Reasons for change (PIL):

- Update to section 2 of the PL to implement the revised Annex to the European Commission guideline on “Excipients in the labelling and package leaflet of medicinal products for human use” with regards to the excipient sodium.

- a statement related to psychiatric reactions in section 2 of the PL is rephrased

- Split of the combined (100ml +200ml) PIL, so that the PIL covers the 200ml bottle only.

Package leaflet: Information for the patient

Ciproxin Solution for Infusion 2mg/ml, 100ml, 200ml

2. What you need to know before you are given Ciproxin

[…]

While under treatment with Ciproxin

[…]

• You may experience psychiatric reactions even when taking quinolone antibiotics, including Ciproxin, for theafter first administration of ciprofloxacintime. If you suffer from depression or psychosis, your symptoms may become worse under treatment with Ciproxin. In rare cases, depression or psychosis can progress to suicidal thoughts of suicide, and self-injurious behaviors such as suicide attempts, or completed suicide (see section 4: Possible side effects). If this happens, depression, psychosis, suicide-related thoughts or behavior occur, contact your doctor immediately.

[…]

Ciproxin contains sodium

Ciproxin Solution for Infusion 2mg/ml contains 154mmol sodium per litre. The 100ml bottle contains 15.4mmol sodium (equivalent to 354mg sodium, 900mg sodium chloride) and the 200ml bottle 31 mmol sodium (equivalent to 708mg sodium, 1800mg sodium chloride). To be taken into consideration by patients on a controlled sodium diet.This medicine contains 708.1 mg sodium (main component of cooking/table salt) in each vial. This is equivalent to 35.4 % of the recommended maximum daily dietary intake of sodium for an adult.

The maximum recommended daily dose of this medicinal product contains 2124.6 mg sodium (found in table salt). This is equivalent to 106.2 % of the adult recommended maximum daily dietary intake for sodium.

Talk to your pharmacist or doctor if you need Ciproxin on a daily basis for a prolonged period of time, especially if you have been advised to have a low salt diet.

6. Contents of the pack and other information

What Ciproxin contains

The active substance is ciprofloxacin.

Each glass bottle with 100 mL infusion solution contains 200 mg of ciprofloxacin.

Each glass bottle with 200 mL infusion solution contains 400 mg of ciprofloxacin.

[…]

What Ciproxin looks like and contents of the pack

[…]

Pack sizes of 1, 5 or 40 bottles containing 100 mL of solution for infusion each

Pack sizes of 1 or 5 bottles containing 200 mL of solution for infusion each

[…]

Marketing Authorisation Holder and Manufacturer

Product Authorisation Holder:

Bayer Limited

The Atrium,

Blackthorn Road,

Dublin 18,

Ireland.

[…]

This medicinal product is authorised in the Member States of the EEA under the following names:

Belgium:              Ciproxine

Cyprus                 Ciproxin

France:                 Ciflox

Germany:             Ciprobay

Greece:                Ciproxin

Ireland:                Ciproxin

Italy:                    Ciproxin

Luxembourg:        Ciproxine

Malta:                   Ciproxin

United Kingdom:  Ciproxin

This leaflet was last revised in October 2020December 2020.

Ciproxin 200 ml SFI

Reasons for change (SmPC):

- Update to sections 2 and 4.4 of the SmPC to implement the revised Annex to the European Commission guideline on “Excipients in the labelling and package leaflet of medicinal products for human use” with regards to the excipient sodium.

- a statement related to psychiatric reactions in section 4.4 of the SmPC is rephrased.

- instructions for visual inspection are added in section 6.6 of the SmPC, in line with the already approved wording in section 4.2.

SmPC

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

[…]

Excipient with known effect: sodium.

4.4 Special warnings and precautions for use

[…]

Psychiatric reactions

Psychiatric reactions may occur even after first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to suicidal ideations/thoughts culminating in attempted suicide or completed suicide. In the occurrence of such cases If depression, psychotic reactions, suicide-related thoughts or behavior occur, ciprofloxacin should be discontinued.

[…]

Information about excipients

NaCl Load

This medicinal product contains 708.1 mg sodium per glass bottle, equivalent to 35.4 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. The maximum daily dose of this product is equivalent to 106.2 % of the WHO recommended maximum daily intake for sodium. Ciproxin is considered high in sodium. This should be particularly taken into account for those on a low salt diet, i.eIn patients for whom sodium intake is of medical concern (patients with congestive heart failure, renal failure, nephrotic syndrome, etc.), the additional sodium load should be taken into account (for sodium chloride content, see section 2).

6.6 Special precautions for disposal and other handling

[…]

At cool temperatures precipitation may occur, which will re-dissolve at room temperature (15 °C ‑ 25 °C). The product should be inspected visually for particles prior to administration. Only clear solution free from particles should be used.

10. DATE OF REVISION OF THE TEXT

November 2019December 2020

Reason for update:

PRAC: Implementation of label changes after PRAC recommendation on signal of heart valve regurgitation, cervical artery & aortic aneurysm and dissection (EPITT 19522)

2. What you need to know before you are given Ciproxin

[….]

Talk to your doctor before you are given Ciproxin

[….]

• if you have been diagnosed with leaking heart valves (heart valve regurgitation).

• if you have a family history of aortic aneurysm or aortic dissection or congenital heart valve disease, or other risk factors or predisposing conditions (e.g. connective tissue disorders such as Marfan syndrome, or vascular Ehlers-Danlos syndrome, Turner syndrome, Sjögren’s syndrome [an inflammatory autoimmune disease], or vascular disorders such as Takayasu arteritis, giant cell arteritis, Behcet´s disease, high blood pressure, or known atherosclerosis, rheumatoid arthritis [a disease of the joints] or endocarditis [an infection of the heart]).

[….]

While under treatment with Ciproxin

[….]

• If you feel sudden, severe pain in your abdomen, chest or back, which can be symptoms of aortic aneurysm and dissection, go immediately to an emergency room. Your risk may be increased if you are being treated with systemic corticosteroids.

• If you start experiencing a rapid onset of shortness of breath, especially when you lie down flat in your bed, or you notice swelling of your ankles, feet or abdomen, or a new onset of heart palpitations (sensation of rapid or irregular heartbeat), you should inform a doctor immediately.

4. Possible side effects

[….]

Cases of an enlargement and weakening of the aortic wall or a tear in the aortic wall (aneurysms and dissections), which may rupture and may be fatal, and of leaking heart valves have been reported in patients receiving fluoroquinolones. See also section 2.

[….]

This leaflet was last revised in October 2020November 2019.

Reason for update:

PRAC: Implementation of label changes after PRAC recommendation on signal of heart valve regurgitation, cervical artery & aortic aneurysm and dissection (EPITT 19522)

4.4 Special warnings and precautions for use

[….]

Aortic aneurysm and dissection, and heart valve regurgitation/incompetence

Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones, particularly in the older population. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or dissection or heart valve disease, or in presence of other risk factors or conditions predisposing:

- for both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome or, vascular Ehlers-Danlos syndrome, Turner syndromeTakayasu arteritis, giant cell arteritis, Behcet´s disease, hypertension, rheumatoid arthritisknown atherosclerosis). or additionally

- for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome) or additionally

- for heart valve regurgitation/incompetence (e.g. infective endocarditis).

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.

4.8 Undesirable effects

[….]

** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.4).

10. DATE OF REVISION OF THE TEXT

October 2020November 2019

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