from pale yellow to amber, depending on the concentration and the length

of storage. This characteristic of the active ingredient is of no significance for the efficacy or tolerance

of the drug.

For IM injection, Ceftriaxone-AFT 1 g is dissolved in 3.5 mL of 1% lidocaine hydrochloride solution.

For IV injection, Ceftriaxone-AFT 500 mg is dissolved in 5 mL, or Ceftriaxone-AFT 1 g in 10 mL, of

sterile water for injections.

For IV infusion, 2 g ceftriaxone are dissolved in 40 mL of one of the following calcium-free infusion

solutions: sodium chloride 0.9%, sodium chloride 0.45% + dextrose 2.5%, dextrose 5%, dextrose 10%,

dextran 6% in dextrose 5%, hydroxyethyl starch 6-10% infusions, sterile water for injections.

Ceftriaxone solutions should not be mixed with or piggybacked into solutions containing other

antimicrobial

drugs or into diluent solutions

other than those listed above,

owing to

possible

incompatibility.

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

7.

MEDICINE SCHEDULE

Prescription Medicine.

8.

SPONSOR

AFT Pharmaceuticals Ltd

Page 15 of 15

PO Box 33-203

Takapuna

Auckland 0740

Phone: 0800 423 823

9.

DATE OF FIRST APPROVAL

13 January 2011

10.

DATE OF REVISION OF THE TEXT

4 May 2018

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