CIPROFLOXACIN TEVA ® INFUSION BAGS 2 MG/ML

Israel - English - Ministry of Health

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Active ingredient:
CIPROFLOXACIN AS LACTATE 2 MG / 1 ML
Available from:
SALOMON,LEVIN & ELSTEIN LTD
ATC code:
S03AA07
Pharmaceutical form:
SOLUTION FOR INFUSION
Administration route:
I.V
Manufactured by:
TEVA PHARMACEUTICAL WORKS PRIVATE LIMITED COMPANY, HUNGARY
Therapeutic group:
CIPROFLOXACIN
Therapeutic indications:
Adults:Uncomplicated and complicated infections caused by ciprofloxacin sensitive pathogens.Children: For the treatment of acute pulmonary exacerbation of cystic fibrosis associated with Pseudomonas aeroginosa infections in pediatric patients aged 5-17 years.
Authorization number:
146693316100
Authorization date:
2011-10-01

" עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי ." רשואמןולע : רבוטקוא 2011

“This leaflet format has been determined by the Ministry of Health and the content thereof

has been checked and approved.” Date of approval: October 2011.

SUMMARY OF PRODUCT CHARACTERSITICS

1. NAME OF THE MEDICINAL PRODUCT

Ciprofloxacin Teva infusion bags 2 mg/ml

Solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Ciprofloxacin , 2 mg per ml solution for intravenous infusion.

1 infusion bag of 100 ml contains ciprofloxacinlactate, equivalent to 200 mg ciprofloxacin.

1 infusion bag of 200 ml contains ciprofloxacinlactate, equivalent to 400 mg ciprofloxacin.

Excipients: contains 5 g of glucose per 100 ml solution.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for infusion.

Clear, colorless or slightly yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

UNCOMPLICATED AND COMPLICATED INFECTIONS CAUSED BY CIPROFLOXACIN SENSITIVE

PATHOGENS:

According toin-vitroinvestigations, the following pathogens can be regarded as sensitive:

E. coli, Shigella, Salmonella, Citrobacter, Klebsiella, Enterobacter, Serratia, Hafnia, Edwardsiella,

Proteus (indole-positive and indole-negative), Providencia, Morganella, Yersinia; Vibrio, Aeromonas,

Plesiomonas, Pasteurella, Haemophilus, Campylobacter, Pseudomonas, Legionella, Neisseria,

Moraxella, Acinetobacter, Brucella; Staphylococcus, Listeria, Corynebacterium, Chlamydia.

The following show varying degrees of sensitivity:

Gardnerella, Flavobacterium, Alcaligenes,Streptococcus agalactiae,Enterococcus faecalis,

Streptococcus pyogenes,Streptococcus pneumoniae, Viridans group streptococci,Mycoplasma

hominis, Mycobacterium tuberculosis, and Mycobacterium fortuitum.

The following are usually resistant:Enterococcus faecium, Ureaplasma urealyticum, Nocardia

asteroides.

With a few exceptions anaerobes are moderately sensitive e.g. Peptococcus, Peptostreptococcus to

resistant e.g.Bacteroides.

Ciprofloxacin is ineffective againstTreponema pallidum.

Children

For the treatment of acute pulmonary exacerbation of cystic fibrosis associated with Pseudomonas

aeruguinosa infection in paediatric patients aged 5-17 years. The use of ciprofloxacin for indications

other than the treatmentof acute pulmonary exacerbations ofcystic fibrosis caused by Pseudomonas

aeruginosa infections is not recommended.

Note:: Special attention must be given to the available information about resistance to ciprofloxacin

before the therapy is started.

Consideration must be given to the official guidelines on the appropriate use of antibacterial products.

4.2 Posology and method of administration

Adults

The dosage of intravenous ciprofloxacin is determined by the severity and type of infection, the

sensitivity of the causative organism(s) and theage, weight and renal function of the patient.

Unless otherwise prescribed, the following guideline doses are recommended:

Intravenous

Respiratory tract infection

(according to severity and organism)

2 x 200-400 mg

Urinary tract infections:

-acute, uncomplicated

-cystitis in women (before menopause)

-complicated

2 x 100 mg

single dose 100 mg

2 x 200mg

Gonorrhea

-extragenital

-acute, uncomplicated

2 x 100 mg

single dose 100 mg

Diarrhea

2 x 200 mg

Other infections (see Indications)

2 x 200-400 mg

Particularly severe, life threatening

infections, i.e.

-Streptococcal pneumonia

-Recurrent infections in cystic fibrosis

-Bone and joint infections

-Septicemia

-Peritonitis

In particular when Pseudomonas,

Staphylococcus or Streptococcus is present

3 x 400 mg

Elderly

Elderly patients should receive a dose as low aspossible depending on the severity of their illness and

the creatinine clearance.

Children

Clinical and pharmacokinetic data support the use of ciprofloxacin in paediatric cystic fibrosis patients

(aged 5-17 years) with acute pulmonary exacerbation associated with Pseudomonas aeruginosa

infection, at a dose of 10 mg/kg iv three times daily (maximum dose 1200 mg).

Method of administration

Ciprofloxacin must be visually checked beforeuse. It should not be used if it is cloudy.

Ciprofloxacin must be administered with an intravenous infusion. For children the infusion takes 60

minutes.

In adult patients the infusion time is 60 minutes for 400 mg of Ciprofloxacin and 30 minutes for 200 mg

of Ciprofloxacin. A slow infusion in a large vein will limit the inconvenience tothe patient to a minimum

and will reduce the risk of venous irritation.

The solution for infusion can be administered eitherdirectly or after mixing with other compatible

solutions for infusion (see sections 6.2, 6.6)

Note: After intravenous initiation oftreatment, the treatment can be switched to oral treatment with

tablets if clinically indicated inthe discretion of the physician. IVtreatment should be followed by oral

route as soon as possible.

4.3 Incompatibilities

See 6.2, 6.6

4.4 Duration of treatment

The duration of treatment depends on the severity ofthe illness and on the clinical and bacteriological

course. It is essential to continuetherapy for at least 3 days after disappearance of the fever or of the

clinical symptoms. Meanduration of treatment::

−1 day for acute uncomplicated gonorrhoea and cystitis,

−up to 7 days for infections of the kidneys, urinary tract, and abdominal cavity,

−over the entire period ofthe neutropenic phase in patients with weakened body defences,

−a maximum of 2 months in osteomyelitis,

−and 7-14 days in all other infections.

In streptococcal infections thetreatment must last at least 10days because of the risk of late

complications.

Infections caused by Chlamydia should also be treated for a minimum of 10 days.

Children

For acute pulmonary exacerbation of cystic fibrosis associated with Pseudomonas aeruginosa infection

in paediatric patiens (age 5-17 years), the duration of treatment is 10-14 days.

4.5 Renal and hepatic impairment

1. Impaired renal function

1.1 Where creatinine clearance is between 31 and 50 ml/min/1.73 m² or where the serum creatinine

concentration is between 1.4 and1.9 mg/100 ml the maximum daily dose should be 800 mg per

day for an intravenous regimen.

1.2Where creatinine clearance isequal or is less than 30 ml/min/1.73 m² or where the serum

creatinine concentration is equal or higher than2.0 mg/100 ml the maximum daily dose should

be 400 mg per day for an intravenous regimen.

2. Impaired renal function + haemodialysis

Dose as in 1.2; on dialysis days after dialysis.

3. Impaired renal function + CAPD

Addition of ciprofloxacin infusion solution to the dialysate (intraperitoneal): 50 mg ciprofloxacin /

liter dialysate administered 4 times a day every 6 hours.

4. Impaired liver function

No dose adjustment is required.

5. Impaired renal and liver function

Dose adjustment as in 1.1 and 1.2

Children

Dosing in children with impaired renalor hepatic function has not been studied.

4.6 Contra-indications

Hypersensitivity to the active ingredient, toother quinolones or to one of the excipients (see

section 6.1).

Concomitant administration of ciprofloxacin and tizanidine (see section 4.8).

4.7 Special warnings and special precautions for use

Severe infections and mixed infections with Gram positive and anaerobic pathogens

Ciprofloxacin as monotherapy is not appropriate for the treatment of severe infections and infections

that could possibly be the result of Gram positive or anaerobic pathogens. For such infections

ciprofloxacin should be combined with one or more other appropriate antibacterial products.

Streptococci infections (amongst which Streptococcus pneumoniae)

Ciprofloxacin is not recommended for the treatment ofstreptococci infections due to its insufficient

efficacy.

Infections of the sexual organs

Epididymo-orchitis and inflammationsin the true pelvis in women (PID, pelvic inflammatory diseases)

can be caused by fluoroquinolone resistantNeisseria gonorrhoeae. Ciprofloxacin must be administered

concomitantly with another appropriate antibacterial product unless ciprofloxacin resistantNeisseria

gonorrhoeaecan be ruled out. If clinical improvementhas not been reached within 3 days after the

initiation of the treatment, thetherapy must be reconsidered.

Intra-abdominal infections

There is limited data available about the efficacy of ciprofloxacinfor the treatment of intra-abdominal

infections after a surgical procedure.

Travellers’ diarrhoea

The choice for ciprofloxacin must be based on information about the resistance of the causal pathogens

in the visited countries to ciprofloxacin.

Infections of the bones and joints

Ciprofloxacin must be used in combination with other antimicrobialproducts depending on the results of

the microbiological documentation.

Inhalation Anthrax

Use in humans has been based on in-vitro sensitivity data and on data from experimental research in

animals combined with limited data in humans. Treating physicians should consult the national and/or

international consensus documents with respect to the treatment of anthrax.

Children and adolescents

The available official guidelines should be followed for the use of ciprofloxacin in children and

adolescents. The treatment with ciprofloxacin should only be initiated by doctors experienced with the

treatment of cystic fibrosis and/ or severeinfections in children and adolescents.

Ciprofloxacin has been found to cause arthropathy inthe weight-bearing joints of not fully grown

animals. Safety data of a randomised, double-blind study, in which ciprofloxacin was used in children

(ciprofloxacin: n=335, mean age =6.3 years old; comparative products: n=349, mean age = 6.2 years

old; age range = 1 to 17 years old) showed an incidence of 7.2% and 4.6% of suspected medicinal

product related arthropathy (is distinguished from joint related clinicalsigns and symptoms) on day +42.

With the follow-up after 1 year the incidence of medicinal product related arthropathy was respectively

9.0% and 5.7%. The increase of suspected cases of medicinal product related arthropathy after some

time was not statistically significant between the groups. Only after the benefits have been carefully

weighed against the risks a treatment should be initiated, because undesirable effects may occur that

are connected to the joints and/ or the surrounding tissue.

Bronchopulmonary infections with cystic fibrosis

A clinical study was performed in children and adolescents from 5-17 years of age. There is less

experience with the treatment ofchildren between 1 and 5 years old.

Complicated urinary tract infections and pyelonephritis

A treatment with ciprofloxacin for urinary tract infections should be taken intoconsideration when other

treatments cannot be used and must be based on the results of the microbiological documentation. A

clinical study was performed in children and adolescents from 1-17 years of age.

Other specific severe infections

Other severe infections accordingto official guidelines or when, after careful consideration of the

benefits versus the risks, other treatments cannot be used or after a usual therapy has failed and when

the microbiological data justify the useof ciprofloxacin. The use of ciprofloxacin for other specific severe

infections, other than those mentioned above, has notbeen studied clinically and the clinical experience

is limited. Therefore caution is needed for the treatment of patients with these infections.

Hypersensitivity

Hypersensitivity and allergic reactions, amongstwhich anaphylactic and anaphylactoid reactions, can

occur after a single dose (see section 4.11) and can be life-threatening. If such a reaction occurs,

ciprofloxacin must be discontinued and an appropriate medical treatment will be required.

Musculoskeletal system

Generally ciprofloxacin should not beused in patients with a history ofa tendon disorder as a result of a

treatment with quinolone. Nevertheless, in very rare cases ciprofloxacin can be prescribed to these

patients for the treatment of certain severe infections after microbiological documentation of the

causative organism and after having weighed the benefits against the risks, particularly if the standard

treatment fails or with bacterial resistance, wherebythe microbiological data possibly justify the use of

ciprofloxacin. Tendinitis and tendonrupture (in particular the Achilles heel), sometimes bilaterally, may

occur with ciprofloxacin use, even during the first 48 hours of the treatment. The risk of tendinopathy

can be higher in elderly patients andin patients who are concomitantlytreated with corticosteroids (see

section 4.11). With any sign of tendinitis (e.g. painful swelling, inflammation) the treatment with

ciprofloxacin must be discontinued. The affected limbs should not bear weight and get rest.

Ciprofloxacin must be used with the necessary caution in patients with myasthenia gravis (see section

4.11).

Photosensitivity

It has been shown that ciprofloxacin can causephotosensitivity reactions. Patients who take

ciprofloxacin should be advised to avoid direct exposureto excessive sunlight orUV radiation during the

treatment (see section 4.11). Therapy should be discontinued if photosensitization (i.e.: sunburn-like

skin reaction) occur.

Central nervous system

Quinolones are known to elicit epileptic seizuresor to lower the threshold for epileptic seizures.

Ciprofloxacin should be used with caution in patients with disordersin the central nervous system, who

may have a tendency to get epileptic seizures. If epileptic seizures occur, Ciprofloxacin must be

discontinued (see section 4.11) Psychic reactions can occur even after the first administration of

ciprofloxacin. In rare cases depression or psychosis can lead to self-destructive behaviour. In these

cases ciprofloxacin must be discontinued. Patients,who received ciprofloxacin, reported cases of

polyneuropathy (based on neurologicalsymptoms like pain, a burning sensation, sensory disorders or

muscle weakness, alone or in combination). The use ofciprofloxacin must be discontinued if the patient

experiences symptoms of neuropathy, including pain, aburning sensation, tingling, a numb feeling and/

or weakness in order to prevent the development ofan irreversible disorder (see section 4.11).

Cardiac disorders

Because ciprofloxacin can be associated with casesof QT prolongation (see section 4.11), caution is

needed with the treatment of patients with an increased risk for torsades de pointes arrhythmia.

Caution is recommended when using fluorochinolonesin patients with known risk factors for QT

prolongation, such as:

-congenital long QT syndrome

-concomitant use of medicinal products that are known to prolong the QT interval (e.g. Class IA

and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

-uncorrected electrolytes unbalance (e.g. hypokalaemia, hypomagnesaemia)

-elderly

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

(see section 4.2 'Elderly', section 4.8, 4.11 and 4.12).

Gastro-intestinal system

Severe and persistent diarrhoea during or after a treatment (up to a few weeks after the treatment) may

indicate colitis as a result of an antibiotic (this islife-threatening with a possible fatal result), which must

be treated immediately (see section 4.11). In such cases ciprofloxacin must be discontinued

immediately and an appropriate treatment initiated. In this situation antiperistaltic drugs are

contraindicated.

Kidneys and urinary tract

Crystalluria has been reported as aresult of the use of ciprofloxacin (see section 4.11). Patients

receiving ciprofloxacin must be well hydrated and an excessive alkalinity of the urine must be avoided.

Hepatic and biliary system

Cases of hepatic necrosis and life-threatening liver failure have beenreported for ciprofloxacin (see

section 4.11) In case of signsand symptoms of a hepatic disorder (like anorexia, jaundice, dark urine or

a pressure-sensitive abdomen) the treatment must be discontinued.

Glucose-6-phosphate-dehydrogenase deficiency

Haemolytic reactions have been reported with the useof ciprofloxacin in patients with a glucose-6-

phosphate dehydrogenase deficiency. Ciprofloxacin must be avoided in these patients unless the

potential benefit outweighs the possible risk. In that case must be monitored for the possible occurrence

of haemolysis.

Resistance

During or after the treatment with ciprofloxacin bacteria can be isolatedthat are resistant to

ciprofloxacin, with or without aclinically manifest superinfection. There may be a special risk for

selection of bacteria resistant to ciprofloxacinduring prolonged treatment andwith the treatment of

nosocomial infections and/ or infections cause byStaphylococcusandPseudomonas strains.

Cytochrome P450

Ciprofloxacin inhibits CYP1A2 and can thereforelead to an increased serum level of concomitantly

administered products that are metabolised by this enzyme (e.g. theophylline, clozapine, ropinirole,

tizanidine). Concomitant administration of ciprofloxacin and tizanidineis contra-indicated. Therefore

patients who are using these productsconcomitantly with ciprofloxacin must be carefully monitored for

clinical signs of an overdose and assessment of the serum levels (for example of theophylline) may be

necessary (see section 4.8).

Methotrexate

Concomitant use of ciprofloxacin and methotrexate is not recommended (see section 4.8).

Interaction with research results.

Thein vitroeffect of ciprofloxacin againstMycobacterium tuberculosiscan lead to false negative

bacteriological research results in samples of patients, who are currently using ciprofloxacin.

Reaction at the site of the injection

Local reactions at the site ofadministration have been reported withthe intravenous administration of

ciprofloxacin. These reactions occur more frequentlywhen the infusion time is 30 minutes or less.

These can express themselves in the form of local skin reactions, which after the completion of the

infusion disappear rapidly. A nextintravenous administration is notcontra-indicated, unless the

reactions occur again or get worse.

Glucose loading

Ciprofloxacin solution for infusion contains 5 g of glucose in 100 ml of solution for infusion. This should

be taken into account for patients with diabetes mellitus.

NaCl load for i.v. formulation (bottles)

In patients for whom sodium intakeis of medical concern (patientswith congestive heart failure, renal

failure, nephrotic syndrome, etc.) the additional sodium load should be taken into account..

4.8 Interactions with other medicinalproducts and other forms of interaction

Effects of other products on ciprofloxacin:

Probenecid

Probenecid has an effect on the excretion of ciprofloxacin via the kidneys.Simultaneous administration

of probenecid and ciprofloxacin leads to an increase of the serum level of ciprofloxacin.

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach

maximum plasma concentrations. No effect wasseen on the bioavailability of ciprofloxacin.

Omeprazole

Concomitant administration of ciprofloxacin and omeprazole results ina slight reduction of Cmax and

AUC of ciprofloxacin.

Effects of ciprofloxacin on other medicinal products:

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 AUCand Cmax of duloxetine.

Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be

expected upon concomitant administration.

Lidocaine

It was demonstrated in healthy subjects that concomitantuse of lidocaine 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.

Tizanidine

Tizanidine should not be administered together with ciprofloxacin (see section 4.6). A clinical study in

healthy volunteers showed an increaseof the tizanidine concentration in the serum (increase of Cmax:

7-fold, range: 4 to 21-fold; increaseof AUC: 10-fold, range: 6 to 24-fold) with concomitant administration

of ciprofloxacin. An increasedtizanidine concentration in the serum has been associated with an

increased hypotensive and sedating effect.

Methotrexate

The renal tubular transport of methotrexate can be inhibited by the concomitant administration of

ciprofloxacin, which may possibly lead to an increased plasma level of methotrexate and an increased

risk of toxic reactions as a result of methotrexate. Concomitant use isnot recommended (see section

4.7).

Theophylline

Simultaneous administration of ciprofloxacin and theophylline can lead to an undesirable increase of the

serum level of theophylline. This can result in side effects of theophylline, whichin very rare cases can

be life-threatening or fatal. Theserum level of theophylline must be checked with simultaneous use and

if needed the dose of theophylline mustbe reduced (see section 4.7).

Other xanthine derivatives

With concomitant administrationof ciprofloxacin and pentoxiphylline(oxpentiphylline) increased serum

levels of these xanthine derivatives were reported.

Phenytoin

Concomitant administration of ciprofloxacin and phenytoin can lead to an increased or reduced serum

level of phenytoin, for which reason it is recommended to check the medicinal product level.

Oral anticoagulant drugs

Concomitant administration ofciprofloxacin and warfarin canenhance the anticoagulating effects

thereof. A large number of cases of an enhanced effect of the oral anticoagulant have been reported in

patients receiving antibacterial products, amongstwhich fluoroquinolones. The risk can vary with the

underlying infection, theage and the general condition of the patient, so the effect of the fluoroquinolone

on the increase of the INR (international normalised ratio) is difficultto determine. It is recommended to

check the INR frequently during and shortly afterconcomitant use of ciprofloxacin and an oral

anticoagulant.

Ropinirole

A clinical study has shown that concomitant use of ropinirole and ciprofloxacin, a moderate inhibitor of

the CYP450 1A2 iso-enzyme, leads to an increase of the C

and AUC of ropinirole with respectively

60% and 84%. Monitoring ropinirole related side effects, as well as adjustment of the dose as

appropriate, is recommended during and shortly after combined use with ciprofloxacin (see section 4.7).

Clozapine

After the concomitant administration of 250 mg ofciprofloxacin and clozapine for 7 days the serum

levels of clozapine and N-desmethyl clozapine wereincreased by respectively 29% and 31%. Clinical

supervision and, if needed, an adjustment of the dose of clozapineare recommended during and shortly

after the combined treatment withciprofloxacin (see section 4.7)

Medicinal products with the potential to prolong the QT

Like other fluorochinolones, ciprofloxacin should be used with caution in patients receiving drugs that

are known to prolong the QT interval (e.g. ClassIA and III antiarrhythmics, tricyclic antidepressants,

macrolides, antipsychotics) (see section 4.7).

NSAIDs

Animal studies have shown that the combination ofvery high doses of quinolones (gyrase inhibitors)

and certain non-steroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke

convulsions.

Cyclosporin

A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and

cyclosporin were administered simultaneously. Therefore, it is necessary to control the serum creatinine

concentrations in these patients frequently (twice a week).

Glibenclamide

In particular cases, concurrent administration ofciprofloxacin and glibenclamide can intensify the action

of glibenclamide (hypoglycaemia).

4.9 Pregnancy and lactation

Pregnancy

The data that are available about the administration of ciprofloxacinto pregnant women do not indicate

malformative or foetal/ neonatal toxicity of ciprofloxacin. Experimental animal studies do not indicate

direct or indirect harmful effectsas a result of reproductive toxicity. Effects on immature cartilage have

been observed in juvenile and prenatal animals that were exposed to quinolones.

Therefore it cannot be ruled out that the medicinal product can damage the cartilage of the joints in the

human not fully grown organism/ the foetus (see section 5.3). As a precaution it is preferred to avoid the

use of ciprofloxacin during the pregnancy.

Lactation

Ciprofloxacin is excreted in the breast milk. Due tothe potential risk of damage tothe joints ciprofloxacin

should not be used during theperiod of breast-feeding.

4.10 Effects on the ability to drive and use machines

Because it does have neurological effects, ciprofloxacin can affect the time to react, which can cause a

reduced ability to drive or use machines. Thisapplies particularly in combination with alcohol.

4.11 Undesirable effects

The side effects reported most frequently are nausea, diarrhoea, vomiting,temporarily elevated

transaminase levels, rash and reactions at the site of the injection or infusion.

Side effects, originating from clinical studies and post-marketing surveillance with Ciprofloxacin (oral,

intravenous and sequential therapy) categorised according to frequency, are listed below. The analysis

of the frequency is based on data from both the oral andthe intravenous administration of ciprofloxacin.

System/ Common Uncommon Rarely Very rarely Frequency

organ class >1/100 to < 1/10 >1/1,000 to <

1/100 >1/10,000 to <

1/1,000 < 1/10,000 unknown(cannot be

determined based on the

available data)

Infections and

parasitic

disorders Mycotic

super

infections Colitis as a

result of an

antibiotic (very

rarely with a

possible fatal

result) (see

section 4.7)

Blood and

lymphatic

system

disorders Eosinophilia Leucopoenia

Anaemia

Neutropoenia

Leukocytosis

Thrombocyto-

poenia

Thrombo-

cytosis Haemolytic

anaemia

Agranulo-

cytosis

Pancytopenia

(life-

threatening)

Bone marrow

depression

(life-

Immune

system

disorders Allergic

reaction

Allergic

oedema /

angio-oedema Anaphylactic

reaction

Anaphylactic

shock (life-

threatening)

(see

section 4.7)

Serum

disease-

Nutrition and

metabolism

disorders Anorexia Hyperglycemia

Psychic

disorders Psycho-

motoric

hyperactivity

/ agitation Confusion

and

disorientation

Anxiety

reaction

Abnormal

dreaming

Depression

Psychotic

reactions

(see section

4.7)

Nervous

system

disorders Headache

Dizziness

Sleep

disorders

Taste

disorders Paraesthesia

and

dysesthesia

Hyperesthesia

Tremor

Epileptic

seizures (see

section 4.7)

Migraine

Coordination

disorders

Gait disorder

Olfactory

nerve

disorders

Intracranial

Peripheral

neuropathy (see

section 4.7)

Ocular

disorders Vision

disorders

Abnormal

colour

observation

Equilibrium

organ and

ear

disorders Tinnitus

Hearing loss

/ reduced

hearing

Cardiac

disorders Tachycardia Ventricular

arrhythmia and torsades

de pointes (reported for

patients with risk factors

for QT prolongation),

Prolongation of QT-

interval in ECG (see

Section 4.7 and 4.12)

Vascular

disorders Vasodilation

Hypotension

Syncope Vasculitis

Respiratory

system,

chest and

mediastinal

disorders Dyspnoea

(including

asthmatic

disorder)

Gastro-

intestinal

system

disorders Nausea

Diarrhoea Vomiting

Gastro-

intestinal and

abdominal

pain

Dyspepsia

Flatulence Pancreatitis

Liver and

biliary

disorders Elevated

transaminase

levels

Elevated

bilirubin levels Abnormal

liver function

Cholestatic

icterus

Hepatitis Liver necrosis

(very rarely

developing

into life-

threatening

liver failure)

(see section

4.7)

Skin and

subcutaneous

tissue

disorders Skin rash

Pruritus

Urticaria Photo-

sensitivity

reactions (see

section 4.7) Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-

Johnson

Syndrome

(possibly life-

threatening)

Toxic

epidermal

necrolysis

(possibly life-

Musculo-

skeletal system

connective

tissue

and bone

disorders Muscle aches

(e.g.

pain in the

extremities,

back

and chest)

Arthralgia Myalgia

Arthritis

Increased

muscle tonus

and

muscle cramps Muscle

weakness

Tendinitis

Tendon

rupture

(mainly the

Achilles heel)

(see section

4.7)

Exacerbation

of symptoms

of

myasthenia

gravis (see

Renal and

Urinary tract

disorders Renal function

disorder Renal failure

Haematuria

Crystalluria

(see section

4.7) Tubulo-

interstitial

nephritis

General

disorders

and

administration

site

disorders Reactions at the

injection and

infusion site

(only with

intravenous

administration) Asthenia

Fever Oedema

Sweating

(hyperhydrosis)

Investigations Elevated

alkaline

phosphatase Abnormal

prothrombin

values

Elevated

amylase values

The following undesirable effects fall in a category with a higher frequency in the sub groups of patients

who received an intravenous or sequential treatment(of an intravenous treatmentswitched over to an

oral treatment):

Common Vomiting, transient elevation of transaminase values, rash

Uncommon Thrombocytopenia, thrombocytosis, confusion and disorientation,

hallucinations, paraesthesia and dysesthesia, epileptic seizures, vertigo,

visual disorders, hearing loss, tachycardia, vasodilatation, hypotension,

temporary abnormal liver function, cholestatic icterus, renal failure, oedema

Rarely Pancytopoenia, bone marrow depression, anaphylactic shock, psychic

reactions, migraine, olfactory nervedisorders, reduced hearing, vasculitis,

pancreatitis, liver necrosis, petechiae, tendon rupture

Paediatric patients

The above mentioned incidence of arthropathy refersto data collected with adult studies. In children

arthropathy is reported commonly (see section 4.7).

4.12 Overdose

An overdose of 12 g has been reported to lead to mildsymptoms of toxicity. Anacute overdose of 16 g

has been reported to cause acute renal failure. Symptoms of overdose include: dizziness, tremor,

headache, fatigue, epileptic seizures, hallucinations, confusion, abdominal complaints, abnormal renal

and hepatic function as well as crystalluria and haematuria. Reversible renal toxicity has been reported.

Except for the usual emergency measures, it is recommended to check the renal function, including the

pH of the urine, and – ifneeded – to acidify to prevent crystalluria;it is also recommended to administer

Mg-or Ca-containing antacids which reduce the absorption of ciprofloxacin. Patients must be well

hydrated.

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

In the event of overdosage, symptomatic treatment should be given. ECG monitoring should be

instituted, as the QT interval may be prolonged.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic category: fluoroquinolones, ATC-code: J01MA02

Action mechanism:

Ciprofloxacin, an antibacterial fluoroquinolone product,has a bactericidal effect by inhibiting both topo-

isomerase II (DNA gyrase) and topo-isomerase IV, which are necessary for bacterial DNA replication,

DNA transcription, DNA recovery and DNA recombination.

PK/PD connection:

The efficacy is mainly dependent on the connection between the maximum serum concentration (C

)

and the minimum inhibitory concentration (MIC)of ciprofloxacin for a bacterial pathogen and the

connection between the AUC (area underthe curve) and the MIC.

Mechanism of resistance:

In vitroresistance against ciprofloxacin can occur throughstep by step mutations in the targets in both

DNA gyrase and topo-isomerase IV.The resulting measure of cross-resistance between ciprofloxacin

and other fluoroquinolones varies. Single mutations do nothave to result in clinical resistance, but

multiple mutations generally do result in clinical resistance to many or all active substances within the

class.

Impermeability and/ or resistance mechanisms, in which the active ingredient is removed via the efflux

pump, may have a variable effect on the sensitivity to fluoroquinolones. This depends on the physico-

chemical properties of the various active ingredients within the class and the affinity of transport

systems for each active ingredient. Allin vitroresistance mechanisms are generally observed in cultures

from hospitals.

Resistance mechanisms that inactivate other antibiotics, such as permeationbarriers (usually with

Pseudomonas aeruginosa), and efflux mechanisms may have an effect on the sensitivity to

ciprofloxacin.

Plasmid determined resistance coded by qnr genes has been reported.

Spectrum of antibacterial effect:

Breakpoints distinguish sensitive strains from strains with a moderate sensitivity and this last from

resistant strains:

EUCAST recommendations

Micro-organisms Sensitive Resistant

Enterobacteria S≤0.5 mg/l R > 1 mg/l

Pseudomonas S≤0.5 mg/l R > 1 mg/l

Acinetobacter S≤1 mg/l R > 1 mg/l

Staphylococcusspp.1 S≤1 mg/l R > 1 mg/l

Haemophilus influenzaeand

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 are connected to a high dose therapy.

* Breakpoints not related to species are mainly determined on the basisof PK/PD data and are

not connected to MIC distributions ofspecific species. They serve solely for species that do not have a

species specific breakpoint and not for those species where a sensitivity test is not recommended.

The prevalence of acquired resistance may varygeographically and with time for certain species and

local information about resistance isdesirable, especially for the treatment of severe infections. If

needed expert advice should be sought when the local prevalence of resistance is such that the

usefulness of the product in at least some types of infections is questionable.

Groups of relevant species according to sensitivity to ciprofloxacin (see section 4.7 forStreptococcus

species).

GENERALLY SENSITIVE SPECIES

Aerobe Gram-positive micro-organisms

Bacillus anthracis(1)

Aerobe Gram-negative micro-organisms

Aeromonasspp.

Brucellaspp.

Citrobacter koseri

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae*

Legionellaspp.

Moraxella catarrhalis*

Neisseria meningitidis

Pasteurellaspp.

Salmonellaspp.*

Shigellaspp.*

Vibriospp.

Yersinia pestis

Anaerobe micro-organisms

Mobiluncus

Other micro-organisms

Chlamydia trachomatis($)

Chlamydia pneumoniae($)

Mycoplasma hominis($)

Mycoplasma pneumoniae($)

SPECIES FOR WHICH ACQUIRED RESISTANCE MAY CAUSE A PROBLEM

Aerobe Gram-positive micro-organisms

Enterococcus faecalis($)

Staphylococcusspp. (2)

Aerobe Gram-negative micro-organisms

Acinetobacter baumannii+

Burkholderia cepacia+*

Campylobacterspp.+*

Citrobacter freundii*

Enterobacter aerogenes

Enterobacter cloacae*

Escherichia coli*

Klebsiella oxytoca

Klebsiella pneumoniae*

Morganella morganii*

Neisseria gonorrhoeae*

Proteus mirabilis*

Proteus vulgaris*

Providenciaspp.

Pseudomonas aeruginosa*

Pseudomonas fluorescens

Serratia marcescens*

Anaerobe micro-organisms

Peptostreptococcusspp.

Propionibacterium acnes

INHERENTLY RESISTANT ORGANISMS

Aerobe Gram-positive micro-organisms

Actinomyces

Enterococcus faecium

Listeria monocytogenes

Aerobe Gram-negative micro-organisms

Stenotrophomonas maltophilia

Anaerobe micro-organisms

Except as described above

Other micro-organisms

Mycoplasma genitalium

Ureaplasma urealyticum

*With approved clinical indications the clinicalefficacy for sensitive isolates was shown.

+ Resistance percentage in one or more EU countries≥50%

($): Natural moderate sensitivity with absence of acquired resistance mechanism

(1): An experimental animal study was performed withrespect to infections caused by inhalation

of spores of theBacillus anthracis. This study shows that the administration of antibiotics shortly

after exposure prevents the outbreak of the disease if the treatment is focused on reducing the

number of spores in the organism to below the infectious dose. The recommended human use is

primarily based on in vitro sensitivity and data from experimental studies in animals together with

limited information in humans. A treatment in adultswith a dose of 500 mg of ciprofloxacin orally

two times per day for two months is considered justas effective in preventing an anthrax infection

in humans. It is recommended that the treatingphysician should consult the national and/or

international consensus documents with respect to the treatment of anthrax.

(2): Methicillin resistantS. Aureusvery frequently shows a co-resistance to fluoroquinolones. The

percentage of resistance to methicillin is approximately 20 to 50% in all species of staphylococci

and is usually higher with nosocomial cultures.

5.2 Pharmacokinetic properties

Absorption

After intravenous infusion of ciprofloxacin the mean maximum serum concentrations were reached at

the end of the infusion. The pharmacokinetics of the intravenously administered ciprofloxacin was linear

within the dose range of up to 400 mg.

The comparison of the pharmacokinetic parameters for an intravenousdose schedule of two and three

times per day has not shown any medicinal product accumulation for ciprofloxacin or its metabolites.

An intravenous infusion of 200 mg ofciprofloxacin over a period of 60 minutes or the oral administration

of 250 mg of ciprofloxacin, both administeredevery 12 hours, provided anequal AUC under the serum

concentration times.

With respect to the AUC an intravenous infusion of400 mg of ciprofloxacin, administered every 12

hours over a period of 60 minutes, was bio-equivalentto an oral dose of 500mg administered every 12

hours.

The intravenous dose of 400 mg that was administered every 12 hours over a period of 60 minutes, led

to a C

that was equivalent to the one that was observed with an oral dose of 750 mg.

With respect to the AUC an infusion of 400 mg ofciprofloxacin, which is administered every 8 hours

over a period of 60 minutes, is equivalent to an oraltreatment with 750 mg administered every 12 hours.

Distribution

The protein binding of ciprofloxacinis weak (20-30%). Ciprofloxacin ismostly present in plasma in an

unionised form and has a large steady-state distributionvolume of 2-3 l/kg ofbodyweight. Ciprofloxacin

reaches high concentrations in various tissues, likethe lungs (epithelial fluid, alveolar macrophages,

biopsy tissue), sinuses, inflamed laesions (cantharidin blister fluid) and the urogenital system (urine,

prostate, endometrium) where total concentrationsare reached that exceed plasma concentrations.

Metabolism

Low concentrations of four metabolites have been reported, whichhave been identified as: desethylene

ciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). The

metabolites show anin vitroantimicrobial effect but weakerthan that of the parent compound.

Ciprofloxacin is known to be a moderate inhibitor of the CYP450 1A2 iso-enzymes.

Elimination

Ciprofloxacin is primarily excreted unchanged both via the kidneys and,although in a lesser measure,

with the faeces.

Excretion of ciprofloxacin (% of the dose)

Intravenous administration

Urine Faeces

Ciprofloxacin 61.5 15.2

Metabolites (M 1 -M 4 ) 9.5 2.6

The renal clearance is between180-300 ml/kg/hr and the totalbody clearance is between 480-600

ml/kg/hr. Ciprofloxacin undergoes bothglomerular filtration and tubular secretion. Severe renal function

impairment leads to longer half-lives ofciprofloxacin of up to 12 hours.

The non-renal clearance of ciprofloxacin is primarily the result of an active trans-intestinal secretion as

well as metabolisation. 1% of the dose is excreted via the bile. Ciprofloxacin is present in the bile in high

concentrations.

Paediatric patients

The available pharmacokinetic data inpaediatric patients are limited.

In a study with children the C

and AUC were not age-related (older than 1 year). No noticeable

increase in the C

and AUC was observed with multiple doses (10 mg/kg three times per day).

In 10 children with severe sepsis, who were younger than 1 year old, the C

was 6.1 mg/l (between

4.6-8.3 mg/l) after an intravenous infusion of 1 hourwith 10 mg/kg. In children between 1 and 5 years

old this was 7.2 mg/l (between 4.7–11.8 mg/l). The AUC levels were 17.4 mg*u/l (between 11.8-32.0

mg*u/l) and 16.5 mg*u/l (between 11.0-23.8 mg*u/l) in the respective age groups.

These levels are within the ranges that were reported for adults with therapeutic doses. On the basis of

the pharmacokinetic analysis of the population of paediatric patients with various infections, the

predicted mean half-life in childrenis approximately 4-5hours and the bio-availability of the oral

suspension fluctuates between 50 and 80%.

5.3 Pre-clinical safety data

Non-clinical data do not indicate a special riskto humans. These data originate from conventional

research in the area of toxicitywith single doses, toxicity with repeated doses, carcinogen potential and

reproductive toxicity. With clinically relevant exposure levels ciprofloxacin is phototoxic in animals, like a

number of other quinolones. Data about photomutagenicity/ photocarcinogenicity show a weak

photomutagenic or photocarcinogenic effectfor ciprofloxacin in vitroand in experimental studies in

animals. This effect was similar tothat of other gyrase inhibitors.

Articular tolerability:

As reported for other gyrase inhibitors, ciprofloxacin causes damage to large, weight-bearing joints in

not fully grown animals. The measure of damage tothe cartilage varies according to age, type and

dose; the damage can be reduced by relieving the jointsfrom weight-bearing. Studies with adult animals

(rat, dog) have not shown evidence of cartilagelaesions. In a study with young dogs, beagles,

ciprofloxacin caused severe articular changes withtherapeutic doses, after a2-week treatment with

therapeutic doses, which were still visible after 5 months.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Glucose monohydrate, lactic acid, hydrochloric acid for pH adjustment (E507), water for injection.

6.2 Incompatibilities

Ciprofloxacin can not be mixed with solutionsthat are unstable with a pH of approx. 4.

The medicinal product should not be mixed with anymedicinal products other than those mentioned in

section 6.6.

6.3 Shelf life after removal of outer overpouch

After removal of the outer overpouch the solution for infusion should be used immediately.

6.4 Special precautions for storage

Store in a cool place in the original overpouch. Do not store in the refrigerator or freezer.

6.5 Nature and contents of container

Transparent bags with 100 or 200 mlsolution for infusion with an aluminium outer bag. The bags have

an infusion port and cap. The bagsare made of multilayer, polyolefin/styrene-ethylene-butylene block

polymer based film, with a polypropylene infusion port and cap. The bagshave a rubber stopper (made

of synthetic isoprene).

The bags are packed per 1, 5, 10 or 12 each.

6.6 Special precautions for removal and other instructions

Use only clear solutions and undamaged containers.

The solution is intended for single use only. Anyunused solution and the bags should be disposed of in

accordance with local requirements.

Use immediately after opening the outer pouch.

Ciprofloxacin is compatible with a physiological saltsolution, Ringer’s solution, Ringer’s lactate solution,

50 mg/ml (5%) or 100 mg/ml (10%)glucose solution, 100 mg/ml (10%) Fructose solution, 50 mg/ml,

(5%) glucose solution with 2.25 mg/ml (0.225%) or4.5 mg/ml (0.45%) sodium chloride solution.

Compatibility with these solutionshas been proven with ciprofloxacin concentrations of 1 mg/ml.

Chemical and physic in-use stability has been shown immediately after dilution. Unless compatibility has

been proven the solution for intravenous infusion should always be administered separately.

The prepared solution must be visually inspected for particulate matter and discolouration prior to

administration. The prepared solution must be clear.

7. REGISTRATION NUMBER

146 69 33161 00.

8. MANUFACTURER

Teva Pharmaceutical Works Private Ltd.,

Hungary.

9. LICENCE HOLDER

Salomon Levin & Elstein Ltd

P.O.Box 3696, Petach Tikva, 49133

DATE OF APPROVED REVISION OF TEXT : October , 2011

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