Section 4.4 - was amended as follows:

Reference added to section 4.8, in the final line of the ‘Paediatric population’ paragraph

Cytochrome P450

Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine).


Section 4.5 - the following text was added:  

Agomelatine

In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2

isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of

agomelatine exposure. Although no clinical data are available for a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant administration (see ‘Cytochrome P450’ in section 4.4).

Zolpidem

Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not

recommended.

Section 4.8 - was amended as follows:

- Antibiotic associated colitis deleted under SOC “Infections and Infestations” and moved to SOC

“Gastrointestinal disorders”

-Addition of mania/hypomania

- Addition of DRESS to ADR list

- “arthralgia” and “arthritis” in brackets after the term “arthropathy”

Section 4.4 - was amended as follows:

Reference added to section 4.8, in the final line of the ‘Paediatric population’ paragraph

Cytochrome P450

Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine).


Section 4.5 - the following text was added:  

Agomelatine

In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2

isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of

agomelatine exposure. Although no clinical data are available for a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant administration (see ‘Cytochrome P450’ in section 4.4).

Zolpidem

Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not

recommended.

Section 4.8 - was amended as follows:

- Antibiotic associated colitis deleted under SOC “Infections and Infestations” and moved to SOC

“Gastrointestinal disorders”

-Addition of mania/hypomania

- Addition of DRESS to ADR list

- “arthralgia” and “arthritis” in brackets after the term “arthropathy”

In section 4.4 Special warnings and precautions for use, the following section has been added:

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.

In section 4.8, the following text has been added:

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. By reporting side effects you can help provide more information on the safety of this medicine.

In section 4.4 Special warnings and precautions for use, the following section has been added:

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.

In section 4.8, the following text has been added:

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. By reporting side effects you can help provide more information on the safety of this medicine.

Section 4.8:

Update to the wording of section 4.8, subsection Reporting of suspected adverse reactions to:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.  

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Section 10:

Update of date of revision of the text to December 2013

Section 4.8:

Update to the wording of section 4.8, subsection Reporting of suspected adverse reactions to:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.  

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Section 10:

Update of date of revision of the text to December 2013

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

For thea full list of excipients, see section 6.1.

4.2       Posology and method of administration

Posology

Paediatric populationChildren and adolescents

ElderlyGeriatric patients

ElderlyGeriatric patients should receive a dose selected according to the severity of the infection and the patient`s creatinine clearance.

Patients with rRenal and hepatic impairment

Recommended starting and maintenance doses for patients with impaired renal function:

4.3     Contraindications

·                Hypersensitivity to the active substance, to other quinolones or to any of the excipients listed in (see section 6.1).

·                Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).

4.4     Special warnings and precautions for use

Paediatric populationChildren and adolescents

The use of ciprofloxacin in children and adolescents should follow available official guidance. Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.

Musculoskeletal System

Ciprofloxacin should be used with caution in patients with myasthenia gravis, because symptoms can be exacerbated (see section 4.8).

Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations.

(See section 4.2 ElderlyGeriatric patients, section 4.5, section 4.8, section 4.9).

Hypoglycemia

As with other quinolones, hypoglycemia has been reported most often in diabetic patients, predominantly in the elderly population. In all diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).

4.5     Interaction with other medicinal products and other forms of interaction

Glibenclamide

In particular cases, concurrent administration of ciprofloxacin and glibenclamide containing medicinal products can intensify the action of glibenclamide (hypoglycaemia).

4.6     Pregnancy and lactation

Breast-feedingLactation

Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.

4.8       Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.

ADRs derived from clinical studies and post-marketing surveillance with Ciproxin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.

Paediatric populationpatients

The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (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 to the Irish Medicines Board (online at www.imb.ie, telephone 01-6764971 or using the yellow card system).

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

via the national reporting system listed in Appendix V*

[*For the printed material, please refer to the guidance of the annotated QRD template.]

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Pharmacokinetic/pharmacodynamicPK/PD relationship:

Efficacy mainly depends on the relation between the maximum concentration in serum (C_max) and the minimum inhibitory concentration (MIC) of ciprofloxacin for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.

5.2     Pharmacokinetic properties

BiotransformationMetabolism

Low concentrations of four metabolites have been reported, which were identified as: desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.

10.     DATE OF REVISION OF THE TEXT

November 2012September 2013

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

For thea full list of excipients, see section 6.1.

4.2       Posology and method of administration

Posology

Paediatric populationChildren and adolescents

ElderlyGeriatric patients

ElderlyGeriatric patients should receive a dose selected according to the severity of the infection and the patient`s creatinine clearance.

Patients with rRenal and hepatic impairment

Recommended starting and maintenance doses for patients with impaired renal function:

4.3     Contraindications

·                Hypersensitivity to the active substance, to other quinolones or to any of the excipients listed in (see section 6.1).

·                Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).

4.4     Special warnings and precautions for use

Paediatric populationChildren and adolescents

The use of ciprofloxacin in children and adolescents should follow available official guidance. Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.

Musculoskeletal System

Ciprofloxacin should be used with caution in patients with myasthenia gravis, because symptoms can be exacerbated (see section 4.8).

Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations.

(See section 4.2 ElderlyGeriatric patients, section 4.5, section 4.8, section 4.9).

Hypoglycemia

As with other quinolones, hypoglycemia has been reported most often in diabetic patients, predominantly in the elderly population. In all diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).

4.5     Interaction with other medicinal products and other forms of interaction

Glibenclamide

In particular cases, concurrent administration of ciprofloxacin and glibenclamide containing medicinal products can intensify the action of glibenclamide (hypoglycaemia).

4.6     Pregnancy and lactation

Breast-feedingLactation

Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.

4.8       Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.

ADRs derived from clinical studies and post-marketing surveillance with Ciproxin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.

Paediatric populationpatients

The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (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 to the Irish Medicines Board (online at www.imb.ie, telephone 01-6764971 or using the yellow card system).

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

via the national reporting system listed in Appendix V*

[*For the printed material, please refer to the guidance of the annotated QRD template.]

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Pharmacokinetic/pharmacodynamicPK/PD relationship:

Efficacy mainly depends on the relation between the maximum concentration in serum (C_max) and the minimum inhibitory concentration (MIC) of ciprofloxacin for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.

5.2     Pharmacokinetic properties

BiotransformationMetabolism

Low concentrations of four metabolites have been reported, which were identified as: desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.

10.     DATE OF REVISION OF THE TEXT

November 2012September 2013

Changes for www.medicines.ie

Deleted text

Inserted text

4.             Clinical particulars

4.1          Therapeutic indications

Ciproxin Solution for Infusion 2mg/ml is indicated for the treatment of the following infections (see sections 4.4 and 5.1). Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy.

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

Adults

·         Lower respiratory tract infections due to Gram-negative bacteria

-          exacerbations of chronic obstructive pulmonary disease

-          broncho-pulmonary infections in cystic fibrosis or in bronchiectasis

-          pneumonia

·         Chronic suppurative otitis media

·         Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria

·         Urinary tract infections

·         Epididymo-orchitis including cases due to Neisseria gonorrhoeae

·         Pelvic inflammatory disease including cases due to Neisseria gonorrhoeae

In the above genital tract infections when thought or known to be due to Neisseria gonorrhoeae it is particularly important to obtain local information on the prevalence of resistance to ciprofloxacin and to confirm susceptibility based on laboratory testing.

•              Genital tract infections

-               epididymo-orchitis including cases due to susceptible Neisseria gonorrhoeae

-               pelvic inflammatory disease including cases due to susceptible Neisseria gonorrhoeae

·         Infections of the gastro-intestinal tract (e.g. travellers` diarrhoea)

·         Intra-abdominal infections

·         Infections of the skin and soft tissue caused by Gram-negative bacteria

·         Malignant external otitis

·         Infections of the bones and joints

·         Treatment of infections in neutropenic patients

·         Prophylaxis of infections in neutropenic patients

·         Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Ciprofloxacin may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

4.2          Posology and method of administration

…………………………….

………………………………

4.4          Special warnings and precautions for use

……………………………….

Genital tract infections

Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Ciprofloxacin should be co-administered with another appropriate antibacterial agent unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae isolates.

For epididymo-orchitis and pelvic inflammatory diseases, empirical ciprofloxacin should only be considered in combination with another appropriate antibacterial agent (e.g. a cephalosporin) unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Urinary tract infections

Resistance to fluoroquinolones of Escherichia coli – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in Escherichia coli to fluoroquinolones.

……………………..

Musculoskeletal System

Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.

Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin even within, as soon as the first 48 hours of treatment. Inflammation and ruptures of tendon may occur even up to several months after discontinuation of ciprofloxacin therapy. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).

At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest.

Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).

………………………………………..

Central Nervous System

Ciprofloxacin like other qQuinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to suicidal ideations/thoughts culminating in attempted suicide or completed suicide self-endangering behaviour. In the occurrence of such these cases, ciprofloxacin should be discontinued.

Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).

Cardiac disorders

Since ciprofloxacin is associated with cases of QT prolongation (see section 4.8), caution should be exercised when treating patients at risk for torsades de pointes arrhythmia.

Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:

-               congenital long QT syndrome

-               concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

-               uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)

-               cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)

Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations.

 (See section 4.2 Geriatric patients, section 4.5, section 4.8, section 4.9).

… ……………………………….

Impaired renal function

Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment is needed in patients with impaired renal function as described in section 4.2 to avoid an increase in adverse drug reactions due to accumulation of ciprofloxacin

……………….

Cytochrome P450

Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine)……….

4.5          Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on ciprofloxacin:

Drugs known to prolong QT interval

Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).

…………………………..

Cyclosporin

A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and cyclosporin containing medicinal products were administered simultaneously. Therefore, it is frequently (twice a week) necessary to control the serum creatinine concentrations in these patients.

Vitamin K antagonistsOral anticoagulants

Simultaneous administration of ciprofloxacin with a vitamin K antagonist warfarin may augment its anti-coagulant effects. There have been many reports of increases in oral anti-coagulant activity in patients receiving antibacterial agents, including fluoroquinolones. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin the fluoroquinolone to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that tThe INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with a vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione)an oral anticoagulant agent.

Glibenclamide

In particular cases, concurrent administration of ciprofloxacin and glibenclamide containing medicinal products can intensify the action of glibenclamide (hypoglycaemia).

Duloxetine

In clinical studies, it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration (see section 4.4).

Ropinirole

It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of C_max and AUC of ropinirole by 60% and