New Zealand - English - Medsafe (Medicines Safety Authority)
Ciprofloxacin hydrochloride Ph Eurequivalent to 250 mg, 500 mg and 750 mg
Name of the Medicinal Product
Qualitative and QuantitativeComposition
1 tablet contains ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin.
1 tablet contains ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin.
1 tablet contains ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin.
White to creamish-white, round, biconvex film coated tabletswith CPR 250
embossed on one side and ‘BL’ on the other.
White to creamish-white caplet shaped film coated tablets with CPR 500embossed
and with scoreline on one side and ‘BL’ on the other.
White to creamish-white capsuleshaped film coated tabletswith CPR 750 embossed
on one sideand ‘BL’ on the other.
Uncomplicated and complicated infections causedby ciprofloxacin sensitive
Infections ofthe lower respiratory tract.
In the treatment of outpatients withpneumonia due to Pneumococcus, ciprofloxacin
should not beused as amedicine offirst choice.Ciprofloxacin can be regarded as a
suitable treatment for pneumonias caused byKlebsiella,Enterobacter,Proteus,E.
coli, Pseudomonas, Haemophilus, Branhamella, Legionella,and Staphylococcus .
Infections ofthe kidneys and/or theefferent urinary tract.
Infections ofthe genitalorgans, including adnexitis, gonorrhoea, prostatitis.
Infections ofthe abdominal cavity (e.g. infectionsof the gastrointestinal tract or of the
Infections ofthe skin and soft tissue.
Infections ofthe bones and joints.
Inhalationalanthrax (post-exposure): To reduce the incidence or progression of
disease following exposure to aerosolizedBacillus anthracis. Ciprofloxacinserum
concentrations achievedin humans serve as a surrogate endpoint reasonably likely
to predict clinical benefitand provide the basis for this indication.
According toin vitroinvestigations, the followingpathogens can be regarded as
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, Moraxella, Acinetobacter, Brucella,
Staphylococcus, Listeria, Corynebacterium,Chlamydia.
The followingshow varying degreesof sensitivity:
Neisseria, Gardnerella,Flavobacterium, Alcaligenes, Streptococcusagalactiae,
Enterococcus faecalis, Streptococcus pyogenes,Streptococcus pneumoniae,
Viridans group Streptococci, Mycoplasmahominis, Mycobacteriumtuberculosis, and
The followingare usually resistant:
Enterococcus faecium,Ureaplasmaurealyticum, Nocardia asteroides.
With a few exceptions anaerobes are moderately sensitive e.g.Peptococcus,
Peptostreptococcus to resistant e.g.Bacteroides.
Ciprofloxacin has beenshown to be active againstBacillus anthracisbothin vitroand
by use of serum levels as a surrogate marker.
Ciprofloxacin is ineffective againstTreponemapallidum.
The prevalence of resistance may vary geographically andwith time for selected
speciesandlocal information on resistance is desirable, particularly when treating
severe infections. This information gives only an approximateguidance whether
microorganisms will besusceptible for ciprofloxacin or not.
For the treatment of acute pulmonary exacerbation of cystic fibrosis associated with
P. aeruginosa infection in paediatricpatients aged 5-17 years.
Inhalational anthrax (post-exposure)
For the indication of inhalational anthrax (post-exposure).
Complicated urinary tract infections and pyelonephritis
For complicated urinary tract infections or pyelonephritis duetoE.coliin paediatric
patients aged 1-17 years.
The risk-benefit assessment indicates that administration ofciprofloxacinto
paediatric patients is appropriate. Treatment should only be initiated aftercareful
benefit/riskevaluation, due to possible adverse events related to joints/surrounding
tissues.Theuse of ciprofloxacin forother indications is not recommended in children.
DOSAGE ANDMETHODOF ADMINISTRATION
Unless otherwise prescribed, the following guideline doses are recommended:
Respiratory tract infection
(according toseverity and organism)
2 x 250-500 mg
Urinary tract infections:
- acute, uncomplicated
- cystitis inwomen
1-2 x 250 mg
single dose250 mg
2 x 250-500 mg
- acute, uncomplicated
1 x 250 mg
single dose250 mg
Diarrhoea 1-2 x 500 mg
(see Indications) 2 x 500 mg
-Particularly severe, life-threatening
infections, i.e.Streptococcal pneumonia
-Recurrentinfections in cysticfibrosis
-Bone and joint infections
2 x 750 mg
Drug administration should begin as
soon as possible aftersuspected or
confirmed exposure 2 x 500 mg
Elderly patients should receive a dose as low as possibledepending on the severity
of their illness and the creatinine clearance.
Clinical andpharmacokinetic data support the use of ciprofloxacin in paediatric cystic
fibrosis patients (aged 5-17 years) with acute pulmonary exacerbation associated
withP. aeruginosainfection, at a dose of 20 mg/kgorally twice daily(maximum daily
Inhalational anthrax (post-exposure)
For the indication of inhalational anthrax (post-exposure), therisk-benefitassessment
indicates that treatment of paediatric patients with ciprofloxacin is appropriate. For
paediatric patients, the recommended oral dose is 15 mg/kg twice daily (not to
exceed a maximum dose of 500 mg per dose, 1000 mg per day). Drug administration
should begin as soon aspossible after suspected or confirmed exposure.
Complicated urinary tract infections and pyelonephritis
For the indication of complicated urinary tract infections and pyelonephritis, the
recommended dose is 10to 20 mg/kg orally every 12 hours with a maximum of 750
mg per dose.
Method of Administration:
The tabletsare swallowed whole with a small amount of fluid. Do not halve table.
Dose equivalence whenthe tablet isdivided hasnot been established.
Tablets canbe taken independent ofmealtimes. (If the tablets are taken onan empty
stomach, the active substance is absorbed more rapidly). In this case, tablets should
not be takenconcurrently with dairyproducts orwith mineral fortified drinks alone
(e.g. milk, yoghurt, calcium fortified orange juice). However,dietary calcium as part of
a meal does not significantly affect ciprofloxacinabsorption.
If the patientis unable totake tablets, because ofthe severity of the illness or for
other reasons, it is recommended tocommence the therapy with an intravenous form
After intravenous administration the treatment can be continued orally.
Duration of Treatment:
The duration of treatment dependson the severity of the illness and on the clinical
and bacteriologicalcourse. It is essential to continue therapy for at least 3days after
disappearance of the fever or of theclinical symptoms. Meanduration oftreatment:
1 day for acute uncomplicated gonorrhoea and cystitis,
up to 7 days for infectionsof the kidneys, urinary tract, and abdominal
a maximumof 2 months in osteomyelitis,
60 days in inhalationalanthrax (post-exposure),
and 7-14 days in all other infections.
In streptococcal infections the treatment must last at least10 days because of the
risk of late complications.
Infections causedbyChlamydiashould also betreated fora minimumof 10 days.
For acute pulmonary exacerbation ofcystic fibrosis associated with P. aeruginosa
infectioninpaediatric patients (aged 5-17 years), the duration of treatment is 10-14
Inhalation anthrax (post-exposure)
For inhalational anthrax (post-exposure),the duration of treatment is 60 days.
Complicated urinary tract infections and pyelonephritis
For complicated urinary tract infections or pyelonephritis duetoE. coli, the duration
of treatment is 10-21 days.
Renal & Hepatic impairment:
1. Impaired renal function:
1.1 Where creatinine clearance is between 30 and 60mL/min/1.73m² or where
the serum creatinine concentration is between 1.4 and 1.9 mg/100 mL the
maximum daily dose should be 1000 mg per day.
1.2 Where creatinine clearance is equal or is less than 30 mL/min/1.73m² or
where the serum creatinine concentration is equal or higher than 2.0 mg/100
mL the maximum daily dose shouldbe 500 mg per day.
2. Impaired renal function+ haemodialysis:
Dose as in point 1.2; ondialysis days after dialysis.
3. Impaired renal function+ continuous ambulatory peritoneal dialysis (CAPD)
Administration of ciprofloxacin film coated tablets (oral) as 1x 500 mg film
coated tablet(or 2 x 250 mg film coated tablets).
4. Impaired liver function
No dose adjustment is required.
5. Impaired renal and liver function
Dose adjustment as in points 1.1 and 1.2 above.
Dosing in children with impaired renal and or hepatic functionhas not been studied.
Ciprofloxacin must not be used in cases of hypersensitivity tociprofloxacin or other
quinolone chemotherapeutics or any of the excipients.
Concurrent administration of ciprofloxacin and tizanidineiscontraindicated since an
undesirableincrease inserum tizanidine concentrations associated withclinically
relevant tizanidine-induced side effects (hypotension, somnolence, drowsiness)can
SPECIALWARNINGSAND PRECAUTIONS FOR USE
May cause tendinitis,hypoglycaemia.
Severe infections and/or infections due to Gram-positive or
For the treatment of severe infections, staphylococcal infections and infections
involving anaerobic bacteria, ciprofloxacin shouldbe used incombination with an
Streptococcus pneumoniae infections
Ciprofloxacin is not recommended for treatment of pneumococcal infections due to
inadequate efficacyagainstStreptococcus pneumoniae.
Genital tract infections
Genital tractinfectionsmay be caused by fluoroquinolone-resistantNeisseria
gonorrhoeae isolates. Ingenital tract infectionsthought or known to be due toN.
gonorrhoeae , it is particularly important to obtainlocal information on theprevalence
of resistance to ciprofloxacin and to confirm susceptibility based on laboratory
Ciprofloxacin is associated with cases of QT prolongation (seeADVERSE
EFFECTS).In general, elderly patients may be more susceptible to medicine-
associatedeffects on the QT interval.
Precaution should be taken when using ciprofloxacin with concomitant medicinesthat
can resultinprolongation with the QT interval (e.g., class IA or III antiarrhythmics) or
in patients with risk factors for torsade de pointes (e.g., known QT prolongation,
Children and adolescents
As with medicinal products in its class, ciprofloxacin has been shown to cause
arthropathy in weight-bearing jointsof immatureanimals. The analysis ofavailable
safety data from ciprofloxacin use inpatients less than 18 years of age, the majority
of whom had cystic fibrosis, didnotdisclose any evidence of medicine related
cartilage orarticular damage. The use of ciprofloxacin for indications other than the
treatment of acute pulmonary exacerbation of cystic fibrosiscaused byP. aeruginosa
infection (children aged5-17 years), complicatedurinary tract infectionsand
pyelonephritis due toE.coli(childrenaged 1-17 years) and for the use in inhalational
anthrax (post-exposure) was not studied. Forother indications clinical experience is
For the indication of inhalational anthrax (post-exposure), therisk-benefitassessment
indicates that administration of ciprofloxacin topaediatric patients is appropriate. For
information regarding paediatric dosing in inhalational anthrax(post-exposure), see
“Inhalational Anthrax – Additional Information in Pharmacodynamic Properties”.
In some instances, the hypersensitivity and allergic reactionsoccurred after the first
administration. The doctor should beinformed immediately.
Anaphylactic/anaphylactoid reactions in veryrare instancescan progress to a life-
threateningshock, in some instancesafter the first administration. In these cases
ciprofloxacinhas to be discontinued,medical treatment (e.g. treatment for shock) is
In the event of severe and persistentdiarrhoea during or after treatment a doctor
must be consulted, sincethis symptom can hide a serious intestinal disease (life-
threateningpseudomembranous colitis with possible fatal outcome), requiring
immediate treatment. In such casesCiprofloxacin must be discontinuedand
appropriatetherapy initiated (e. g. vancomycin, orally, 4 x 250 mg/day).Medicines
that inhibit peristalsis are contraindicated.
There can bea temporary increase in transaminases, alkaline phosphatase or
cholestatic jaundice, especially in patients withprevious liver damage.
At any sign of tendinitis(e.g. painfulswelling, inflammation),a physicianshould be
consulted and the antibiotic treatment be discontinued. Care should be taken to keep
the affectedextremity at rest and avoidany inappropriate physical exercise due to
increased risk of tendonrupture.
Tendon rupture (predominantly Achilles tendon) has been reported predominantly in
the elderly on prior systemic treatment with glucocorticoids.
Ciprofloxacin should beused with caution in patients with ahistory of tendon
disorders related to quinolone treatment.
In epilepticsand in patients who have suffered from previousCNS-disorders (e.g.
lowered convulsion threshold, previous historyof convulsion, reduced cerebral blood
flow, alteredbrain structure or stroke), ciprofloxacin shouldonly be used where the
benefits of treatment exceed the risks, sincethese patients are at risk because of
possiblecentral-nervous side effects.
In some instances the CNS reactions occurred after the firstadministration of
ciprofloxacin.In rare cases depression or psychosis canprogress to selfendangering
behaviour. In these cases ciprofloxacin has tobe discontinued and thedoctor should
be informed immediately.
Skin and Appendages:
Ciprofloxacin has beenshown to produce photosensitivity reactions. Patients taking
ciprofloxacinshould avoid direct exposure toexcessive sunlight or UV-light. Therapy
should be discontinuedif photosensitisation (i.e.sunburn-like skin reactions) occurs.
Ciprofloxacin is known tobe a moderate inhibitorof the CYP 450 1A2 enzymes. Care
should be taken when other medicinal productsare administered concomitantly
which are metabolised via the same enzymatic pathway (e.g. theophylline,
methylxantines, caffeine, duloxetine, clozapine).
Increased plasma concentrations associated withmedicinespecific sideeffects may
be observed due to inhibition of theirmetabolic clearance by ciprofloxacin.(See
section “Interaction withother medicinal products and other forms of interaction”).
Interaction with tests
Ciprofloxacinin vitropotency may interfere with theMycobacteriumspp.culture test
by suppression of mycobacterial growth, causingfalse negative results inspecimens
from patients currently taking ciprofloxacin.
Interaction with other medicinal products and other forms of
Class IA or III antiarrhythmics
Precaution should be taken when using ciprofloxacin together with classIAor III
antiarrhythmics asciprofloxacin mayhave an additive effect onthe QT interval.
Chelation Complex Formualtion
The simultaneous administration ofciprofloxacinand multivalent cation-containing
medicinal products andmineral supplements (e.g. calcium,magnesium,aluminium,
iron), polymeric phosphate binders (e.g. sevelamer, lanthanum carbonate), sucralfate
or antacidsand highly buffered medicines (e.g. didanosine tabelts), containing
magnesium,aluminium, or calcium reduce the absorption ofciprofloxacin.
Consequently, ciprofloxacin shouldbeadministered either 1-2 hoursbefore, or at
least 4 hoursafterthese preparations.
This restriction does notapply to antacids belonging to the class of H2 receptor
Food and Dairy Products
The concurrent administration of dairyproducts or mineral fortified drinksalone (e.g.
milk, yoghurt, calcium fortified orange juice) andciprofloxacinshould be avoided
because absorption of ciprofloxacinmay be reduced. Dietary calcium aspart of a
meal, however, does not significantly affect absorption.
Concomitant administration of ciprofloxacin and omeprazole results inaslight
and AUC of ciprofloxacin.
Concurrent administration of ciprofloxacin and theophyllinecan cause anundesirable
increase inthe serum theophylline concentration. This canlead to theophylline-
induced sideeffects; invery rare cases theseside effectscan be life-threatening or
fatal. If concurrent use ofthe two products is unavoidable, the serum theophylline
concentrationshould therefore be checked and the theophylline dose appropriately
Other xanthine derivatives
On concurrent administration of ciprofloxacin and caffeine orpentoxifylline
(oxpentifylline) containingproducts, raised serum concentrations of thesexanthine
derivatives were reported.
Animal studies have shown that the combination of very highdoses of quinolones
(gyrase inhibitors) and certain non-steroidal anti-inflammatory agents (butnot
acetylsalicylic acid) canprovoke convulsions.
A transient rise in theconcentrationof serum creatinine wasobserved when
ciprofloxacinand cyclosporin were administered simultaneously. Therefore, it is
necessary tomonitor the serum creatinine concentrations inthese patients frequently
(twice a week).
Vitamin K antagonists
Simultaneous administration of ciprofloxacin with a Vitamin K antagonistmay
anticoagulant effects. The risk may varywith the underlying infection, age and
general status of the patient so that the contribution of ciprofloxacin to the increasein
INR (international normalized ratio)is difficult toassess.TheINR should be
monitored frequently during and shortly after co-administration of ciprofloxacin with a
Vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).
In particularcases,concurrent administration ofciprofloxacinand glibenclamide can
intensify theaction of glibenclamide (hypoglycaemia).
Renal tubular transportof methotrexate may be inhibited by concomitant
administration of ciprofloxacin potentially leadingto increased plasma levels of
methotrexate. This might increase the risk of methotrexate associated toxic
reactions. Therefore, patients undermethotrexatetherapy should be carefully
monitored when concomitant ciprofloxacin therapy is indicated.
Metoclopramide accelerates the absorption of ciprofloxacinresulting ina shorter time
to reach maximum plasma concentrations. No effect was seen on the bioavailability
In a clinicalstudy in healthy subjects, there was an increasein tizanidineserum
increase: 7-fold,range: 4 to21-fold; AUC increase:10-fold,
range: 6 to24-fold) when given concomitantlywith ciprofloxacin. Associated with the
increasedserum concentrations was a potentiated hypotensive and sedative effect.
Tizanidinemust not be administered together with ciprofloxacin (see
In clinical studies it wasdemonstrated that concomitant use of duloxetine with strong
inhibitors ofthe CYP4501A2 isozyme such as fluvoxamine, may result in an
increase ofAUC and C
of duloxetine. Although no clinicaldata are available on a
possibleinteraction withciprofloxacin,similar effects can be expected upon
In a clinicalstudy it was shown that concomitantuse of ropinirole with ciprofloxacin, a
moderate inhibitor of theCYP450 1A2 isozyme, resulted inincreases inthe C
AUC of ropinirole of 60% and 84%, respectively. Monitoring ropinirole-related side
effects doseadjustment as appropriate is recommended during and shortly after co-
administration with ciprofloxacin.
It was demonstrated in healthy subjects that concomitant use of lidocainewith
ciprofloxacin,a moderate inhibitor ofCYP450 1A2 isozyme, reduces clearance of
intravenous lidocaine by22%.
Although lidocaine treatment was well tolerated,a possible interaction with
ciprofloxacinassociatedwith side effects may occur upon concomitant
Following concomitant and administration of 250mg ciprofloxacin for 7 days, serum
concentrationof clozapine and N-desmethylclozapine were increased by 29% and
31%, respectively. Clinical surveillance and appropriate adjustment of clozapine
dosage during and shortly after co-administration with ciprofloxacin are advised.
and AUC of sildenafil were increased approximately two-fold in healthy subjects
after an oral dose of 50mg given concomitantly with 500 mg ciprofloxacin. Therefore,
caution should be usedprescribingciprofloxacinconcomitantly with sildenafil taking
into consideration the risks and the benefits.
Pregnancy and Lactation
Since the safety of ciprofloxacin in pregnant women has not been established and
since, on the basis of animal studies, itis not entirely improbable that the medicine
could causedamage to articular cartilage in theimmature foetal organism (see
PRECLINICAL SAFETY DATA), ciprofloxacin must not be prescribed topregnant
Animal studies have not shown any evidenceof teratogeniceffects (malformations).
Ciprofloxacin is excretedin breastmilk. Due to the potential risk of articular damage,
ciprofloxacinshould notbe used during breast-feeding (seePRECLINICAL SAFETY
Effect on Ability to Drive and Use Machines
Fluoroquinolones including ciprofloxacin may result in animpairment of the patient's
ability to drive or operate machinerydue to CNSreactions. This applies particularly in
combination with alcohol.
Adverse Reactions based on all clinical studieswith ciprofloxacin sortedby CIOMS III
categories offrequency are listed below (n = 51721 patients,data lock point: 15 May
The frequencies of Adverse Drug Reactions (ADRs) reported with ciprofloxacin are
summarised in the tablebelow. Within each frequency grouping, undesirable effects
are presented in orderof decreasing seriousness.
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1000 to <1/100)
Rare (≥1/10000 to <1/1000)
Very rare (<1/10000)
Not known (cannot be estimated from the available data)
The ADRs identified only during post-marketing surveillance,and for which a
frequency could not beestimated, are listed under “not known”.
Class Common UncommonRare Very Rare Not Known
Disorders Eosinophilia Leukopenia
Disorders Anorexia Hyperglycaemia
agitation Confusion and
Taste disorders Par- and
Eye Disorders Visual
disturbances Visual colour
Hearing loss Hearing
Disorders Tachycardia QT
Disorders Increase in
infective) Liver necrosis
Disorders Arthralgia Myalgia
tone andcramping Muscular
impairment Renal failure
Disorders and Unspecific pain
Feeling unwell Oedema
Sweating Gait disturbance
Site Disorders Fever(hyperhidrosis)
Investigations Increase in
phosphatase Prothrombin level
* These events were reported duringthe post-marketing period and were observed
predominantly among patients with further risk factors for QT prolongation(see
SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
The followingundesirable effects have a higher frequency category in the subgroups
of patients receiving intravenous or sequential (intravenous to oral) treatment:
Common Vomiting, transient increase in transaminases,rash
Uncommon Thrombocytopenia, thrombocytaemia, confusionand disorientation,
hallucinations, par- anddysaesthesia, seizures,vertigo, visual
disturbances, hearing loss, tachycardia, vasodilatation,
hypotension, transient hepatic impairment, jaundice, renal failure,
Rare Pancytopenia, bone marrow depression, anaphylactic shock,
psychotic reactions, migraine, smelldisorders, hearing impaired,
vasculitis, pancreatitis, liver necrosis, petechiae,tendon rupture
In the event of acute, excessive oralover dosage, reversible renal toxicity has been
reported in some cases.
Therefore, apart from routine emergency measures, it is recommended tomonitor
renal functionand to administer Mg- or Ca-containing antacids which reduce the
Only a smallamount of ciprofloxacin(< 10 %) is removed fromthe bodyafter
haemodialysis or peritoneal dialysis.
Ciprofloxacin is a synthetic broad spectrum antibacterial agent (ATCCODE: J 01 MA
Mechanism of Action
Ciprofloxacin is effectivein vitroagainst a wide range of Gram-negativeand Gram-
positive organisms. Thebactericidal action ofciprofloxacin results from inhibition of
bacterial typeII topoisomerases (DNA gyrase and topoisomerase IV), which are
required forbacterial DNA replication,transcription, repair, and recombination.
Mechanism of Resistance
In vitro resistance to ciprofloxacin iscommonly due to mutations in bacterial
topoisomerases and DNA gyrase through multiple-step mutations. Singlemutations
may result in reduced susceptibility rather than clinical resistance, but multiple
mutations generally result in clinicalresistance tociprofloxacin and cross-resistance
across the quinolone class.
Resistancemechanisms that inactivate other antibiotics such as permeation barriers
(common inPseudomonas aeruginosa) and effluxmechanisms may affect
susceptibility to ciprofloxacin.
Plasmid-mediated resistance encoded by theqnrgene has been reported.
Resistancemechanisms that inactive penicillins,cephalosporins, aminoglycosides,
macrolides,and tetracyclines may not interferewith the antibacterial activity of
ciprofloxacinand there is no known cross-resistance between ciprofloxacin and other
classes of antimicrobials. Organisms resistant tothese medicines may be susceptible
The minimum bactericidal concentration (MBC)generally does not exceed the
minimal inhibitory concentration (MIC) bymore than a factorof 2.
In vitroSusceptibilityto Ciprofloxacin
The prevalence of acquired resistance may vary geographically and with time for
selectedspecies andlocal information of resistance is desirable, particularly when
treating severe infections. As necessary, expertadvice should be soughtwhere the
local prevalence of resistance is such thatutility of the agent, in at leasesome types
of infections, is questionable.
The bacterialgenus andspecieslisted below have been shown to commonly be
susceptible tociprofloxacinin vitro:
Aerobic Gram-Positive Microorganisms
Staphylococcus aureus (methicillin-susceptible)
Aerobic Gram-Negative Microorganisms:
Aeromonas spp. Moraxella catarrhalis
Brucella spp. Neisseria meningitidis
Citrobacter koseri Pasteurella spp.
Francisella tularensis Salmonella spp.
Haemophilus ducreyi Shigella spp.
Haemophilius influenzae Vibrio spp.
Legionella spp. Yersinia pestis
The followingmicroorganisms show varying degrees of susceptibility to ciprofloxacin:
Acinetobacter baumann ,Burkholderia cepacia,Campylobacterspp.,
Citrobacterfreudii, Enterococcusfaecalis,Enterobacter aerogenes, Enterobacter
clocae, Escherichia coli,Klebsiella pneumoniae, Klebsiella oxytoca, Morganella
morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris,Providencia
spp., Pseudomonas aeruginosa, Pseudomonas fluorescens,Serratia marcescens,
Streptococcus pneumoniae, Peptostreptococcus spp., Propionibacteriumacnes.
The followingmicroorganisms are considered inherently resistant to ciprofloxacin:
Staphylococcus aureus (methicillin-resistant) andStenotrophomonas maltophilia,
Actinomyces ,Enteroccus faecium,Listeria monocytogenes,Mycoplasma genitalium,
Ureaplasmaurealitycum , Anaerobicmicroorganisms (ExceptMobiluncus,
Inhalational anthrax – additional information
Studies have been conducted in experimental animal infections due to inhalations of
Bacillus anthracis spores; these studies reveal that antibiotics starting early after
exposition,avoid the occurrence of the diseaseif the treatment is made up to the
decrease ofthe number of spores inthe organism under the infective dose.
The recommended use in human subjects is based primarily onin vitrosusceptibility
and on animal experimental data togetherwith limited humandata. Two month
treatment duration in adults with oral ciprofloxacin given at the following dose, 500
mg bid, is considered aseffective toprevent anthrax infection in humans. The
treating physicianis referred to national and /or internationalconsensusdocuments
regarding treatment of anthrax.
The mean serum concentrations ofciprofloxacinassociatedwith a statistically
significant improvementin survival inthe rhesus monkey model of inhalational
anthrax are reached orexceeded in adultand paediatric patients receiving oral
regimens (see DOSAGE ANDMETHODOF ADMINISTRATION).
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean
dose of 11 LD
(~5.5 x10 5 ) spores(range 5-30 LD
) ofB. anthraciswas conducted.
The minimal inhibitory concentration(MIC) of ciprofloxacin for the anthrax strain used
in this study was 0.08μg/mL. In the animals studied, mean serum concentrations of
ciprofloxacinachieved at expected T
(1 hour post-dose) following oraldosing to
steady state ranged from 0.98 to 1.69μg/mL.Mean steady-state trough
concentrations at 12 hours post-doseranged from 0.12 to 0.19μg/mL.
Mortality due to anthrax for animals that received a 30-day regimen of oral
ciprofloxacinbeginning 24hours post-exposure was significantly lower (1/9),
compared to the placebogroup (9/10) [p = 0.001]. The one ciprofloxacin-treated
animal that died of anthrax did so following the 30-day medicine administration
Following oral administration of single doses of250 mg, 500 mg, and 750 mg of
ciprofloxacinfilm coatedtablets, ciprofloxacin isabsorbed rapidly and extensively
mainly fromthe small intestine, reaching maximum serum concentrations 1-2 hours
Mean Ciprofloxacin Serum Concentrations (mg/L) after
(Time from tablet intake)
Time (h) 250 mg 500 mg 750 mg
0.5 0.9 1.72.9
1.0 1.3 2.53.5
2.0 0.9 2.02.9
4.0 0.5 1.71.7
8.0 0.3 0.60.8
The absolute bioavailability is approximately 70-80%. Maximum serum
) and total areas under serum concentration vs. time curves
(AUC) increased in proportion to dose.
The proteinbinding of ciprofloxacin is low (20-30%), and the substanceis present in
plasma largely in a non-ionised form. Ciprofloxacin can diffuse freely into the
extravascular space. The large steady-statevolume of distribution of 2-3L/kg body
weight shows that ciprofloxacin penetrates into tissues resulting in concentrations
which clearly exceed the corresponding serum levels.
Small concentrations of4 metabolites have been reported. They were identified as
desethyleneciprofloxacin(M 1), sulphociprofloxacin (M 2), oxociprofloxacin(M 3) and
formylciprofloxacin (M 4). M 1 to M 3display antibacterial activity comparable to or
inferior to that of nalidixic acid. M 4,with the smallest quantity, is largely equivalent to
norfloxacin in its antimicrobial activity.
Ciprofloxacin is largelyexcreted unchanged both renally and, to a smaller extent,
Excretion of Ciprofloxacin (%of dose)
Ciprofloxacin 44.7 25.0
) 11.3 7.5
Renal clearance is between 0.18-0.3 L/h/kg andthe total body clearance between
0.48-0.60 L/h/kg. Ciprofloxacin undergoes both glomerular filtration and tubular
Non-renal clearance of ciprofloxacin is mainly due to active transintestinal secretion
as well as metabolisation. 1% of thedose is via the biliary excreted route.
Ciprofloxacin is presentin the bileinhigh concentrations.
In a study in children, C
and AUC were not age-dependent. No notable increasein
and AUC upon multiple dosing(10 mg/kg/TID) was observed.
Theacute toxicityof ciprofloxacinafter oral administrationcan be classified as very
Mouse Approx. 5000
Rat Approx. 5000
Rabbit Approx. 2500
Subacute tolerability studies over 4 weeks:
Doses up toand including 100 mg/kg were tolerated without damage byrats.
Pseudoallergic reactionsdue to histamine release were observed in dogs.
Subchronic Toxicity Studies over 3 months
All doses upto and including 500 mg/kg were tolerated without damage by rats. In
monkeys, crystalluria and changes in the renal tubules were observed in the highest-
dose group(135 mg/kg).
Chronic tolerability studies over 6 months
Doses up toand including 500 mg/kg and 30 mg/kg were tolerated without damage
by rats and monkeys, respectively. Changes inthe distal renal tubuleswere again
observed in some monkeys in the highest-dosegroup (90 mg/kg).
In carcinogenicity studiesin mice (21 months) and rats (24months) with doses up to
approx. 1000 mg/kg bw/day in mice and 125 mg/kg bw/day in rats (increased to 250
mg/kg bw/day after 22 weeks), there was no evidence of a carcinogenicpotential at
any dose level.
Fertility studies in rats
Fertility, theintrauterineand postnatal development of the young, and thefertility of
F1 generation were not affected by ciprofloxacin.
These yielded no evidence of any embryotoxic or teratogenic actionof ciprofloxacin.
Perinatal and postnataldevelopment in rats
No effects onthe perinatal or postnatal development of the animals were detected. At
the end of the rearing period histological investigations did not bring to light any sign
of articular damage in the young.
Eightin vitromutagenicitytests have been conducted with ciprofloxacin.
Test resultsare listed below:
Salmonella : Microsome Test (Negative)
E. coli : DNA Repair Assay (Negative),
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRTTest (Negative),
Syrian Hamster EmbryoCell Transformation Assay (Negative)
Saccharomyces cerev .:Point Mutation Assay (Negative), Mitotic
Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte PrimaryCulture DNA Repair Assay (UDS) (Positive)
Thus, two of the eight tests were positive, but results of thefollowing fourin vivotest
systems gave negative results:
Rat Hepatocyte DNA Repair Assay
Dominant Lethal Test (Mice)
Chinese Hamster Bone Marrow
Although two of the eightin vitroassays (i.e. the Mouse Lymphoma Cell Forward
Mutation Assay and the Rat Hepatocyte PrimaryCulture DNA Repair Assay [UDS])
were positive, all of theinvivotest systems covering all relevant endpoints gave
In summary, ciprofloxacin poses nosignificant mutagenic potential. Thisassessment
is confirmedby the negative outcome of the long-term carcinogenicity studies in mice
Special tolerability studies
It is known from comparative studies in animals,both with the older gyrase inhibitors
(e.g. nalidixic and pipemidic acid) and the more recent ones (e.g. norfloxacin and
ofloxacin), that this substance class produces acharacteristic damage pattern.
Kidney damage, cartilagedamage in weight-bearing joints of immature animals, and
eye damagemay be encountered.
The crystallisation observed in the animal studiesoccurred preferentially under pH
conditions that do not apply in man.
The precipitation of crystals in renaltubules does not immediately and automatically
lead to kidney damage.In the animal studies damage occurred only after high doses,
with correspondingly highlevels of crystalluria. For example,although theyalways
caused crystalluria, evenhigh doseswere tolerated over 6 months without damage
and without foreign-body reactions occurring inindividual distal renal tubules.
Damage to the kidneyswithoutthe presence ofcrystalluriahas not been observed.
The renal damage observed in animal studiesmust not, therefore, as is the case e.g.
with the aminoglycosides, be regarded as a primary toxic action of ciprofloxacin on
the kidney tissue, but as typical secondary inflammatory foreign-body reactions due
to the precipitation of a crystalline complex of ciprofloxacin,magnesium,and protein.
Articular tolerability studies
As with other gyrase inhibitors, ciprofloxacin causes damage to the large,weight-
bearing jointsin immature animals.
The extent of the cartilagedamage varies according to age, species, anddose; the
damage can be reducedby taking the weight off the joints. Studies with mature
animals (rat, dog) revealed no evidence of cartilage lesions.In a study in young
beagle dogs ciprofloxacin at high doses (1.3 to 3.5 times the therapeuticdose)
caused articular changes after two weeks of treatment, which were stillobserved
after 5 months. At therapeutic doses, no effects were observed.
Studies aimed at excluding cataractogenic effects
On the basis of the investigationsitmay be stated from a toxicological point of view
that ciprofloxacin treatment does notinvolve anyrisk of cataract induction,
particularlybecause inparental administrationmaximal bioavailability can be
assumed and the duration of administration was6 months.
Retina tolerability studies
Ciprofloxacin binds to the melanin containing structures including the retina. Potential
effects ofciprofloxacinon the retinawere assessed in various pigmented animal
species.Ciprofloxacin treatment had no effect onthe morphological structures of the
retina and onelectroretinographic findings.
List of Excipients
Microcrystalline cellulose, maize starch, magnesium stearate, colloidalanhydrous
silica, sodiumstarch glycolate type A (potato starch), hypromellose, purified talc,
titanium dioxide (E171), polyethylene glycol.
Store below 25°C.
Nature and Contents of Container:
Blister packs containing7, 10, 14, 20, 28, 56 or100 tablets
(Not all pack sizes may be available).
Multichem NZ Limited
8 Apollo Drive
North Shore City 0632
Telephone:09 488 0330
Date of Preparation
24 August 2010