Rocephin 1 g Powder for Solution for Injection/Infusion *
Pharmacy Only: Prescription

  • Company:

    Roche Products (Ireland) Ltd
  • Status:

    Updated
  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)
  • Active Ingredient(s):

    *Additional information is available within the SPC or upon request to the company

Updated on 24 January 2023

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Updated on 06 September 2021

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Updated on 06 September 2021

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Updated on 28 June 2021

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  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.5 - Nature and contents of container
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Updated on 28 June 2021

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Updated on 28 June 2021

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  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.2 - Incompatibilities
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Updated on 28 June 2021

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Updated on 27 January 2021

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Updated on 27 January 2021

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Updated on 08 June 2020

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Updated on 08 June 2020

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Updated on 08 June 2020

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Updated on 08 June 2020

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Updated on 20 May 2019

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Updated on 20 May 2019

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Type 1A - DRESS/JHR update

Updated on 29 August 2018

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Updated on 29 August 2018

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MAH Transfer from RPL to Roche Products (Ireland) Limited issue of new PA licence number(s) approved 17-Aug-18

Updated on 06 July 2018

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Updated on 05 July 2018

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Updated on 20 February 2018

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Updated on 20 February 2018

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  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

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6.6       Special precautions for disposal and other handling

 

Preparation of solutions for injection and infusion

 

[ ... ] 

The displacement volume of 1 g of Rocephin is 0.71 ml in water for injections and 1% lidocaine hydrochloride solution. When adding 10 ml of water for injections, the final concentration of the reconstituted solution is 93.37 mg/ml. When adding 3.5 ml of 1% lidocaine hydrochloride solution, the final concentration of the reconstituted solution is 237.53 mg/ml.

 

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

 

 

10.              DATE OF REVISION OF THE TEXT

 

24 26 May January 20172018

 

 

Updated on 15 February 2018

File name

PIL_8251_174.pdf

Reasons for updating

  • New PIL for new product

Updated on 15 February 2018

Reasons for updating

  • Change to section 6 - date of revision
  • Change to information for healthcare professionals

Updated on 26 June 2017

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

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1.                  QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each 1g vial contains 1g ceftriaxone as 1.19g ceftriaxone sodium.

Each vial contains 1 g ceftriaxone as ceftriaxone sodium.

Excipient with known effect:

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

 

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 bottles or to further dilute a reconstituted vial or bottle 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 treatment with a combination of another antibiotic with Rocephin is intended, 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

 

Three years. 

Reconstituted product: Chemical and physical in-use stability has been demonstrated for 6 hours at or below 25°C or 24 hours at 2-8°C.  The product must be protected from light.  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 reconstitution has taken place in controlled and validated aseptic conditions.

Unopened vials or bottles: 3 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 not be longer than the times stated above for the chemical and physical in-use stability. normally not be longer than 24 hours at 2 to 8°C, unless preparation for the solution has taken place in controlled and validated aseptic conditions

 

6.4       Special precautions for storage

 

Do not store above 25°C. Keep vial in the outer carton in order to protect from light.

 

For storage of reconstituted product see section 6.3.

Do not store above 30°C, keep vial or bottle 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 containers

 

Type I Ph. Eur. clear glass vials with teflonised rubber stopper and aluminium cap containing a sterile, white to yellowish orange crystalline powder. 

Rocephin 1g vials in packs of 1.

Type 1 Ph. Eur 15 ml glass vial with fluorobutyl rubber stopper and aluminium cap, containing a sterile powder, equivalent to 1 g ceftriaxoneas ceftriaxone sodium.

 

Pack size of 1 vial or bottle.

 

 

6.6       Special precautions for disposal and other handling

 

Preparation of solutions for injection and infusion

 

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

These maintain chemical and physical stability for at least 6 hours at or below 25°C or 24 hours at 2-8°C. Protect from light.

Rocephin should not be mixed in the same syringe with any drug other than 1% Lidocaine Hydrochloride solution (for intramuscular injection only).

The infusion line should be flushed after each administration.

 

For IVi.v. injection 1 g Rocephin is dissolved in 10 ml of water for injections. The injection should be administered over 5 minutes, directly into the vein or via the tubing of an intravenous infusion.

 

For IMi.m. injection 1 g Rocephin is dissolved in 3.5 ml of 1% Lidocaine Hydrochloride solution. The solution should be administered by deep intramuscular injection. Dosages greater than 1 g should be divided and injected at more than one site.

 

 

The use of freshly prepared solutions is recommended. 

 

For single use only.  Discard any unused content. 

 

When reconstituted for intramuscular or intravenous injection or intravenous infusion, the white to yellowish-orange crystalline powder gives a pale yellow to amber solution.  The displacement value of 250 mg of Rocephin is 0.18 ml. 

 

Each gram of Rocephin contains approximately 3.6 mmol sodium. 

 

Intramuscular injection: 1g Rocephin should be dissolved in 3.5ml of 1.06% Lidocaine Injection.  The solution should be administered by deep intramuscular injection.  Dosages greater than 1g should be divided and injected at more than one site. 

Solutions in Lidocaine must not be administered intravenously. 

 

Intravenous injection: 1g Rocephin should be dissolved in 10 ml of Water for Injections BP.  The injection should be administered over 5 minutes, directly into the vein or via the tubing of an intravenous infusion. 

 

Intravenous infusion: 2g of Rocephin should be dissolved in 40 ml of one of the following calcium-free solutions: Dextrose Injection BP 5% or 10%, Sodium Chloride Injection BP, Sodium Chloride and Dextrose Injection BP (0.45% sodium chloride and 2.5% dextrose), dextran 6% in Dextrose Injection BP 5%, hydroxyethyl starch 6 - 10% infusions, sterile water for injection.  The infusion should be administered over at least 30 minutes. 

 

Concentrations for the intravenous injection: 100 mg/ml

Concentrations for the intravenous infusion: 50 mg/ml

(Please refer to section 4.2 for further information).

 

Solutions containing Rocephin should not be mixed with or added to solutions containing other agents.  In particular, Rocephin is not compatible with calcium-containing solutions such as Hartmann’s solution and Ringer’s solution.

 

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

 

10.              DATE OF REVISION OF THE TEXT

 

2nd September 2015 24 May 2017

 

Updated on 23 June 2017

Reasons for updating

  • Change to section 5 - how to store or dispose
  • Change to section 6 - date of revision

Updated on 11 September 2015

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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4.4          Special warnings and precautions for use

[…]

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 false-positive 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.

[…]

4.8          Undesirable effects

[…]

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 pre-term 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 renal precipitation have been reported, primarily in children older than 3 years of age and who have been treated with either high daily doses (e.g. ³ 80 mg/kg/day) or total doses exceeding 10 grams and who presented with other risk factors (e.g. fluid restrictions or confinement to bed). The risk of precipitate formation is increased in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may lead to renal insufficiency and anuria, and is reversible upon discontinuation of ceftriaxone (see section 4.4).

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).

[…]

10.               DATE OF REVISION OF THE TEXT

 15 December 20142nd September 2015

 

Updated on 09 September 2015

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 22 December 2014

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

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Implementation of harmonised text following article 30 referral

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4.1       Therapeutic Iindications

 

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.

 

 

Ceftriaxone is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible micro-organisms (see section 5.1) and when parenteral therapy is required: 

Respiratory tract infections including pneumonia, acute and chronic bronchitis and ear, nose and throat infections. 

Renal and urinary tract infections. 

Septicaemia.   Meningitis. 

Abdominal infections including peritonitis and infections of the biliary tract. 

Soft tissue infections including cellulitis and wound infections. 

Gonorrhoea. 

Peri-operative prophylaxis of infections associated with surgery.  Infections in patients with impaired defence mechanisms. 

Treatment may be started before the results of susceptibility tests are known. 

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

 

4.2       Posology and Mmethod of Aadministration

 

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*

Treatment frequency**

Indications

1‑2 g

Once daily

Community acquired pneumonia

Acute exacerbations of chronic obstructive pulmonary disease

Intra-abdominal infections

Complicated urinary tract infections (including pyelonephritis)

2 g

Once daily

Hospital acquired pneumonia

Complicated skin and soft tissue infections

Infections of bones and joints

2‑4 g

Once daily

 

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*

Treatment frequency**

Indications

50‑80 mg/kg

 

Once daily

 

Intra-abdominal infections

Complicated urinary tract infections (including pyelonephritis)

Community acquired pneumonia

Hospital acquired pneumonia

50‑100 mg/kg (Max 4 g)

Once daily

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 (max 4 g)

Once daily

Bacterial meningitis

100 mg/kg (max 4 g)

Once daily

Bacterial endocarditis

*   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*

Treatment frequency

Indications

20‑50 mg/kg

Once daily

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

 

Intramuscular administration

Rocephin can be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over 5 minutes, or by deep intramuscular injection. Intravenous intermittent injection should be given over 5 minutes preferably in larger veins. Intravenous doses of 50 mg/kg or more in infants and children up to 12 years of age should be given by infusion. In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy. 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. Intramuscular administration should be considered when the intravenous route is not possible or less appropriate for the patient. For doses greater than 2 g intravenous administration should be used.

 

If lidocaine is used as a 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.

 

Intravenous administration

Rocephin can be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over 5 minutes, or by deep intramuscular injection. Intravenous intermittent injection should be given over 5 minutes preferably in larger veins. Intravenous doses of 50 mg/kg or more in infants and children up to 12 years of age should be given by infusion. In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see section 4.3 and 4.4). 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. Intramuscular administration should be considered when the intravenous route is not possible or less appropriate for the patient. For doses greater than 2 g intravenous administration should be used.

 

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).

 

Diluents containing calcium, (e.g. Ringer’s solution or 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. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2).

 

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.

 

Rocephin may be administered by deep intramuscular injection, slow intravenous injection, or as a slow intravenous infusion, after reconstitution of the solution according to the directions given below and also see section 6.6.

Diluents containing calcium, (e.g. Ringer’s solution or Hartmann’s solution), should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2).

Dosage and mode of administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient's condition.  Under most circumstances a once-daily dose - or, in the specified indications, a single dose - will give satisfactory therapeutic results. 

Adults and children 12 years and over

Standard therapeutic dosage:  1g once daily. 

Severe infections:  2 - 4g daily, normally as a single dose every 24 hours. 

The duration of therapy varies according to the course of the disease.  As with antibiotic therapy in general, administration of Rocephin 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. 

Acute, uncomplicated gonorrhoea:  A single dose of 250mg intramuscularly should be administered.  Simultaneous administration of probenecid is not indicated. 

Peri-operative prophylaxis:  Usually 1g as a single intramuscular or slow intravenous dose 30-90 minutes prior to surgery.  In colorectal surgery, 2g should be given intramuscularly, by slow intravenous injection or by slow intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria. 

Elderly

These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory (see below). 

Neonates, infants and children under 12 years

 

The following dosage schedules are recommended for once daily administration:

 

Neonates

A daily dose of 20 - 50mg/kg body weight, not to exceed 50mg/kg.  In the neonate, the intravenous dose should be given over 60 minutes to reduce the displacement of bilirubin from albumin, thereby reducing the potential risk of bilirubin encephalopathy (see section 4.3).

Infants and Children under 12 years

Standard therapeutic dosage:  20 - 50mg/kg body-weight once daily. 

Up to 80mg/kg body-weight daily may be given in severe infections.  For children with body weights of 50 kg or more, the usual adult dosage should be used. Doses of 50mg/kg or over should be given by slow intravenous infusion over at least 30 minutes. Doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates.

Renal and hepatic impairment

In patients with impaired renal function, there is no need to reduce the dosage of Rocephin provided liver function is intact.  Only in cases of pre-terminal renal failure (creatinine clearance < 10ml per minute) should the daily dosage be limited to 2g or less. 

In patients with liver damage there is no need for the dosage to be reduced provided renal function is intact. 

In severe renal impairment accompanied by hepatic insufficiency, the plasma concentration of Rocephin should be determined at regular intervals in order to ensure that the plasma level is in excess of the minimum inhibitory concentration of the causative organism(s), assuming this is sensitive, and dosage adjusted so that accumulation of Rocephin does not occur. 

In patients undergoing dialysis, no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.

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 ceftriaxone-calcium 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.

Rocephin is contraindicated in patients with known hypersensitivity to beta-lactam antibiotics. 

In patients hypersensitive to penicillin, the possibility of allergic cross-reactions should be borne in mind. 

Hyperbilirubinaemic newborns and preterm newborns should not be treated with ceftriaxone. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients.

Ceftriaxone is contraindicated in:

·                                                        Premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life),

·                                                        Full-term newborns (up to 28 days of age)

·                                                    with jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired

·                                    if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see sections 4.4, 4.8 and 6.2).

Contraindications of lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine is used as a solvent.

 

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 cephalosporin-associated 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 false-positive results. Urine glucose determination during therapy with Rocephin should be done enzymatically (see section 4.8).

 

 

 

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.

 

The stated dosage should not be exceeded. 

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

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

Ceftriaxone should be given with caution to patients who have other allergic diatheses. 

In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined under section 4.2.  

An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Rocephin. 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.

 

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

 

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

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

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

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftriaxone.  Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to administration of antibacterial agents (see section 4.8). 

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

Interaction with Calcium-Containing Products

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

In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV 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 TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If use of 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, considering the advice to flush infusion lines between solutions. (See sections 4.3, 4.8, 5.2 and 6.2).

Shadows which have been mistaken for gallstones have been detected by 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 Rocephin therapy.  Rarely, have these findings been associated with symptoms.  In symptomatic cases, conservative non-surgical management is recommended.  Discontinuation of Rocephin treatment in symptomatic cases should be at the discretion of the clinician (see section 4.8).

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

Safety and effectiveness of Rocephin in neonates, infants and children have been established for the dosages in section 4.2

During prolonged treatment, the blood cell count should be checked regularly. 

Each gram of Rocephin contains approximately 3.6mmol sodium.  To be taken into consideration by patients on a controlled sodium diet.

In case lidocaine is used as a solvent Ceftriaxone solutions should only be used for intramuscular injection.

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 calcium-containing 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 calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing 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 false-positive 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.

 

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

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

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

Simultaneous administration of probenecid does not reduce the elimination of Rocephin and its use with Rocephin is not indicated. 

In vitro, chloramphenicol has been shown to be antagonistic with respect to ceftriaxone and other cephalosporins.  The clinical relevance of this finding is unknown, but caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed. 

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

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

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

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

4.6       Fertility, Ppregnancy 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.

 

 

Pregnancy

For ceftriaxone limited clinical data on exposed pregnancies are available.  Ceftriaxone crosses the placental barrier.  Reproductive studies in animals have shown no evidence of embryotoxicity, foetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development.  In primates, no embryotoxicity or teratogenicity has been observed.  Since safety in human pregnancy is not established ceftriaxone should not be used unless absolutely indicated. 

Lactation

Low concentrations of ceftriaxone are excreted in human milk.  Caution should be exercised when ceftriaxone is administered to a nursing woman.

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.

 

Since Rocephin sometimes induces dizziness the ability to drive and use machines can be impaired.

4.8     Undesirable Eeffects

 

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)

 

System Organ Class

Common

Uncommon

Rare

Not Known a

Infections and infestations

 

Genital fungal infection

Pseudo-membranous colitisb

Superinfectionb

Blood and lymphatic system disorders

Eosinophilia Leucopenia

Thrombocytopenia

Granulocytopenia

Anaemia

Coagulopathy

 

Haemolytic anaemiab

Agranulocytosis

Immune system disorders

 

 

 

Anaphylactic shock

Anaphylactic reaction

Anaphylactoid reaction

Hypersensitivityb

Nervous system disorders

 

Headache

Dizziness

 

Convulsion

Ear and labyrinth disorders

 

 

 

Vertigo

Respiratory, thoracic and mediastinal disorders

 

 

Bronchospasm

 

Gastrointestinal disorders

Diarrhoeab

Loose stools

Nausea

Vomiting

 

Pancreatitisb

Stomatitis

Glossitis

Hepatobiliary disorders

Hepatic enzyme increased

 

 

Gall bladder precipitationb

Kernicterus

Skin and subcutaneous tissue disorders

Rash

Pruritus

Urticaria

Stevens Johnson Syndromeb

Toxic epidermal necrolysisb

Erythema multiforme

Acute generalised exanthematous pustulosis

Renal and urinary disorders

 

 

Haematuria

Glycosuria

Oliguria

Renal precipitation (reversible)

General disorders and administration site conditions

 

Phlebitis

Injection site pain

Pyrexia

Oedema

Chills

 

Investigations

 

Blood creatinine increased

 

Coombs test false positiveb

Galactosaemia test false positiveb

Non enzymatic methods for glucose determination false positiveb

a               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.

b           See section 4.4

 

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 pre-term 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 renal precipitation have been reported, primarily in children older than 3 years of age and who have been treated with either high daily doses (e.g. ³ 80 mg/kg/day) or total doses exceeding 10 grams and who presented with other risk factors (e.g. fluid restrictions or confinement to bed). The risk of precipitate formation is increased in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may lead to renal insufficiency and anuria, and is 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 HPRA Pharmacovigilance,

Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.  Website:  www.hpra.ie; E-mail: medsafety@hpra.ie.

 

Rarely severe adverse reactions have been reported in preterm and full-term newborns (aged <28 days).  These reactions have caused death in some cases.  These newborns had been treated with intravenous ceftriaxone and calcium.  Some of them had received ceftriaxone and calcium at different times and on different intravenous lines.  Precipitations of ceftriaxone – calcium salt have been observed in lungs and kidneys of these dead preterm newborns.  The high risk of precipitation is due to the low blood volume of the newborns.  Moreover the half life is longer than in adults (see sections 4.3, 4.4 and 5.2).

The most frequently reported adverse events for ceftriaxone are diarrhoea, nausea and vomiting.  Other reported adverse events include hypersensitivity reactions such as allergic skin reactions and anaphylactic reactions, secondary infections with yeast, fungi or resistant organisms as well as changes in blood cell counts. 

Infections and infestations

Rare (³ 0.01 % - < 0.1 %): Mycosis of the genital tract.

Superinfections of various sites with yeasts, fungi or other resistant microorganisms are possible.

 

Pseudomembraneous colitis is a rare undesirable effect caused by infection with Clostridium difficile during treatment with Rocephin. Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use (see section 4.4).

 

Blood and lymphatic system disorders

Rare (³ 0.01 % - < 0.1 %): Neutropenia, leucopenia, eosinophilia, thrombocytopenia, anaemia (including haemolytic anaemia), slight prolongation of prothrombin time.

Very rare (< 0.01 %) including isolated reports: Positive Coombs’ test, coagulation disorders, agranulocytosis (< 500/m3), mostly after 10 days of treatment and following total doses of 20g ceftriaxone and more. 

Immune system disorders

Rare (³ 0.01 % - < 0.1 %): Anaphylactic (e.g. bronchospasm) and anaphylactoid reactions (see section 4.4). 

Nervous system disorders

Rare (³ 0.01 % - < 0.1 %): Headache, dizziness. 

Gastrointestinal disorders

Common (³ 1% - < 10%):  Loose stools or diarrhoea, nausea, vomiting.

Rare (³ 0.01 % - < 0.1 %): Stomatitis, glossitis.  These side effects are usually mild and commonly disappear during treatment or after discontinuation of treatment.

Very rare (< 0.01 %) including isolated reports: Pseudomembranous colitis (mostly caused by Clostridium difficile), pancreatitis (possibly caused by obstruction of bile ducts). 

Hepato-biliary disorders

Rare (³ 0.01 % - < 0.1 %): Increase in serum liver enzymes (AST, ALT, alkaline phosphatase), jaundice.

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed (see section 4.4), mostly 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, in some studies to above 30%.  The incidence seems to be lower with slow infusion (20-30 minutes).  This effect is usually asymptomatic, but in rare cases, the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone. 

Skin and subcutaneous tissue disorders

Uncommon (³ 0.1 % - < 1 %): Allergic skin reactions such as maculopapular rash or exanthema, urticaria, dermatitis, pruritis, oedema.

Very rare (< 0.01 %) including isolated reports: Erythema multiforme, Stevens Johnson Syndrome, Lyell’s Syndrome/toxic epidermal necrolysis. 

Renal and urinary disorders

Rare (³ 0.01 % - < 0.1 %): Increase in serum creatinine, oliguria, glycosuria, haematuria.  

Very rare (< 0.01 %) including isolated reports: Renal precipitation, mostly in children older than 3 years who have been treated with either high daily doses (e.g. ≥ 80 mg/kg/day) or total doses exceeding 10g and with other risk factors such as dehydration or immobilisation. Renal precipitation is reversible upon discontinuation of ceftriaxone. Anuria and renal impairment have been reported in association.  

General disorders and administration site conditions

Rare (³ 0.01 % - < 0.1 %): Phlebitis and injection site pain following intravenous administration. This can be minimised by slow injection over at least 2-4 minutes. Rigors, pyrexia.

An intramuscular injection without lidocaine solution is painful.

4.9     Overdosage

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.

 

In the case of overdosage, nausea, vomiting, diarrhoea, can occur. Ceftriaxone concentrations would not be reduced by haemodialysis or peritoneal dialysis.  There is no specific antidote.  Treatment 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:

Pathogen

Dilution Test
(MIC, mg/L)

Susceptible

Resistant

Enterobacteriaceae

≤ 1

> 2

Staphylococcus spp.

a.

a.

Streptococcus spp.
(
Groups A, B, C and G)

b.

b.

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

 

Ceftriaxone is a long-acting, broad spectrum cephalosporin antibiotic for parenteral use. 

The 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 organisms including both aerobic and anaerobic species.  Ceftriaxone is highly stable to most beta-lactamases, both penicillinases and cephalosporinases, of Gram-positive and Gram-negative bacteria. 

The outstanding feature of Rocephin is its relatively long plasma elimination half-life of approximately 8 hours, which makes single or once-daily dosage of the drug appropriate for most patients. 

Microbiology

Ceftriaxone is usually active against the following micro-organisms in vitro and in clinical infections (see section 4.1).  The list is not exhaustive and focuses on those organisms of particular clinical interest. 
 
 Gram-positive aerobes

Staphylococcus aureus (including penicillinase-producing strains)

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus group A (Streptococcus pyogenes)

Streptococcus group B (Streptococcus agalactiae)

Streptococcus viridans

Streptococcus bovis 

Note

Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone.  In general, Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are resistant. 

Gram-negative aerobes

Aeromonas spp.

Alcaligenes spp.

Moraxella catarrhalis (beta-lactamase negative and positive)

Citrobacter spp.

Enterobacter spp. (some strains are resistant)

Escherichia coli

Haemophilus ducreyi

Haemophilus influenzae (including penicillinase-producing strains)

Haemophilus parainfluenzae

Klebsiella spp. (including K. pneumoniae)

Moraxella spp.

Morganella morganii (= Proteus morganii)

Neisseria gonorrhoeae (including penicillinase-producing strains)

Neisseria meningitidis

Plesiomonas shigelloides

Proteus mirabilis

Proteus vulgaris

Providencia spp.

Pseudomonas spp. (some strains are resistant)

Salmonella spp. (including S. typhi)

Serratia spp. (including S. marcescens)

Shigella spp.

Vibrio spp. (including V. cholerae)

Yersinia spp. (including Y. enterocolitica

Note

Many strains of the above organisms that are multiply resistant to other antibiotics, e.g. 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. 

Synergy between Rocephin and aminoglycosides has been demonstrated with many Gram-negative bacilli under experimental conditions. Although enhanced activity of such combinations is not always predictable, it should be considered in severe, life-threatening infections due to organisms such as Pseudomonas aeruginosa.  Because of physical incompatibility the two drugs must be administered separately at the recommended dosages. 

Anaerobic organisms

Bacteroides spp. (many strains notably B. fragilis are resistant)

Clostridium spp. (except C. difficile)

Fusobacterium spp. (except F. mortiferum and F. varium)

Gaffkia anaerobica (formerly peptococcus)

Peptostreptococcus spp. 

Susceptibility to ceftriaxone can be determined by the disc 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 the following interpretative breakpoints for ceftriaxone: 

Dilution susceptibility testing:  Susceptible £ 8mg/litre; moderately susceptible 16 - 32mg/litre; resistant ≥ 64mg/litre. 

Diffusion susceptibility testing using a 30 microgram ceftriaxone disc:  Susceptible ≥ 21mm; moderately susceptible 20 - 14mm; resistant £ 13mm. 

Organisms should be tested with the ceftriaxone disc since it has been shown by in vitro tests to be active against certain strains resistant to cephalosporin class discs. 

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

 

Absorption

 

Intramuscular administration

After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively. 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.

 

Intravenous administration

After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively. 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).

 

The pharmacokinetics of Rocephin are largely determined by its concentration-dependent binding to serum albumin.  The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300mg/l.  Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma. 

Plasma concentrations:  Mean peak concentrations after bolus intravenous injection are about 120mg/l following a 500mg dose and about 200mg/l following a 1g dose; mean levels of 250mg/l are achieved after infusion of 2g over 30 minutes.  Intramuscular injection of 500mg Rocephin in 1.06% Lidocaine produces mean peak plasma concentrations of 40 - 70mg/l within 1 hour.  Bioavailability after intramuscular injection is 100%. 

Excretion:  Rocephin is eliminated mainly as unchanged ceftriaxone, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts.  The total plasma clearance is 10 - 22ml/min.  The renal clearance is 5 - 12ml/min.  The elimination half-life in adults is about 8 hours.  The half-life is not significantly affected by the dose, the route of administration or by repeated administration.  Due to its high protein binding, ceftriaxone is not dialysable. 

Pharmacokinetics in special clinical situations: 

Children
In the first week of life, 80% of the dose is excreted in the urine; over the first month, this falls to levels similar to those in adults. In infants aged less than 8 days the average elimination half-life is usually two to three times longer than that of young adults.

 

Elderly