Klacid IV 500mg Powder for Concentrate for Solution for Infusion

  • Name:

    Klacid IV 500mg Powder for Concentrate for Solution for Infusion

  • Company:
    info
  • Active Ingredients:

    Clarithromycin lactobionate

  • Legal Category:

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

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 16/12/19

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Summary of Product Characteristics last updated on medicines.ie: 3/5/2019

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Mylan IRE Healthcare Limited

Mylan IRE Healthcare Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 16 December 2019 PIL

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 7 May 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 3 May 2019 SmPC

Reasons for updating

  • 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 10 - Date of revision of the text

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

Updated on 14 January 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 5 - how to store or dispose
  • Change to section 6 - what the product contains
  • Change to section 6 - date of revision

Updated on 14 January 2019 SmPC

Reasons for updating

  • 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 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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

Updated on 10 January 2019 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

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

Updated on 26 November 2018 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 2 - excipient warnings
  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 26 November 2018 SmPC

Reasons for updating

  • 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 10 - Date of revision of the text

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

Updated on 29 May 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use

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

Updated on 9 March 2018 SmPC

Reasons for updating

  • New SmPC for new product

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

Updated on 9 March 2018 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 6.1 - List of excipients
  • 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 6.6 - 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)

Free text change information supplied by the pharmaceutical company



2. QUALITATIVE AND QUANTITATIVE COMPOSITION
 
 Each vial contains 500 mg C clarithromycin (as lactobionate).

When reconstituted and diluted as directed, the final diluted solution contains approximately 1.9mg/ml of Clarithromycin.
  
Excipient with known effect:

6.  PHARMACEUTICAL PARTICULARS

6.1      List of excipients

 Lactobionic acid
 Sodium hydroxide (for pH-adjustment)

6.2      Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. Klacid IV for Infusion should only be diluted with the diluents recommended (see section 6.6). Do not use with diluents containing preservatives or inorganic salts

6.3      Shelf life

Unopened: 3 years.

Storage conditions of the R reconstituted and /D diluted Solutions medicinal product: For the initial solution c Chemical and physical in -use stability has been
demonstrated for 24 48 hours at 2 to 8 5°C and for 24 hours at 25°C.

From a microbiological point of view, the reconstituted and diluted 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 /dilution has taken place in controlled and validated aseptic conditions.

For the final solution chemical and physical in-use stability has been
demonstrated for 48 hours at 5°C and for 6 hours at 25°C. From a microbiological point of view, the final diluted 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 /dilution has taken place in controlled and validated aseptic conditions.

6.4      Special precautions for storage

Unopened: Do not store above 30°C. Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product precautions for the reconstituted /diluted solutions, please, see section 6.3.

6.5      Nature and contents of container

The container is a 30ml Ph. Eur. Type I flint glass tubing vial with a 20mm grey halo-butyl lyophilisation stopper or 15ml Ph. Eur. Type I flint glass tubing vial with a grey bromobutyl lyophilisation stopper. There is a 20mm flip-off lacquer coated aluminium and polypropylene or equivalent cap. Both vial sizes contain the same quantity of clarithromycin.

Not all vial sizes may be marketed.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product.

Klacid IV should be administered as an IV infusion over 60 minutes, using a solution concentration of about 2mg 1.9mg/ml.  Clarithromycin should not be given as a bolus or an intramuscular injection.

Dilution:
Both dilution steps should be complete before use.
Prepare all solutions using aseptic techniques.
The final solution for infusion is prepared as follows:
1. Prepare the initial solution of clarithromycin I.V. by adding 10 ml of Sterile Water for Injection to the 500 mg vial.  Use only Sterile Water for Injection, as other diluents may cause precipitation during reconstitution.  Do not use diluents containing preservatives or inorganic salts.  Note: When the product is reconstituted as directed above, the resulting solution contains an effective antimicrobial preservative; each ml contains 50 mg clarithromycin. For storage conditions after reconstitution of the medicinal product, see section 6.3.
2. The reconstituted product (500 mg in 10 ml Water for Injection) should be added to a minimum of 250 ml of one of the following diluents before administration:
• 5% dextrose in Lactated Ringer's Solution,
• 5% dextrose,
• Lactated Ringer's,
• 5% dextrose in 0.3% sodium chloride,
• Normosol-M in 5% dextrose,
• Normosol-R in 5% dextrose,
• 5% dextrose in 0.45% sodium chloride,
 5% dextrose in 0.9% sodium chloride.
For storage conditions after dilution of the medicinal product, see section 6.3.

 

Updated on 8 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 8 March 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 5 - how to store or dispose
  • Change to section 6 - what the product looks like and pack contents
  • Change to information for healthcare professionals

Updated on 3 May 2017 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

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

Free text change information supplied by the pharmaceutical company

7. MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited
Unit 35/36
Grange Parade
Baldoyle Industrial Estate
Dublin 13
Ireland
BGP Products Ireland Limited
4051 Kingswood Drive
Citywest Business Campus
Dublin 24


10. DATE OF REVISION OF THE TEXT

May 2016April 2017

Updated on 28 April 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 11 July 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 4 July 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications

Updated on 7 June 2016 SmPC

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 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

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

Free text change information supplied by the pharmaceutical company

4.1 Therapeutic Indications
– addition of examples of infections to align information for all products in range

4.2 Posology and Method of Administration
- update of dosing in adolescents (12-18 years) for IV formulation

4.3 Contraindications
– addition of cross references to other sections of SPC

4.5 Interaction with other medicinal products and other forms of interaction
- addition of cross reference to other section of SPC
4.8 Undesirable effects
– correction of footnotes of the AE table
- deletion of text regarding insufficient data for IV dosing in patients less than 18 years

Updated on 3 June 2016 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions

Updated on 18 January 2016 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • 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 4.8 - Undesirable effects

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

Free text change information supplied by the pharmaceutical company

- In section 2 - Addition of excipient quantity statement for sodium
- In section 4.1 -
addition of notes re Sensitivity Testing for certain indications
- In section 4.3 - update regarding QT prolongation
- In section 4.4 - update regarding oromucosal midazolam, deletion of warning for ototoxic drugs (aminoglycoside), update regarding QT prolongation, deletion of Henoch-Schonlein purpura,
- In section 4.5 - addition of interaction re oral midazolam, addition of interaction with quetiapine, deletion of interation with aminoglycosides, update of colchicine interaction
- In section 4.8 - deletion of ADR "screaming", addition of "ventricular fibrillation"

Updated on 15 January 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to drug interactions

Updated on 21 April 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number

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

Free text change information supplied by the pharmaceutical company

Section 7: Update the Marketing Authorisation Holder from Abbott Laboratories Ireland Ltd. to BGP Products Ireland Limited. 

Section 8: Update the Product Authorisation no. from PA 38/51/3 to PA 2010/4/3

Updated on 20 April 2015 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 9 April 2015 SmPC

Reasons for updating

  • 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 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect

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

Free text change information supplied by the pharmaceutical company

- Section 4.3: Addition of contraindication for ticagrelor and ranolazine. Update of contraindication for colchicine.
- Section 4.4: Deletion of 'exacerbation of symptoms of myasthenia gravis. Update of information relating to colchicine, QT prolongation, statins and oral hypoglycaemic agents/insulin.
- Section 4.5: Addition of information regarding HMG-CoA Reductase Inhibitors (statins), dispyramide, oral hypoglycaemic agents/insulin, aminoglycosides, calcium channel blockers. Deletion of information regarding verapamil.
- Section 4.6: Update of pregancy information.
- Section 4.8: Deletion of erythrasma, hypoglycaemia, Henoch-Schonlein purpura. Addition of angioedema. Update of sections 'Description of selected adverse reactions' and 'Paediatric populations' and 'Immunocompromised patients'. Addition of text for 'Reporting of suspected adverse reactions'

Updated on 31 March 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to drug interactions
  • Addition of information on reporting a side effect.

Updated on 20 February 2015 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • 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 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.6 - Special precautions for disposal and other handling

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

Free text change information supplied by the pharmaceutical company

Section 2: Addition of sodium content statement
Section 4.2: Instructions for Preparation for Use deleted (moved to section 6.6), 
Section 4.3: Addition of contraindication for concomitant administration with oral midazolam
Section 4.4: Clarification regarding intravenous midazolam, addition of sodium content warning
Section 4.5: Minor amendments
Section 4.8: Addition of mania
Section 5.1: Addition of pharmacotherapeutic group, ATC code and other information
Section 6.6: Addition of Instructions for Preparation for Use (moved from section 4.2 & updated)

Updated on 19 February 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to drug interactions

Updated on 20 February 2013 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

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

Free text change information supplied by the pharmaceutical company

- Section 4.3: Update of text regarding statins and risk of myopathy
- Section 4.4: Update of warning regarding statins
- Section 4.8: Addition of paraesthesia
- Other minor corrections to text throughout the SPC

Updated on 18 February 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to drug interactions

Updated on 21 August 2012 SmPC

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 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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

Free text change information supplied by the pharmaceutical company

4.1 Therapeutic Indications

The following text has been deleted:

Clarithromycin IV is indicated in adults and children 12 years and older.

4.2 Posology and method of administration

Adults has been defined as ‘adults 18 years of age or older’.

‘Children under 12 years’ has been changed to ‘children’ and the following paragraph about children have been added:
There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age (see Klacid Paediatric Suspension).

The following paragraphs have been deleted:

Use of clarithromycin IV is not recommended for children younger than 12 years. Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension (granules for oral suspension).

Children under 12 years: As for adults.

4.3 Contraindications

The following sentences have been added:

Concomitant administration of clarithromycin with lovastatin or simvastatin is also contraindicated.

Colchicine is contraindicated in patients with renal or hepatic impairment who are taking P-glycoprotein or a strong CYP3A4 inhibitor.

4.4 Special warnings and precautions for use

The following paragraph has been added:

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

The following text has been deleted:

coronary artery disease, severe cardiac insufficiency, hypomagnesemia, bradycardia (<50 bpm), or when co-administered with other medicinal products associated with

The following paragraphs has been added:

a medical condition associated with an increased tendency toward QT prolongation and torsades de pointes.

(see section 4.5). Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).

DRESS and Henoch-Schonlein purpura have been added as hypersensitivity reactions.

4.5 Interaction with other medicinal products and other forms of interaction

The following paragraph has been added:

Etravirine
Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.

4.6 Pregnancy and lactation

The title ‘Pregnancy’ has been added.

The following text has been deleted:

Breast-feeding of infants

Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded.

The following text has been added:

Lactation

The safety of clarithromycin use during breast-feeding of infants has not been established.

b. Tabulated summary of adverse reactions

Henoch-Schonlein purpura has been added under Not Known for Skin and subcutaneous tissue disorders.

The following text has been added under the adverse reactions table:

* Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin.
** In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol.

c. Description of selected adverse reactions

The following paragraphs have been deleted:

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.

In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications (see section 4.4).

A special attention to diarrhoea should be paid as Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. (see section 4.4)

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated (see section 4.4).

As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely been reported with clarithromycin (see section 4.4 and 4.5).

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents (see section 4.4).

In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).
Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.

In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications (see section 4.4).

A special attention to diarrhoea should be paid as Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. (see section 4.4)

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated (see section 4.4).

As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely been reported with clarithromycin (see section 4.4 and 4.5).

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents (see section 4.4).

In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).

The following text has been deleted:

There have been rare reports of hypoglycemia, some of which have occurred in patients on concomitant oral hypoglycemic agents or insulin (see section 4.4 and 4.5).

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).

There is a risk of serious haemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently (see section 4.4 and 4.5).

d. Paediatric populations

The following text has been deleted:

Special population: Adverse Reactions in Immunocompromised Patients (see section e)

2000mg

The incidences were comparable for patients treated with 100mg and 200mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg of clarithromycin.

Slightly higher incidences of abnormal values were noted for patients who received 4000mg daily for all parameters except White Blood Cell.

10. Date of revision of the text

The date has been updated to July 2012.

Updated on 15 August 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to drug interactions
  • Change to date of revision

Updated on 18 August 2011 PIL

Reasons for updating

  • Change due to user-testing of patient information

Updated on 1 March 2011 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

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

Free text change information supplied by the pharmaceutical company

Section 4.2: Correction of error in text - "Children under 12 years: As for adults" should read "Children over 12 years: As for adults"

Updated on 18 February 2011 SmPC

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

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

Free text change information supplied by the pharmaceutical company

Update of the SPC sections 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 & 4.9.

Updated on 26 January 2011 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 22 October 2010 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life

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

Free text change information supplied by the pharmaceutical company

In section 6.3 (shelf-life), the shelf life has been changed from 4 years to 3 years.

Updated on 14 October 2010 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.4 - Special precautions for storage

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

Free text change information supplied by the pharmaceutical company

Section 2: Addition of text 'For full list of excipients, see section 6.1'
Section 6.2: Addition of text 'See section 6.6'
Section 6.4: Addition of text 'Keep vial in the outer carton in order to protect from light'.

Updated on 15 January 2010 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 9 November 2009 SmPC

Reasons for updating

  • 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 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

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

Free text change information supplied by the pharmaceutical company

4.3       Contraindications

 

Klacid IV for Infusion is contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs.

 

Use in patients with serious impairment of hepatic function.

 

Clarithromycin and ergot derivatives should not be co-administered.

 

Concomitant administration of clarithromycin and any of the following drugs is contraindicated:  astemizole, cisapride, pimozide and terfenadine.  Elevated cisapride, pimozide and terfenadine levels have been reported in patients receiving either of these drugs and clarithromycin concomitantly.  This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsade de pointes.  Similar effects have been observed with concomitant administration of astemizole and other macrolides.

 

 

 

 

 

 

 

 

 

4.4       Special warnings and precautions for use

 

The physician should not prescribe clarithromycin I.V. to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy.

 

Clarithromycin is principally excreted by the liver and kidney. Caution should be exercised in administering this antibiotic to patients with impaired hepatic and renal function or those concomitantly receiving potentially hepatotoxic drugs.

 

Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

 

Prolonged or repeated use of clarithromycin may result in overgrowth of non-susceptible bacteria.   If super-infection occurs, clarithromycin should be discontinued and appropriate therapy instituted.

 

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5).

 

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile.

 

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.

 

Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin therapy.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

 

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects:

 

Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients, taking clarithromycin and pimozide concomitantly (see section 4.3, Contraindications).

 

Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see section 4.3, Contraindications). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin (tablets) and terfenadine resulted in a 2 to 3-fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect.  Similar effects have been observed with concomitant administration of astemizole and other macrolides.

 

Ergotamine/dihydroergotamine

Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3, Contraindications).

Effects of Other Medicinal Products on Clarithromycin

The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-(R)-hydroxy-cvlarithromycin (14-OH-clarithromycin), a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

 

Ritonavir

A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 gm/day should not be coadministered with ritonavir.

 

Effect of Clarithromycin on Other Medicinal Products

 

Antiarrhythmics

There have been postmarketed reports of torsade de points occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum levels of these medications should be monitored during clarithromycin therapy.

 

CY3A4-based interactions

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

 

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

 
HMG-CoA Reductase Inhibitors

As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

 

Omeprazole

Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.

 

Oral anticoagulants

Spontaneous reports in the post-marketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously.

 

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.

 

Theophylline, carbamazepine

       Results of clinical studies indicate that there was a modest but statistically significant (p≤ 0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin.

 

       Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.

 

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

 

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

 

Other drug interactions

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4 Warnings and Precautions).

 

Digoxin

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

 

Zidovudine

       Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine.

 

       Bi-directional drug interactions

       Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

 

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.

 

Saquinavir

            Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see section 4.4 Warnings and Precautions). Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with the combination therapy of saquinavir and ritonavir, therefore when this combination therapy is co-administered with clarithromycin consideration should be given to the potential effects of ritonavir on clarithromycin (see Section 4.5-Ritonavir).

 

 

Verapamil

Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.

 

No clinically relevant studies addressing physical compatability of clarithromycin with other intravenous admixtures have been performed at this time.

4.8       Undesirable effects

 

Table 1 displays adverse events reported in patients administered clarithromycin I.V.during clinical studies as well as events seen with oral formulation. Adverse events are displayed by body system and frequency (common ≥ 1/100, < 1/10).

 

Table 1.

Adverse Events Reported in Clinical Studies

System Organ Class

Frequency

Adverse Events

 

Nervous system disorders

 

Common

headache

taste perversion

Gastrointestinal disorders

Common

diarrhoea

nausea

abdominal pain

dyspepsia

vomiting

General disorders and administration site conditions*

Common

injection site inflammation

tenderness

phlebitis

pain

Investigations

Common

hepatic enzyme increased

* specific to calrithromycin I.V.

 

Post Marketing Experience

 

Clarithromycin is marketed in several different formulations. Table 2 is a compilation of adverse reactions for all formulations including clarithromycin I.V. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin.

 

Table 2

Adverse Reactions from Post-Marketing Surveillance

 

System Organ Class

Adverse Reaction

Infections and infestations

oral candidiasis

Blood and lymphatic system disorders

leukopaenia

thrombocytopaenia

Immune System disorders

anaphylactic reaction hypersensitivity

Metabolism and nutrition disorders1

hypoglycaemia

Psychiatric disorders

psychotic disorder

hallucination

 

disorientation

 

confusional state

 

depersonalization

depression

anxiety

insomnia

abnormal dreams

Nervous system disorders

Convulsion

dizziness

ageusia

anosmia

dysgeusia

parosmia

Ear and labyrinth disorders

deafness

vertigo

tinnitus

Cardiac disorders2

torsade de pointes

electrocardiogram QT prolonged

ventricular tachycardia

Gastrointestinal disorders

pancreatitis acute

glossitis

stomatitis

tongue discoloration

tooth discoloration

Hepatobiliary disorders3

hepatic failure

hepatitis

hepatitis cholestatic

jaundice cholestatic

jaundice hepatocellular

hepatic function abnormal

Skin and subcutaneous tissue disorders

Stevens-Johnson syndrome

toxic epidermal necrolysis

urticaria

rash

Musculoskeletal and connective tissue disorders

myalgia

Renal and urinary disorders

nephritis interstitial

Investigations

blood creatinine increase

hepatic enzyme increased

1 There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin.

2 As with other macrolides, QT prolongation, ventricular tachycardia, and torsades de pointes have rarely been reported with clarithromycin.

3 In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

 

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see sections 4.4 Warnings and Precautions and 4.5 Interaction with other medicinal products and other forms of interactions).

Adverse events in immunocompromised patients:  Although there are currently no data regarding use of clarithromycin I.V. in this patient population, data are available regarding the use of oral clarithromycin in HIV-infected patients.

 

In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness.  

 

In adult patients, the most frequently reported adverse events by patients treated with total daily doses of 1000 mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, SGOT and SGPT elevations.  Additional low-frequency events included dyspnoea, insomnia and dry mouth.  The incidences were comparable for patients treated with 1000mg and 2000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg of clarithromycin.    

 

In these immuncompromised patients evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test.  On the basis of these criteria, about 2% to 3% of those patients who received 1000mg or 2000mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts.  A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen (BUN) levels.  Slightly higher incidences of abnormal values were noted for patients who received 4000mg daily for all parameters except WBC.



5.1       Pharmacodynamic properties

 

Clarithromycin is a semi-synthetic derivative of erythromycin A.  It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis.  Clarithromycin demonstrates excellent in vitro activity against standard strains of clinical isolates.  It is highly potent against a wide variety of aerobic and anaerobic gram positive and negative organisms.  The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.

 

The 14-(R)-hydroxy metabolite of clarithromycin, formed in man by first pass metabolism also has anti-microbial activity.  The MICs of this metabolite are equal to or two-fold higher than the MICs of the parent compound except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

 

Klacid IV for Infusion is usually active against the following organisms in vitro. Please see below for table of MIC breakpoints.

 

Gram-positive Bacteria:  Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococcus (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

 

Gram-negative Bacteria:  Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae; Legionella pneumophila, Bordetella pertussis, Helicobacter pylori; Campylobacter jejuni.

 

Mycoplasma:  Mycoplasma pneumoniae; Ureaplasma urealyticum.

 

Other Organisms:  Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Chlamydia pneumoniae.

 

Anaerobes:  Macrolide-susceptible Bacteriodes fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.

 

Clarithromycin has bactericidal activity against several bacterial strains.  These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Morazella (Brahamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter spp.

 

The activity of clarithromycin against H. pylori is greater at neutral pH than at acid pH.

 

Breakpoints

The following breakpoints for clarithromycin, separating susceptible organisms from resistant organisms, have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST).

Breakpoints (MIC, μg/ml)

Microorganism

Susceptible (£)

Resistant (>)

Streptococcus spp.

0.25 mg/ml

0.5 mg/ml

Staphylococcus spp.

1 mg/ml

2 mg/ml

Haemophilus spp.

1 mg/ml

32 mg/ml

Moraxella catarrhalis

0.25 mg/ml

0.5 mg/ml

Clarithromycin is used for the eradication of H. pylori; minimum inhibitory concentration (MIC) ≤ 0.25 mg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory Standards Institute (CLSI).

Updated on 6 October 2009 PIL

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Updated on 24 July 2007 PIL

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Updated on 11 May 2006 SmPC

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Updated on 21 April 2006 SmPC

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Updated on 25 October 2005 SmPC

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Updated on 6 September 2005 SmPC

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