Ciproxin 500mg Film-coated Tablets *

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 take Ciproxin

[….]

Talk to your doctor before taking 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 taking 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.

 

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below).via HPRA Pharmacovigilance Website: www.hpra.ie. By reporting side effects you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

 

Malta:

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

 

[….]

 

This leaflet was last revised in October 2020November2019.

 

 

 

 

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

System Organ Class	Common ≥ 1/100 to < 1/10	Uncommon ≥ 1/1,000 to < 1/100	Rare ≥ 1/10,000 to < 1/1,000	Very Rare < 1/10,000	Frequency not known (cannot be estimated from the available data)
[….]
Cardiac Disorders**			Tachycardia		Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see sections 4.4 and 4.9)
Vascular Disorders**			Vasodilatation Hypotension Syncope	Vasculitis
[….]

 

[….]

** 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

November 2019October 2020

 

 

 

Section 4.4 - was amended as follows:

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.

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 November 2013

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

For thea full list of excipients, see section 6.1.

 

3.       PHARMACEUTICAL form

The tablets can be divided into equal doseshalves.

 

 

4.2       Posology and method of administration

 

Posology

 

 

Paediatric populationChildren and adolescents

 

Indications	Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Cystic fibrosis	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	10 to 14 days
Complicated urinary tract infections and pyelonephritis	10 mg/kg body weight twice daily to 20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	10 to 21 days
Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure.	10 mg/kg body weight twice daily to 15 mg/kg body weight twice daily with a maximum of 500 mg per dose.	60 days from the confirmation of Bacillus anthracis exposure
Other severe infections	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	According to the type of infections

 

Elderly Geriatric patients

Elderly Geriatric 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

 

 

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.

The single dose of ciprofloxacin, that may be used in uncomplicated cystitis in pre-menopausal women, is expected to be associated with lower efficacy than with the longer treatment duration. This is all the more to be taken into account as regards the increasing resistance level of Escherichia coli to quinolones.

 

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

 

Chelation Complex Formation

The simultaneous administration of ciprofloxacin (oral) and multivalent cation-containing drugs and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer or lanthanum carbonate), sucralfate or antacids, and highly buffered drugs (e.g. didanosine tablets) containing magnesium, aluminium, or calcium reduces the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1‑2 hours before or at least 4 hours after these preparations. The restriction does not apply to antacids belonging to the class of H2 receptor blockers

 

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.

 

System Organ Class	Common ≥ 1/100 to < 1/10	Uncommon ≥ 1/1, 000 to < 1/100	Rare ≥ 1/10 ,000 to < 1/1 ,000	Very Rare < 1/10 ,000	Frequency not known (cannot be estimated from the available data)
Infections and Infestations		Mycotic superinfections	Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4)
Blood and Lymphatic System Disorders		Eosinophilia	Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopenia Thrombocytaemia	Haemolytic anaemia Agranulocytosis Pancytopenia (life-threatening) Bone marrow depression (life-threatening)
Immune System Disorders			Allergic reaction Allergic oedema / angiooedema	Anaphylactic reaction Anaphylactic shock (life-threatening) (see section 4.4) Serum sickness-like reaction
Metabolism and Nutrition Disorders		Decreased appetiteAnorexia	Hyperglycaemia Hypoglycaemia (see section 4.4)
Psychiatric Disorders		Psychomotor hyperactivity / agitation	Confusion and disorientation Anxiety reaction Abnormal dreams Depression (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4) Hallucinations	Psychotic reactions (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4)
Nervous System Disorders		Headache Dizziness Sleep disorders Taste disorders	Par- and Dysaesthesia Hypoaesthesia Tremor Seizures (incl. status epilepticus see section 4.4) Vertigo	Migraine Disturbed coordination Gait disturbance Olfactory nerve disorders Intracranial hypertension and pseudotumor cerebri	Peripheral neuropathy and polyneuropathy (see section 4.4)
Eye Disorders			Visual disturbances (e.g. diplopia)	Visual colour distortions
Ear and Labyrinth Disorders			Tinnitus Hearing loss / Hearing impaired
Cardiac Disorders			Tachycardia		Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see sections 4.4 and 4.9)
Vascular Disorders			Vasodilatation Hypotension Syncope	Vasculitis
Respiratory, Thoracic and Mediastinal Disorders			Dyspnoea (including asthmatic condition)
Gastrointestinal Disorders	Nausea Diarrhoea	Vomiting Gastrointestinal and abdominal pains Dyspepsia Flatulence		Pancreatitis
Hepatobiliary Disorders		Increase in transaminases Increased bilirubin	Hepatic impairment Cholestatic icterus Hepatitis	Liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section 4.4)
Skin and Subcutaneous Tissue Disorders		Rash Pruritus Urticaria	Photosensitivity reactions (see section 4.4)	Petechiae Erythema multiforme Erythema nodosum Stevens-Johnson syndrome (potentially life-threatening) Toxic epidermal necrolysis (potentially life-threatening)	Acute generalised exanthematous pustulosis (AGEP)
Musculoskeletal, and Connective Tissue and Bone Disorders		Musculoskeletal pain (e.g. extremity pain, back pain, chest pain) Arthralgia	Myalgia Arthritis Increased muscle tone and cramping	Muscular weakness Tendinitis Tendon rupture (predominantly Achilles tendon) (see section 4.4) Exacerbation of symptoms of myasthenia gravis (see section 4.4)
Renal and Urinary Disorders		Renal impairment	Renal failure Haematuria Crystalluria (see section 4.4) Tubulointerstitial nephritis
General Disorders and Administration Site Conditions		Asthenia Fever	Oedema Sweating (hyperhidrosis)
Investigations		Increase in blood alkaline phosphatase	Increased amylase		International normalised ratio increased (in patients treated with Vitamin K antagonists)

 

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

Red text = text removed

Blue text = text added in

 

Section 4.1 Therapeutic indications

·               Gonococcal uretritis and cervicitis

 

·               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

·   gonococcal uretritis and cervicitis due to susceptible Neisseria gonorrhoeae

·   epididymo-orchitis including cases due to susceptible Neisseria gonorrhoeae

·   pelvic inflammatory disease including cases due to susceptible Neisseria gonorrhoeae

          …………………………………………………………

·               Treatment of infections in neutropenic patients

 

·                Prophylaxis of infections in neutropenic patients

.............................................................................................

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

 

 

Section 4.2 Posology and method of administration

………………………………………………….

Indications		Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin
Urinary tract infections (see section 4.4)	Uncomplicated cystitis	250 mg twice daily to 500 mg twice daily	3 days
	Complicated cystitis, Uncomplicated pyelonephritis	In pre-menopausal women, 500 mg single dose may be used
	Complicated pyelonephritis	500 mg twice daily	7 days
	Prostatitis	500 mg twice daily to 750 mg twice daily	2 to 4 weeks (acute) to 4 to 6 weeks (chronic)

…………………………………………………..

Indications	Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin
Treatment of infections or prophylaxis of infections in neutropenic patients Neutropenic patients with fever that is suspected to be due to a bacterial infection. Ciprofloxacin should be co-administered with appropriate antibacterial agent(s) in accordance to official guidance.	500 mg twice daily to 750 mg twice daily	Therapy should be continued over the entire period of neutropenia

…………………………………………………..

Section 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.

 

Gonococcal uretritis, cervicitis, epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae isolates.

Therefore, ciprofloxacin should be administered for the treatment of gonococcal uretritis or cervicitis only if ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded.

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.

The single dose of ciprofloxacin is expected to be associated with lower efficacy than with the longer treatment duration. This is all the more to be taken into account as regards the increasing resistance level of Escherichia coli to quinolones.

…………………………………………………………..

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).

……………………………………………………………

Central Nervous System

Ciprofloxacin like other Quinolones quinolones 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). Co-administration of ciprofloxacin and tizanidine is contra-indicated. Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary (see section 4.5).

………………………………………………….

 

Section 4.5 Interaction with other medicinal products and other forms of interactions

Effects of other 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).

 

…………………………………………..

 

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.

 

Omeprazole

Concomitant administration of ciprofloxacin and omeprazole containing medicinal products results in a slight reduction of Cmax and AUC of ciprofloxacin.

 

………………………………………………..

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 antagonists Oral Anticoagulants

Simultaneous administration of ciprofloxacin with warfarin a vitamin K antagonist may augment its anti-coagulant effects. There have been many reports of increases in oral anticoagulant 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 the fluroquinoloneciprofloxacin to the increase in INR (international normalised ratio) is difficult to assess. It is recommended thatThe INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant agent  a vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).

 

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).

 

………………………………………..

Lidocaine

It was demonstrated in healthy subjects that concomitant use of lidocaine containing medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.

 

………………………………………….

Sildenafil

Cmax and AUC of sildenafil were increased approximately twofold in healthy subjects after an oral dose of 50 mg given concomitantly with 500 mg ciprofloxacin. Therefore, caution should be used prescribing ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.

 

 

 

 

 

 

Section 4.8 Undesirable effects

………………………………….

System Organ Class	Common ≥ 1/100 to < 1/10	Uncommon ≥ 1/1 000 to < 1/100	Rare ≥ 1/10 000 to < 1/1 000	Very Rare < 1/10 000	Frequency not known (cannot be estimated from available data)
Psychiatric Disorders		Psychomotor hyperactivity / agitation	Confusion and disorientation Anxiety reaction Abnormal dreams Depression (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4) Hallucinations	Psychotic reactions (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4)
Nervous System Disorders		Headache Dizziness Sleep disorders Taste disorders	Par- and Dysaesthesia Hypoaesthesia Tremor Seizures (incl. status epilepticus see section 4.4) Vertigo	Migraine Disturbed coordination Gait disturbance Olfactory nerve disorders Intracranial hypertension	Peripheral neuropathy (see section 4.4)
Eye Disorders			Visual disturbances (e.g. diplopia)	Visual colour distortions
Cardiac Disorders					Ventricular arrhythmia, and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see section 4.4 and 4.9) QT prolongation, torsades de pointes*
Skin and Subcutaneous Tissue Disorders		Rash Pruritus Urticaria	Photosensitivity reactions (see section 4.4)	Petechiae Erythema multiforme Erythema nodosum Stevens-Johnson syndrome (potentially life-threatening) Toxic epidermal necrolysis (potentially life-threatening)	Acute generalised exanthematous pustulosis (AGEP)
Investigations		Increase in blood alkaline phosphatase	Prothrombin level abnormal Increased amylase		International normalised ratio increased (in patients treated with Vitamin K antagonists)

*        These events were reported during the postmarketing period and were observed predominantly among patients with further risk factors for QT prolongation (see section 4.4).

 

Section 4.9 Overdose

…………………………

Apart from routine emergency measures, e.g. ventricular emptying followed by medical carbon, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids may theoretically reduce the absorption of ciprofloxacin in overdoses.

Only a small quantity of ciprofloxacin (<10%) is eliminated by haemodialysis or peritoneal dialysis.

 

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.

 

Section 5.1 Pharmacodynamic properties

……………………………….

EUCAST Recommendations

 

Microorganisms	Susceptible	Resistant
Enterobacteriaceae	S ≤0.5 mg/L	R > 1 mg/L
Pseudomonas spp.	S ≤ 0.5 mg/L	R > 1 mg/L
Acinetobacter spp.	S ≤ 1 mg/L	R > 1 mg/L
Staphylococcus spp.1	S ≤ 1 mg/L	R > 1 mg/L
Haemophilus influenzae and Moraxella catarrhalis	S ≤ 0.5 mg/L	R > 0.5 mg/L
Neisseria gonorrhoeae	S ≤ 0.03 mg/L	R > 0.06 mg/L
Neisseria meningitidis	S ≤ 0.03 mg/L	R > 0.06 mg/L
Non-species-related breakpoints*	S ≤ 0.5 mg/L	R > 1 mg/L
1     Staphylococcus spp. - breakpoints for ciprofloxacin relate to high dose therapy. *    Non-species-related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended.

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 20th December 1988

Date of last renewal: 20^th December 2008 9^th October 2010

 

 

Section 10. Date of Revision of the text

September 2010

November 2012

Superceded Text: June 2010	Updated text: October 2010
2.         QUALITATIVE AND QUANTITATIVE COMPOSITION	2.         QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 582.0mg ciprofloxacin hydrochloride equivalent to 500mg Ciprofloxacin.   For a full list of excipients, see Section 6.1.	Each film-coated tablet contains 500 mg ciprofloxacin (as hydrochloride).   For a full list of excipients, see section 6.1.
3.       PHARMACEUTICAL form	3.       PHARMACEUTICAL form
Film-coated tablet, oblong, white to slightly yellow, marked with 'Bayer' on one face and 'CIP 500' and a scoreline on the reverse.	Film-coated tablet   Oblong, nearly white to slightly yellowish tablets marked with “CIP score 500” on one side and “BAYER” on the reverse side.   The tablets can be divided into equal halves.
6.1     List of excipients	6.1     List of excipients
Each tablet core contains: microcrystalline cellulose, maize starch, crospovidone, silica, colloidal anhydrous, magnesium stearate.   The tablet film-coat consists of a mixture of: hypromellose 2910, Macrogol 4000, titanium dioxide (E171).	Tablet core : Cellulose microcrystalline Crospovidone Maize starch Magnesium stearate Silica colloidal anhydrous   Film-coat: Hypromellose Macrogol 4000 Titanium dioxide (E171)
6.4     Special precautions for storage	6.4     Special precautions for storage
No special storage precautions are necessary.	This medicinal product does not require any special storage conditions.
6.5       Nature and contents of container	6.5       Nature and contents of container
Blister strips in cardboard outers comprising:   a) 250µm, 40g/m2 PVC/PVDC foil with 20µm hard aluminium backing foil.   Pack sizes 10, 20, 100 tablets.   b) 300µm polypropylene foil with 20µm hard aluminium backing foil with a 3.5g/m2 heat seal polypropylene coating.   Pack sizes: 10, 20, 100 tablets.   Not all pack sizes may be marketed.	One of the following primary packaging materials is used:   Transparent colourless or white opaque PVC/PVDC/Aluminum blister Transparent colourless or white opaque PP/Aluminum blister Aluminum/Aluminum blister   Pack sizes of 6, 8, 10, 12, 14, 16, 20, 28, 50, 100, 160 or 500 film-coated tablets   Not all pack sizes may be marketed.
10.     DATE OF REVISION OF THE TEXT	10.     DATE OF REVISION OF THE TEXT
June 2010	September 2010

 

None provided