Israel - English - Ministry of Health
" 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
UNCOMPLICATED AND COMPLICATED INFECTIONS CAUSED BY CIPROFLOXACIN SENSITIVE
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
With a few exceptions anaerobes are moderately sensitive e.g. Peptococcus, Peptostreptococcus to
Ciprofloxacin is ineffective againstTreponema pallidum.
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
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:
Respiratory tract infection
(according to severity and organism)
2 x 200-400 mg
Urinary tract infections:
-cystitis in women (before menopause)
2 x 100 mg
single dose 100 mg
2 x 200mg
2 x 100 mg
single dose 100 mg
2 x 200 mg
Other infections (see Indications)
2 x 200-400 mg
Particularly severe, life threatening
-Recurrent infections in cystic fibrosis
-Bone and joint infections
In particular when Pseudomonas,
Staphylococcus or Streptococcus is present
3 x 400 mg
Elderly patients should receive a dose as low aspossible depending on the severity of their illness and
the creatinine clearance.
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
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.
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
Infections caused by Chlamydia should also be treated for a minimum of 10 days.
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
Dosing in children with impaired renalor hepatic function has not been studied.
Hypersensitivity to the active ingredient, toother quinolones or to one of the excipients (see
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
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.
There is limited data available about the efficacy of ciprofloxacinfor the treatment of intra-abdominal
infections after a surgical procedure.
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.
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 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.
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
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).
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)
-cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
(see section 4.2 'Elderly', section 4.8, 4.11 and 4.12).
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
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.
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
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.
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).
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.
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 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 accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach
maximum plasma concentrations. No effect wasseen on the bioavailability of ciprofloxacin.
Concomitant administration of ciprofloxacin and omeprazole results ina slight reduction of Cmax and
AUC of ciprofloxacin.
Effects of ciprofloxacin on other medicinal products:
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.
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 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.
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
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.
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
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).
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).
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
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).
In particular cases, concurrent administration ofciprofloxacin and glibenclamide can intensify the action
of glibenclamide (hypoglycaemia).
4.9 Pregnancy and lactation
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.
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
infections Colitis as a
result of an
rarely with a
disorders Eosinophilia Leucopoenia
disorders Anorexia Hyperglycemia
/ agitation Confusion
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)
bilirubin levels Abnormal
Hepatitis Liver necrosis
disorders Skin rash
section 4.7) Petechiae
disorders Muscle aches
pain in the
muscle cramps Muscle
disorders Renal function
disorder Renal failure
disorders Reactions at the
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
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
The above mentioned incidence of arthropathy refersto data collected with adult studies. In children
arthropathy is reported commonly (see section 4.7).
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
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
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.
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
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
Resistance mechanisms that inactivate other antibiotics, such as permeationbarriers (usually with
Pseudomonas aeruginosa), and efflux mechanisms may have an effect on the sensitivity to
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
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
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
GENERALLY SENSITIVE SPECIES
Aerobe Gram-positive micro-organisms
Aerobe Gram-negative micro-organisms
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY CAUSE A PROBLEM
Aerobe Gram-positive micro-organisms
Aerobe Gram-negative micro-organisms
INHERENTLY RESISTANT ORGANISMS
Aerobe Gram-positive micro-organisms
Aerobe Gram-negative micro-organisms
Except as described above
*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
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
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
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.
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.
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.
Ciprofloxacin is primarily excreted unchanged both via the kidneys and,although in a lesser measure,
with the faeces.
Excretion of ciprofloxacin (% of the dose)
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
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.
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.
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
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.
Teva Pharmaceutical Works Private Ltd.,
9. LICENCE HOLDER
Salomon Levin & Elstein Ltd
P.O.Box 3696, Petach Tikva, 49133
DATE OF APPROVED REVISION OF TEXT : October , 2011