Ciproxin

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Ciprofloxacin hydrochloride 582 mg equivalent to ciprofloxacin 500 mg, as monohydrate
Available from:
Bayer New Zealand Limited
INN (International Name):
Ciprofloxacin hydrochloride 582 mg (equiv. ciprofloxacin 500 mg, as monohydrate)
Dosage:
500 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Ciprofloxacin hydrochloride 582 mg equivalent to ciprofloxacin 500 mg, as monohydrate Excipient: Colloidal silicon dioxide Crospovidone Hypromellose Macrogol 4000 Magnesium stearate Maize starch Microcrystalline cellulose Titanium dioxide
Units in package:
Blister pack, PP/Al, 14 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Bayer AG
Therapeutic indications:
In Adults Uncomplicated and complicated infections caused by ciprofloxacin sensitive pathogens: Infections of the lower respiratory tract.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVdC/Alu, Al/Al or PP/Al - 14 tablets - 60 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-4284b
Authorization date:
1988-02-04

CIPROXIN ®

TABLETS

(Ci·PROX·in)

ciprofloxacin

ConsumerMedicineInformation

WHATISINTHIS

LEAFLET

Thisleafletanswers some common

questions aboutCiproxintablets.

Itdoesnotcontainallthe available

information.Itdoesnottake the

placeoftalkingtoyourdoctoror

pharmacist.

Allmedicineshave risks and

benefits. Yourdoctorhasweighed

therisksofyoutakingCiproxin

tabletsagainstthebenefitsthey

expectitwillhave foryou.

Ifyou have anyconcernsabout

takingthis medicine, askyour

doctoror pharmacist.

Keepthis leafletwith the

medicine.

Youmayneedtoread itagain.

WHATCIPROXINIS

USEDFOR

Ciproxintablets areusedforthe

treatmentofinfectionsofthe lungs,

skin,bones,joints, kidneys,bladder,

prostate andbowel.Ciproxinis also

usedtotreatinhalationalanthrax

(aninfectioncausedbybreathingin

the sporesofbacteria).

Ciproxintablets containtheactive

ingredient,ciprofloxacin,whichis

an antibioticbelongingto agroupof

medicinescalledquinolones

(pronouncedkwin-o-lones). These

antibioticsworkbykillingthe

bacteriathatare causingyour

infection.

Ciproxinwillnotworkagainst

infectionscausedbyviruses suchas

coldsorthe flu.

Ask your doctorifyou have any

questions aboutwhythis

medicine has been prescribedfor

you.

Yourdoctormayhave prescribedit

foranotherreason.

BEFOREYOUTAKE

CIPROXIN

Whenyou must nottakeit

Do not take Ciproxin ifyou have

an allergyto:

ciprofloxacin,theactive

ingredientinCiproxin

anyoftheingredientslistedat

the endofthisleaflet

othermedicinesbelongingto

thequinolonechemicalfamily

(e.g. moxifloxacin,norfloxacin,

nalidixicacid).

Some ofthe symptoms ofan

allergicreactionmayinclude:

shortnessofbreath

wheezingordifficultybreathing

swellingoftheface, lips,

tongueorotherpartsofthe

body

rash,itchingorhiveson the

skin.

Do not takeCiproxinifyou are

alsotaking amedicine called

tizanidine,amusclerelaxant used

to treatspasticity associatedwith

multiple sclerosis,injuryor

diseasesofthe spinalcord.

Ciproxincaninterfere with

tizanidine andcanlead to

Do not take thismedicineafter the

expiry date printedon thepack

andblister.

The expirydate isprintedonthe

cartonandoneachblisterafter

“EXP”(e.g.1113refers to

November2013). The expirydate

referstothelastdayofthatmonth.

Ifithasexpiredreturnittoyour

pharmacistfordisposal.

Do not take thismedicineifthe

packaging istorn or shows signs

oftampering.

Ifthepackagingisdamaged,return

ittoyourpharmacistfordisposal.

Ifyou arenotsurewhetheryou

should starttakingthis medicine,

talkto your doctor.

Beforeyou start totakeit

Tellyour doctorifyou have

allergiesto anyother medicines,

foods, preservativesor dyes.

Tellyour doctorifyou are

pregnantorplan to become

pregnant.Ciproxinisnot

recommendedifyouarepregnantbut

yourdoctorwillassessthebenefitif

required.Medicines similarto

Ciproxinhave causedjointdiseasein

immature animals.

Tellyour doctorifyou are

breastfeeding.

Ciproxinis excreted intothebreast

milk. Yourdoctorwilltellyou

whetheryoushouldtake itand

temporarilystopbreastfeedingwhile

youare takingthe tablets.

Ciproxin isnotrecommended in

children under 18 years ofage

exceptfor useininhalational

anthrax.

Ciproxin should be usedwith

caution inelderly patientsas they

aremoreproneto sideeffects.

Tellyour doctorifyou:

sufferfromepilepsy(seizures,

convulsions),havehada stroke,

orhave kidneyorliverdisease

havearrhythmias(fastor

irregularheartbeats).Ciproxin

mayincreasetheriskof

arrhythmias,especiallyinthe

elderlyorpatients withlow

potassiumlevels

havepreviouslytaken

corticosteroids.You maybe at

increasedriskofswellingofthe

tendons.Symptoms includepain,

tendernessand sometimes

restrictedmovement

have myasthenia gravis, a

condition where themuscles

become weak. Ciproxincan

worsenthesymptomsofthis

condition

have ahistoryoftendon

disorders withtheuseof

quinolones(e.g. moxifloxacin,

norfloxacin,nalidixic acid)

Ifyou have nottold yourdoctoror

pharmacistaboutanyofthe above,

tellthembeforeyoustarttaking

Ciproxin.

Taking other medicines

Tellyour doctorifyou are taking

any other medicines, including

thosethatyou buywithouta

prescriptionfromyour pharmacy,

supermarketorhealthfood shop.

Some medicines maybe affectedby

Ciproxin. These medicinesinclude:

medicinesusedtotreat

arrhythmias(fastorirregular

heartbeats)

theophylline, amedicineused to

oralanticoagulants,warfarinand

its metabolites, medicinesused

tostopbloodclots

phenytoin,a medicineused to

treatepilepsy

oralantidiabetic agents

didanosine, amedicineusedto

treatviralinfections

cyclosporin,a medicineusedto

suppresstheimmune system

non-steroidalanti-inflammatory

drugs(NSAIDs), medicines

usedtotreatpain,arthritisand

otherinflammatoryconditions

methotrexate, a medicineusedto

treatcertaintypesofcancers,

severepsoriasisorsevere

rheumatoid arthritis

duloxetine,a medicineusedto

treatdepression,anxiety,and

nervepaininpeople with

diabetes

clozapine, amedicineusedto

treatschizophrenia

ropinirole, a medicineusedto

treatParkinson’sdiseaseor

restlesslegs syndrome

thelocalanaesthetic lidocaine,a

medicineusedtonumbpainor

causelossofsensation

sildenafil, amedicineusedto

treaterectiledysfunction

These medicines maybe affectedby

Ciproxin,ormayaffecthowwellit

works.You mayneeddifferent

amountsofyourmedicine,oryou

mayneedtotakedifferent

medicines.

Some medicines mayinterfere with

the absorptionofCiproxin.These

include:

multivitamins, mineral

supplements, antacids(usedfor

indigestion)andothermedicines

containingiron, zinc,

magnesium, aluminiumor

calcium

sucralfate, amedicineusedto

treatduodenalorstomachulcers

medicinesusedtotreatHIV

probenecid, a medicineusedto

treatgout

omeprazole, a medicineusedto

treatstomachulcers andother

conditions wherestomach

producestoomuch acid

sevelamer, a medicineused to

treathighblood levelsof

phosphorusinpatients with

kidneydiseasewhoareon

dialysis

metoclopramide,a medicine

usedtorelievenauseaand

vomiting,heartburn, and

stomachpain

Youcanstilltakethese medicines

while youaretakingCiproxin.

However,youmusttakeCiproxinat

least2hoursbeforeor2hours after

takinganyofthesemedicines.

Yourdoctorandpharmacisthave

more informationonmedicinesto

becarefulwithoravoidwhile

takingthismedicine.

HOWTOTAKE

CIPROXIN

Followalldirections given to you

by your doctoror pharmacist

carefully.

Theymaydifferfromthe

informationcontainedinthis leaflet.

Ifyou donot understandthe

instructionsprinted onthe

pharmacistlabel, ask your doctor

or pharmacistfor help.

How much to take

Yourdoctororpharmacistwilltell

youhowmuchandhowoften you

should takeCiproxin. Thiswill

dependon the typeofinfectionand

anymedicalconditions you may

have.

Theusualadultdosage formost

infectionsisonetablettwicedaily

for7to14days. Youmayneedto

take yourtablets fora longerperiod

forsome typesofinfection.The

dosewillbedeterminedbyyour

doctoras itdependsuponthetypeof

infectionyouhave.

Whentotakeit

Ciproxintablets areusuallytaken

twiceaday. Takeyourtabletsatthe

same time eachdaypreferablyonan

emptystomach.However, theycan

betakenwithorwithoutfood.

How long to takeit

The lengthoftreatmentmayvary

fromone to28days orlonger

dependingon the typeofinfection.

ContinuetakingCiproxinuntil

you havefinishedthe blisterpack

orfor aslong as your doctor tells

you. Donotstop takingyourtablets

becauseyou are feelingbetter.If

youdonotcompletethe fullcourse

prescribedbyyourdoctor, the

infectionmaynotclearcompletely

oryoursymptoms mayreturn.

If you forget to takeit

Ifitis almosttime foryournext

dose, skipthedoseyoumissedand

take yournextdose whenyouare

meantto. Otherwise,take itassoon

asyouremember, and thengoback

totakingitasyouwouldnormally.

Donottake adoubledosetomake

upforthedose thatyoumissed.

Ifyouarenotsure whattodo,ask

yourdoctororpharmacist.

Ifyouhave troubleremembering

when totake yourmedicine, ask

yourpharmacistforsomehints.

If you taketoo much

(overdose)

Immediatelytelephoneyour

doctor, orthePoisons Information

Centre(telephonein Australia

131126,in NewZealand0800

POISONor 0800 764766), or go

to theAccidentandEmergency

departmentatyour nearest

hospital,ifyou thinkyouor

anyone elsemayhavetaken too

muchCiproxin. Do thiseven if

poisoning.Youmayneedurgent

medicalattention.

WHILEYOUARE

TAKINGCIPROXIN

Thingsyou must do

Tellallthedoctors, dentists and

pharmacistswhoaretreating you

that you aretakingCiproxin.

Tellyour doctorifyou need to

have a surgicalor dental

procedure thatyouaretaking

Ciproxin.

Ciproxin may affectthe results of

certainlaboratory tests.Ifyouare

abouttohave anytests,tellyour

doctorthatyouaretakingthis

medicine.

Ifyou areaboutto bestarted on

any newmedicine,remind your

doctorandpharmacistthatyou

aretaking Ciproxin.

Drinkplentyofwaterwhileyouare

takingCiproxin.Thishelpstostop

crystals formingin theurine.

Ifyou become pregnantwhileyou

aretakingCiproxin, tellyour

doctorimmediately.

Ifyou develop diarrhoea,tellyour

doctoror pharmacistimmediately

-evenifitoccurs severalweeks

afteryouhave stopped taking

Ciproxin.Diarrhoea maymeanthat

youhave aseriouscondition

affectingyourbowel.Youmayneed

urgentmedicalcare. Donottake any

medications fordiarrhoeawithout

checkingwithyourdoctoror

pharmacist.

Tellyour doctorimmediatelyif

you experiencesymptomsof

depressionor self-endangering

behaviour.Ciproxinshouldbe

Thingsyou must notdo

Do not give yourCiproxintablets

to anyone else,evenifthey have

the samecondition as you.

DonotuseCiproxintotreatother

conditionsunlessyourdoctortells

youto.

Do not stop taking your tablets

becauseyou arefeeling better,

unless your doctor told you to do

so.Ifyoudonotcomplete thefull

courseprescribedbyyourdoctor,

someofthebacteriacausingyour

infectionmaynotbe killed.These

bacteria maycontinue togrowand

multiplysothatyourinfectionmay

notclearupcompletelyoritmay

return.

What to becarefulof

Avoid excessiveexposureto direct

sunlight.Yourskinmaybecome

morepronetosunburn. Ifsuch a

reactionoccurs, stoptakingCiproxin

immediatelyandtellyourdoctor.

Becareful driving or operating

machineryuntilyou knowhow

Ciproxinaffects you.Ciproxin

tablets maycausedizzinessinsome

patients, especiallyafterthefirstfew

doses.Yourabilitytodrive and/or

operate machinerymaybe impaired.

Ifyoudrinkalcoholwhile taking

this medicine,dizziness maybe

worse.

Ciproxintablets mayincreasethe

stimulatoryeffects ofcaffeine.

SIDEEFFECTS

Tellyour doctoror pharmacistas

soon as possible ifyou donotfeel

wellwhileyou are taking

Ciproxin.

Allmedicineshave side effects.

Sometimestheyare serious, mostof

thetime theyarenot.Inserious

cases, youmayneed medical

attention.

Do not be alarmed bythe

followinglistsofside effects. You

may notexperienceany ofthem.

Ask your doctoror pharmacistto

answerany questions youmay

have.

Tellyour doctorifyou notice any

ofthefollowing andtheyworry

you:

nausea

diarrhoea

Thesearethecommonsideeffects

ofCiproxin. Theyareusuallymild

and short-lived.

Tellyour doctorimmediately, or

go totheAccidentand

Emergency departmentatyour

nearesthospitalifyou noticeany

ofthefollowing:

severe skinrashes,peelingof

the skinand/ormucosal

reactions

signsofallergysuchasrash,

swellingofthe face, lips,

mouth,throatorotherpartsof

thebody, shortnessofbreath,

wheezingortroublebreathing

fainting

yellowingoftheskinandeyes,

alsocalled jaundice

severe wateryorbloody

diarrhoea, evenifitoccurs

severalweeks aftertakingyour

tablets

fits (seizures,convulsions)

confusion,nightmares,

hallucinations,andpsychotic

reaction (evenprogressingto

self-endangeringbehaviour)

fastorirregularheartbeats

visualdisturbances

ringinginthe ear,lossof

hearing

abdominalpain/cramps.Very

rarelythis canprogresstoa

seriousconditionaccompanied

byfeverandfatigue.

Theseseriousside effectsare rare.

Ifyouhave them,youmayneed

urgentmedicalattention.

Photosensitivity(gettingsunburnt

veryeasily)canoccasionallyoccur

withCiproxin. However, itis

temporaryandstayingoutofdirect

sunlightwhileonCiproxintablets

willpreventitfromhappening.

Rarely, there canbe aworseningof

the symptoms ofmyasthenia gravis.

Thisis aconditioninwhich the

musclesbecome weakandtire

easily, causingdroopingeyelids,

doublevision,difficultyinspeaking

and swallowing,andsometimes

muscle weaknessinthe arms or

legs.

Rarely, the Achillestendon

(extendingfromthe calftotheheel

ofthe foot)orothertendonshave

beentornafterCiproxintherapy.

Tellyourdoctorimmediatelyifyou

feelanydiscomfort,painor

inflammationofatendon.

Rarely,youmayexperience

hyperglycaemia (highbloodsugar),

orhypoglycaemia(lowblood

sugar). Symptomsof

hyperglycaemiaincludeincreased

thirst, appetite andurination.

Symptoms ofhypoglycaemia

includeweakness, shaking,

sweating,lightheadedness,

headache,behaviouralchanges,

confusion,numbness/pins and

needlesinthelips, fingersortoes,

irritabilityandhunger.Tellyour

doctorifyou experience these

symptoms.

Ifyouexperienceanyofthese

symptoms during treatmentwith

Ciproxin tablets,tellyourdoctor

or pharmacistimmediately.

Ciproxin may needto be

discontinued.

Tellyour doctoror pharmacistif

you noticeanything elsethat is

Otherside effectsnotlisted above

mayalsooccurinsomepatients.

AFTERUSING

CIPROXIN

Storage

Keepyourtabletsinthe blister

pack untilitistimeto take them.

Ifyoutakethetabletsoutofthebox

ortheblisterpacktheymay notkeep

well.

Keepyourtabletsin acooldry

placewherethetemperature stays

below25

C.

Do not storeCiproxinorany

othermedicinein the bathroom,

near a sink, or on awindowsill.

Do not leaveitinthe car.

Heatanddampcandestroysome

medicines.

Keepyourtabletswherechildren

cannotreachthem.Alocked

cupboardatleastone andahalf

metresabove the groundisa good

place tostore medicines.

Disposal

Ifyourdoctortells youto stop

takingCiproxintabletsorthetablets

havepassed theirexpirydate, ask

yourpharmacistwhattodo with

anythatareleftover.

Return any unusedmedicine to

your pharmacist.

PRODUCT

DESCRIPTION

What it lookslike

Ciproxin250 mgtabletsarewhite,

film-coated, round, scoredand

markedCIP250on top and the

BayerCrossonbottom(available in

blisterpacks of2[Australiaonly]

and14tablets).

Ciproxin500 mgtabletsarewhite,

film-coated,oblong, scored and

markedCIP500on top and Bayer

onthebottom(availableinblister

packsof14tablets).

Ciproxin750 mgtabletsarewhite,

film-coated,oblong, markedCIP

750ontopand Bayeronthebottom

(available inblisterpacksof14

tablets).

Ingredients

Active Ingredientpertablet:

Ciproxin250-ciprofloxacin(as

hydrochloride)250 mg

Ciproxin500-ciprofloxacin(as

hydrochloride)500 mg

Ciproxin750-ciprofloxacin(as

hydrochloride)750 mg

Inactive ingredients:

colloidalsilicondioxide

crospovidone

macrogol4000

maizestarch

magnesiumstearate

microcrystallinecellulose

hypromellose

titaniumdioxide (CI778991).

Supplier

MadeinGermanyfor:

BayerAustralia Limited

ABN22000138714

875Pacific Highway

Pymble NSW2073

BayerNewZealandLimited

3ArgusPlace,Hillcrest,

NorthShoreAuckland0627

Freephone0800233988

AustralianRegistration

Numbers

Ciproxin250-AUSTR35317

Ciproxin500-AUSTR35361

Ciproxin750-AUSTR35367

Dateof preparation

June2012

SeeTGAwebsite( www.tga.gov.au )

forlatestAustralianConsumer

See MEDSAFEwebsite

( www.medsafe.govt.nz )forlatest

NewZealand ConsumerMedicine

Information.

®TrademarkofBayerAG,

Germany

© BayerAustralia Ltd

Allrightsreserved.

191001 Ciproxin DS

Page 1 of 31

NEW ZEALAND DATA SHEET

1.

CIPROXIN

®

Ciproxin 250 mg, film-coated tablets*

Ciproxin 500 mg, film-coated tablets*

Ciproxin 750 mg, film-coated tablets*

Ciproxin 50 mg/mL, oral suspension*

Ciproxin 100 mg/mL, oral suspension**

Ciproxin 2 mg/mL, solution for infusion*

*currently unavailable

** currently available

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1

Film-coated tablets

Ciproxin 250 mg:

1 tablet contains 291 mg ciprofloxacin hydrochloride, corresp. to 250 mg ciprofloxacin as

monohydrate

Ciproxin 500 mg:

1 tablet contains 582 mg ciprofloxacin hydrochloride, corresp. to 500 mg ciprofloxacin as

monohydrate

Ciproxin 750 mg:

1 tablet contains 873 mg ciprofloxacin hydrochloride, corresp. to 750 mg ciprofloxacin as

monohydrate

2.2

Oral suspension

Ciproxin 50 mg/mL:

1 bottle consists of 7.95 g of microcapsules which contain 5.0 g ciprofloxacin

1 bottle with 99.2 g suspension diluent to prepare 100 mL of Ciproxin Suspension 5 %

1 measuring spoonful (approx. 5.0 mL) contains approx. 250 mg ciprofloxacin

One measuring spoon (5.0 mL suspension) contains approx. 1.4 g of sucrose

Ciproxin 100 mg/mL:

1 bottle consists of 15.9 g of microcapsules which contain 10.0 g ciprofloxacin

191001 Ciproxin DS

Page 2 of 31

1 bottle with 91.7 g suspension diluent to prepare 100 mL of Ciproxin Suspension 10 %

1 measuring spoonful (approx. 5.0 mL) contains approx. 500mg ciprofloxacin

One measuring spoon (5.0 mL suspension) contains approx. 1.3 g of sucrose

2.3

Solution for infusion

Ciproxin 2 mg/mL:

1 glass bottle of 100 mL infusion solution contains 254.4 mg ciprofloxacin lactate, corresp. to

200 mg ciprofloxacin. Sodium chloride content is 900 mg .

For the full list of excipients, see section 6.1 List of excipients.

3.

PHARMACEUTICAL FORM

3.1

Film-coated tablet

Ciproxin 250 mg:

Round, nearly white to slightly yellowish film-coated scored tablets marked with “CIP 250” on

one side and a “Bayer cross” on the reverse side. The tablet can be divided into equal

halves.

Ciproxin 500 mg:

Oblong, nearly white to slightly yellowish film-coated scored tablets marked with “CIP 500” on

one side and a “Bayer” on the reverse side. The tablet can be divided into equal halves.

Ciproxin 750 mg:

Oblong, nearly white to slightly yellowish film-coated tablets marked with “CIP 750” on one

side and a “Bayer” on the reverse side.

3.2

Oral suspension

Ciproxin 50 mg/mL:

Granules: white to slightly yellowish granules

Solvent: white to slightly yellowish suspension (with strawberry odour)

Ciproxin 100 mg/mL:

Granules: white to slightly yellowish granules

Solvent: white to slightly yellowish suspension (with strawberry odour)

Appearance before reconstitution: For the appearance of the reconstituted oral

suspension, see section 4.2.2 Method of administration.

191001 Ciproxin DS

Page 3 of 31

3.3

Solution for infusion

Ciproxin 2 mg/mL (with 0.9% NaCl)

Clear, nearly colourless to slightly yellowish solution.

The pH-value of the solution for infusion ranges from 3.9 to 4.5.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

4.1.1

Adults

Uncomplicated and complicated infections caused by ciprofloxacin sensitive pathogens:

Infections of the lower respiratory tract.

In the treatment of outpatients with pneumonia due to Pneumococcus, ciprofloxacin should

not be used as a medicine of first choice. Ciprofloxacin can be regarded as a suitable

treatment for pneumonias caused by Klebsiella, Enterobacter, Proteus, E. coli, Pseudomonas,

Haemophilus, Branhamella, Legionella, and Staphylococcus.

Infections of the kidneys and/or the efferent urinary tract.

Infections of the genital organs, including adnexitis, gonorrhoea, prostatitis.

Infections of the abdominal cavity (e.g. infections of the gastrointestinal tract or of the biliary

tract, peritonitis).

Infections of the skin and soft tissue.

Infections of the bones and joints.

Sepsis.

Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease

following exposure to aerosolized Bacillus anthracis. Ciprofloxacin serum concentrations

achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical

benefit and provide the basis for this indication.

According to in vitro investigations, 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, Moraxella, Acinetobacter, Brucella; Staphylococcus, Listeria, Corynebacterium,

Chlamydia.

The following show varying degrees of sensitivity:

Neisseria, Gardnerella, Flavobacterium, Alcaligenes, Streptococcus agalactiae, Enterococcus

faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Viridans group Streptococci,

Mycoplasma hominis, Mycobacterium tuberculosis, and Mycobacterium fortuitum.

191001 Ciproxin DS

Page 4 of 31

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 has been shown to be active against Bacillus anthracis both in vitro and by use

of serum levels as a surrogate marker.

Ciprofloxacin is ineffective against Treponema pallidum.

The prevalence of resistance may vary geographically and with time for selected species and

local information on resistance is desirable, particularly when treating severe infections. This

information gives only an approximate guidance whether microorganisms will be susceptible

for ciprofloxacin or not.

Consideration should be given to available official guidance on the appropriate use of

antibacterial agents.

4.1.2

Children

Cystic fibrosis

For the treatment of acute pulmonary exacerbation of cystic fibrosis associated with P.

aeruginosa infection in paediatric patients 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 due to E.coli in paediatric patients

aged

1 - 17 years.

The risk-benefit assessment indicates that administration of ciprofloxacin to paediatric

patients is

appropriate. Treatment should only be initiated after careful benefit/risk

evaluation, due to

possible adverse events related to joints/surrounding tissues. The use of

ciprofloxacin for other

indications is not recommended in children.

4.2

Dose and method of administration.

4.2.1

Dose

4.2.1.1

Adults

Unless otherwise prescribed, the following guideline doses are recommended:

191001 Ciproxin DS

Page 5 of 31

Tablets

Suspension

5%

Suspension

10%

Intravenous

Respiratory

tract

infection

(according to

severity and organism)

2 x 250-500mg

2 x 1-2*

2 x ½ -1*

2 x 200-400mg

Urinary tract infections:

- acute, uncomplicated

- cystitis in women

(before

menopause)

- complicated

1-2 x 250mg

single dose

250mg

2 x 250-500mg

2 x ½* to

1-2 x 1*

1 x 1*

2 x 1-2*

1 x ½*

2 x ½ - 1*

2 x 100mg

single dose

100mg

2 x 200mg

Gonorrhoea

- extragenital

- acute, uncomplicated

1 x 250mg

single dose

250mg

1 x 1*

1 x ½*

2 x 100mg

single dose

100mg

Diarrhoea

1-2 x 500mg

1-2 x 2*

1-2 x 1*

2 x 200mg

Other infections (see

section 4.1 Therapeutic

2 x 500mg

2 x 2*

2 x 1*

2 x 200-400mg

Particularly severe, life

threatening infections,

i.e.

Streptococcal pneumonia

-Recurrent infections

in cystic fibrosis

-Bone and joint infections

-Septicaemia

-Peritonitis

In particular when

Pseudomonas,

Staphylococcus or

Streptococcus is present

2 x 750mg

2 x 3*

2 x 1 ½*

3 x 400mg

Inhalational anthrax

(post- exposure)

Drug administration

should begin as soon

as possible after

suspected or

confirmed exposure

2 x 500mg

2 x 2*

2 x 1*

2 x 400mg

* Number of measuring spoonful

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4.2.1.2

Paediatric population

Cystic Fibrosis

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

patients (aged 5 -17 years) with acute pulmonary exacerbation associated with P.

aeruginosa infection, at a dose of 20 mg/kg orally twice daily (maximum daily dose 1500 mg)

or 10 mg/kg iv three times daily (maximum daily dose 1200mg).

Inhalational anthrax (post-exposure)

For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment

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). For intravenous infusion, the recommended

dose is 10 mg/kg twice daily (not to exceed a maximum dose of 400 mg per dose, 800 mg

per day). Drug administration should begin as soon as possible 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 6 to 10 mg/kg i.v. every 8 hours with a maximum of 400 mg per dose

or 10 to 20 mg/kg orally every 12 hours with a maximum of 750 mg per dose.

4.2.2

Method of administration

4.2.2.1

Film-coated tablets

The tablets are swallowed whole with a small amount of fluid.

Tablets can be taken independent of mealtimes. If the tablets are taken on an empty

stomach, the active substance is absorbed more rapidly. In this case, tablets should not be

taken concurrently with dairy products or with mineral fortified drinks alone (e.g. milk,

yoghurt, and calcium fortified orange juice). However, dietary calcium as part of a meal does

not significantly affect ciprofloxacin absorption.

If the patient is unable to take tablets, because of the severity of the illness or for other

reasons, it is recommended to commence the therapy with an intravenous form of

ciprofloxacin. After intravenous administration the treatment can be continued orally.

4.2.2.2

Suspension

Oral suspension can be taken independent of mealtimes. If taken on an empty stomach, the

active substance is absorbed more rapidly. In this case, the suspension should not be taken

concurrently with dairy products or with mineral fortified drinks alone (e.g. milk, yoghurt, and

calcium fortified orange juice). However, dietary calcium as part of a meal does not

significantly affect ciprofloxacin absorption.

If the patient is unable to take suspension, because of the severity of the illness or for other

reasons,

recommended

commence

therapy

with

intravenous

form

ciprofloxacin. After intravenous administration the treatment can be continued orally.

The reconstituted product is a white to slightly yellowish suspension with strawberry odour.

Occasionally the suspension may contain yellow-orange droplets and globular particles. This

has no influence on the pharmaceutical quality of the product.

191001 Ciproxin DS

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Always use the graduated measuring spoon to obtain the exact dose for administering the

suspension.

No additions should be made to the mixed final ciprofloxacin suspension.

4.2.2.3

Intravenous

Ciprofloxacin should be administered by intravenous infusion over a period of 60 minutes.

Slow infusion into a large vein will minimise patient discomfort and reduce the risk of

venous irritation. The infusion solution can be infused either directly or after mixing with

other compatible infusion solutions.

Unless compatibility with other infusion solutions/drugs has been confirmed, the infusion

solution must always be administered separately. The visual signs of incompatibility are

e.g. precipitation, clouding, and discolouration.

Incompatibility appears with all infusion solutions/drugs that are physically or chemically

unstable at the pH of the solution (e.g. penicillins, heparin solutions), especially in

combination with solutions adjusted to an alkaline pH (pH of the ciprofloxacin infusion

solutions: 3.9 - 4.5). Only clear solutions are to be used.

For instructions on use of the medicine before administration, see section 6.6 Special

precautions for disposal.

4.2.2.4

Duration of treatment

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

bacteriological course. It is essential to continue therapy for at least 3 days after

disappearance of the fever or of the clinical symptoms.

Mean duration of treatment:

Adults

-

1 day for acute uncomplicated gonorrhoea and cystitis

-

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

-

a maximum of 2 months in osteomyelitis

-

60 days in inhalational anthrax (post-exposure)

-

7-14 days in all other infections

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

complications.

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

Children

Cystic Fibrosis

For acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa infection in

paediatric patients (aged 5-17 years), the duration of treatment is 10-14 days.

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 due to E. coli, the duration of

treatment

is 10-21 days.

191001 Ciproxin DS

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4.2.2.5

Missed dose

If a dose is missed, it should be taken as soon as the patient remembers and then treatment

should be continued as prescribed. Double doses should not be taken to compensate for a

missed dose.

4.2.3

Additional information on special populations

4.2.3.1

Elderly

Elderly patients should receive a dose as low as possible depending on the severity of

their illness and the creatinine clearance.

4.2.3.2

Renal & Hepatic impairment

Adults

Impaired renal function

Where creatinine clearance is between 30 and 60 mL/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 for oral administration or 800 mg per day for an intravenous

regimen.

Where creatinine clearance 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

should be 500 mg per day for oral administration or 400 mg per day for an intravenous

regimen.

Impaired renal function + haemodialysis

Dose as in 1.2; on dialysis days after dialysis.

Impaired renal function + continuous ambulatory peritoneal dialysis (CAPD)

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

ciprofloxacin / litre dialysate administered 4 times a day every 6 hours

b. Administration of ciprofloxacin film coated tablets (oral) as 1 x 500 mg film coated

tablet (or 2 x 250 mg film coated tablets).

Impaired liver function

No dose adjustment is required.

Impaired renal and liver function

Dose adjustment as in 1.1 and 1.2

Children

Dosing in children with impaired renal and or hepatic function has not been studied.

4.3

Contraindications

Hypersensitivity to ciprofloxacin or other quinolone or any of the excipients (see section 6.1

List of excipients)

Concurrent administration of Ciproxin and tizanidine (see section 4.5 Interaction with other

medicinal products and other forms of interaction)

4.4

Special warnings and precautions for use

Fluoroquinolones, including ciprofloxacin, have been associated with disabling and

potentially persistent adverse reactions involving different body systems that have occurred

together in the same patient. These include, but are not limited to, serious adverse reactions

involving the nervous system (see precautions regarding Seizures, Psychiatric reactions and

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Peripheral neuropathy in section 4.4 Special warnings and precautions for use) and

musculoskeletal system (see precautions regarding Myasthenia gravis and Tendinitis and

tendon rupture in section 4.4 Special warnings and precautions for use).

May cause tendinitis, hypoglycaemia.

Severe infections and/or infections due to Gram-positive or anaerobic bacteria

For the treatment of severe infections, staphylococcal infections and infections involving

anaerobic bacteria, Ciproxin should be used in combination with an appropriate antibacterial

agent.

Streptococcus pneumoniae infections

Ciproxin is not recommended for treatment of pneumococcal infections due to limited

efficacy against Streptococcus pneumoniae.

Genital tract infections

Genital tract infections may be caused by fluoroquinolone-resistant Neisseria gonorrhoea

isolates. In genital tract infections thought or known to be due to N. gonorrhoea, it is

particularly important to obtain local information on the prevalence of resistance to

ciprofloxacin and to confirm susceptibility based on laboratory testing.

Cardiac disorders

Ciproxin is associated with cases of QT prolongation (see section 4.8 Undesirable effects).

As women tend to have a longer baseline QTc interval compared with men, they may be

more sensitive to QTc-prolonging medications. Elderly patients may also be more

susceptible to drug-associated effects on the QT interval. Precaution should be taken when

using Ciproxin with concomitant drugs that can result in prolongation with the QT interval

(e.g. class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

(see section 4.5 Interaction with other medicinal products and other forms of interaction’) or

in patients

with risk factors for QT prolongation or torsade de pointes (e.g. congenital long

QT syndrome, uncorrected electrolyte imbalance such as hypokalemia or hypomagnesemia

and cardiac disease

such as heart failure, myocardial infarction, or bradycardia).

Children and adolescents

As with medicinal products in its class, Ciproxin has been shown to cause arthropathy in

weight-bearing joints of immature animals (see section 4.8 Undesirable effects). The

analysis of available safety data from ciprofloxacin use

in patients less than 18 years of age,

the majority of whom had cystic fibrosis, did not disclose any evidence of drug related

cartilage or articular damage. The use of Ciproxin for indications other than the treatment of

acute pulmonary exacerbation of cystic fibrosis caused by P. aeruginosa infection (children

aged 5-17 years), complicated urinary tract infections and

pyelonephritis due to E.coli

(children aged 1-17 years) and for the use in inhalational anthrax (post-exposure) was not

studied. For other indications clinical experience is limited.

For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment

indicates

that administration of Ciproxin to paediatric patients is appropriate. For

information regarding

paediatric dosing in inhalational anthrax (post-exposure), (see

’Inhalational Anthrax – Additional

Information in Pharmacodynamic Properties’).

191001 Ciproxin DS

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Hypersensitivity

In some instances, the hypersensitivity and allergic reactions occurred after the first

administration (see section 4.8 Undesirable effects). The doctor should be informed

immediately.

Anaphylactic/anaphylactoid reactions in very rare instances can progress to a life threatening

shock, in some instances after the first administration (see section 4.8 Undesirable effects).

In these cases Ciproxin has to be discontinued, and medical treatment (e.g. treatment for

shock) is required.

Gastrointestinal system

In the event of severe and persistent diarrhoea during or after treatment a doctor must be

consulted, since this symptom can hide a serious intestinal disease (life threatening

pseudomembranous colitis with possible fatal outcome), requiring immediate treatment (see

section 4.8 Undesirable effects). In such

cases Ciprofloxacin must be discontinued and

appropriate therapy initiated (e. g. vancomycin,

orally, 4 x 250 mg/day). Drugs that inhibit

peristalsis are contraindicated in this situation.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with

ciprofloxacin. In the event of any signs and symptoms of hepatic disease (such as anorexia,

jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued (see

section 4.8 Undesirable effects). There can be temporary increase in transaminases alkaline

phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who

are treated with Ciproxin (see section 4.8 Undesirable effects).

Myasthenia gravis

Ciproxin should be used with caution in patients with myasthenia gravis, because symptoms

be exacerbated.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (predominantly Achilles tendon) sometimes bilateral, may

occur

with Ciproxin, even within the first 48 hours of treatment. Cases occurring up to

several months after completion of therapy have been reported. The risk of

tendinopathy may be increased in elderly patients, during strenuous physical activity, in

patients treated concomitantly with

corticosteroids, in patients with renal impairment and in

patients with solid organ transplants.

At any sign of tendinitis (e.g. painful swelling, inflammation), the affected extremity should be

kept at rest, any inappropriate physical exercise should be avoided, a physician should be

consulted and the antibiotic treatment should be discontinued. Ciproxin should be used with

caution in patients with a history of tendon disorders related to fluoroquinolone treatment.

Seizures

Ciproxin, like other fluoroquinolones, is known to trigger seizures or lower the seizure

threshold.

In epileptics and in patients who have suffered from previous CNS-disorders (e.g.

lowered convulsion threshold, previous history of convulsion, reduced cerebral blood flow,

altered brain structure or stroke), Ciproxin should only be used where the benefits of

treatment exceed the risks, since these patients are at risk because of possible undesirable

191001 Ciproxin DS

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CNS effects. Cases of status epilepticus have been reported (see section 4.8 Undesirable

effects). If seizures occur, Ciproxin should be discontinued.

Psychiatric reactions

Psychiatric reactions may occur even after the first administration of fluoroquinolones,

including

Ciproxin. In rare cases depression or psychotic reactions can progress to suicidal

ideations/thoughts and self-injurious behaviour, such as attempted or completed suicide (see

section 4.8 Undesirable effects). In the event that the patient develops these reactions,

Ciproxin should be discontinued and the appropriate measures instituted.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in parasthesias, hypoesthesias,

dysethesias, or weakness have been reported in patients receiving fluoroquinolones

including ciprofloxacin. Patients under treatment with Ciproxin should be advised to inform

their doctor

prior to continuing treatment if symptoms of neuropathy such as pain, burning,

tingling,

numbness or weakness develop (see section 4.8 Undesirable effects).

Skin and appendages

Ciproxin has been shown to produce photosensitivity reactions. Patients taking Ciproxin

should

avoid direct exposure to excessive sunlight or UV-light. Therapy should be

discontinued if photosensitisation (i.e. sunburn-like skin reactions) occurs (see section 4.8

Undesirable effects).

Cytochrome P450

Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 enzymes. Care should

be taken when other medicinal products are administered concomitantly which are

metabolised via the same enzymatic pathway (e.g. theophylline, methylxantines, caffeine,

duloxetine, ropinirole, clozapine, olanzapine, agomelatine). Increased plasma concentrations

associated with drug specific

undesirable effects may be observed due to inhibition of their

metabolic clearance by ciprofloxacin (see section 4.5 Interaction with other medicinal

products and other forms of interaction).

Dysglycaemia

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycaemia

and hyperglycaemia have been reported with Ciproxin. In Ciproxin-treated patients,

dysglycaemia occurred predominantly in elderly diabetic patients receiving concomitant

treatment with an oral hypoglycaemic agent (e.g. sulfonylurea) or with insulin. In diabetic

patients, careful monitoring of blood glucose is recommended (see section 4.8 Undesirable

effects).

Aortic aneurysm and dissection

Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake

of fluoroquinolones, particularly in the older population.

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and

after consideration of other therapeutic options in patients with positive family history of

aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or

191001 Ciproxin DS

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dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm

and dissection (eg Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis,

giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).

In case of sudden abdominal, chest or back pain, patients should be advised to immediately

consult a physician in an emergency department.

Injection site reaction

Local i.v. site reactions have been reported with the intravenous administration of

Ciprofloxacin (see section 4.8 Undesirable effects). These reactions are more frequent if the

infusion time is 30 minutes or less. These may appear as local skin reactions which resolve

rapidly upon completion of the infusion. Subsequent

intravenous administration is not

contraindicated unless the reactions recur or worsen.

Interaction with tests

Ciprofloxacin in vitro potency may interfere with the Mycobacterium tuberculosis culture test

by suppression of mycobacterial growth, causing false negative results in specimens from

patients

currently taking Ciproxin.

Sucrose load for suspension formulation

As the oral suspension contains sucrose, it is unsuitable for patients with rare hereditary

problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase

insufficiency (see section 2 Qualitative and Quantitative composition.)

NaCl load for i.v. formulation (bottles)

The additional sodium load should be taken into account when using Ciproxin IV in patients

for whom sodium intake is of medical concern (e.g. patients with congestive heart failure,

renal

failure, nephrotic syndrome, etc.) See section 2 Qualitative and Quantitative

composition for sodium content.

4.5

Interaction with other medicines and other form of interaction

Drugs known to prolong QT interval

Ciproxin, like other fluoroquinolones, should be used with caution in patients receiving drugs

known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic

antidepressants, macrolides, antipsychotics) (see section 4.4 Special warnings and

precautions for use).

Chelation complex formation

The simultaneous administration of Ciproxin (oral) and multivalent cation-containing

medicinal

products and mineral supplements (e.g. calcium, magnesium, aluminium, iron),

polymeric

phosphate binders (e.g. sevelamer, lanthanum carbonate), sucralfate or antacids

and highly

buffered drugs (e.g. didanosine tablets), containing magnesium, aluminium, or

calcium reduce

the absorption of ciprofloxacin. Consequently, Ciproxin should be

administered either 1-2 hours

before, or at least 4 hours after these preparations.

This restriction does not apply to antacids belonging to the class of H

receptor blockers.

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Food and dairy products

The concurrent administration of dairy products or mineral fortified drinks alone (e.g. milk,

yoghurt, calcium fortified orange juice) and oral Ciproxin should be avoided because

absorption of ciprofloxacin may be reduced. Dietary calcium as part of a meal, however, does

not significantly affect absorption.

Probenecid

Probenecid interferes with renal secretion of Ciproxin. Co-administration of probenecid

containing

medicinal products and Ciproxin increases the ciprofloxacin serum concentrations.

Omeprazole

Concomitant administration of oral Ciproxin and omeprazole results in a slight reduction of

AUC of ciprofloxacin.

Theophylline

Concurrent administration of Ciproxin and theophylline containing medicinal products can

cause an undesirable increase in the serum theophylline concentration. This can lead to

theophylline-induced side effects. In very rare cases, these side effects can be life

threatening or fatal. If concurrent use of the two products is unavoidable, the serum

theophylline concentration should therefore be checked and the

theophylline dose

appropriately reduced (see Cytochrome P450 section in 4.4 Special warnings and

precautions for use).

Other xanthine derivatives

On concurrent administration of Ciproxin and caffeine or pentoxifylline (oxpentifylline)

containing products, raised serum concentrations of these xanthine derivatives were

reported.

Phenytoin

Altered (decreased or increased) serum levels of phenytoin were observed in patients

receiving ciprofloxacin and phenytoin simultaneously. To avoid the loss of seizure control

associated with

decreased phenytoin levels, and to prevent phenytoin overdose-related

adverse effects when

Ciproxin is discontinued in patients receiving both agents, monitoring

of phenytoin therapy, including phenytoin serum concentration measurements, is

recommended during and shortly

after co-administration of Ciproxin with phenytoin.

NSAID

Animal studies have shown that the combination of very high doses of fluoroquinolones (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 Ciproxin and

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

creatinine concentrations in these patients frequently (twice a week).

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Vitamin K antagonists

Simultaneous administration of Ciproxin with a Vitamin K antagonist may augment its

anticoagulant effects. The risk may vary with the underlying infection, age and general status

of the patient so that the contribution of ciprofloxacin to the increase in INR (international

normalized ratio) is difficult to assess. The INR should be monitored frequently during and

shortly after co-administration of Ciproxin with a Vitamin K antagonist (e.g., warfarin,

acenocoumarol,

phenprocoumon, or fluindione).

Methotrexate

Renal tubular transport of methotrexate may be inhibited by concomitant administration of

Ciproxin potentially leading to increased plasma levels of methotrexate. This might increase

risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate

therapy

should be carefully monitored when concomitant Ciproxin therapy is indicated.

Metoclopramide

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

reach maximum plasma concentrations. No effect was seen on the bioavailability of

ciprofloxacin.

Tizanidine

In a clinical study in healthy subjects, there was an increase in tizanidine serum

concentrations

increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6

to 24-fold) when given

concomitantly with Ciproxin. Associated with the increased serum

concentrations was a

potentiated hypotensive and sedative effect (see Cytochrome P450

section in 4.5 Special warnings and precautions for use). Tizanidine must not be

administered together with ciprofloxacin (see section 4.3 Contraindications).

Duloxetine

In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors

the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and C

duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin,

similar effects can be expected upon concomitant administration (see Cytochrome P450

section in 4.4 Special warnings and precautions for use).

Ropinirole

In a clinical study it was shown that concomitant use of ropinirole with ciprofloxacin, a

moderate

inhibitor of the CYP450 1A2 isozyme, resulted in increases in the C

and AUC

of ropinirole of

60% and 84%, respectively. Monitoring ropinirole-related side effects dose

adjustment as appropriate is recommended during and shortly after co-administration with

Ciproxin (see Cytochrome P450 section in 4.4 Special warnings and precautions for use).

Lidocaine

It was demonstrated in healthy subjects that concomitant use of lidocaine with ciprofloxacin,

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.

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Clozapine

Following concomitant administration of 250 mg Ciproxin with clozapine for 7 days, serum

concentrations of

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 Ciproxin are advised (see Cytochrome P450 section

in 4.4 Special warnings and precautions for use).

Sildenafil

and AUC of sildenafil were increased approximately twofold in healthy subjects after

an oral

dose of 50 mg given concomitantly with 500 mg Ciproxin. Therefore, caution should

be used

prescribing Ciproxin concomitantly with sildenafil taking into consideration the risks

and the

benefits.

Agomelatine

In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450

1A2 isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a large

increase of agomelatine exposure. Although no clinical data are available for a possible

interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be

expected upon concomitant administration

(see Cytochrome P450 section 4.4 Special

warnings and precautions for use).

Zolpidem

Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is

not recommended.

4.6

Fertility, pregnancy and lactation

4.6.1

Fertility

Fertility studies in rats

Fertility, the intrauterine and postnatal development of the young, and the fertility of F1

generation were not affected by ciprofloxacin.

Embryotoxicity studies

These yielded no evidence of any embryotoxic or teratogenic action of ciprofloxacin.

Perinatal and postnatal development in rats

No effects on the 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.

4.6.2

Pregnancy

The data that are available from the use of Ciproxin in pregnant women, indicate neither

malformative nor feto/neonatal toxicity. Animal studies do not indicate reproductive toxicity.

Based

on animal studies, it cannot be excluded that the drug could cause damage to

articular cartilage in the immature foetal organism (see section 5.3 Preclinical safety data),

therefore the use of Ciproxin is not recommended during pregnancy.

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Animal studies have not shown any evidence of teratogenic effects (malformations) (see

section 5.3 Preclinical safety data).

4.6.3

Breast-feeding

Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, the

use of Ciproxin is not recommended during breast-feeding (see section 5.3 Preclinical

safety data).

4.7

Effects on ability to drive and use machines

Fluoroquinolones including Ciproxin may result in an impairment of the patient's ability to

drive or operate machinery due to CNS reactions (see section 4.8 Undesirable effects).

This applies particularly in combination with alcohol.

4.8

Undesirable effects

4.8.1

Summary of the safety profile

Adverse Reactions based on all clinical studies with Ciproxin (oral, parenteral) sorted by

CIOMS

III categories of frequency are listed below (n = 51721 patients, data lock point: 15

May 2005).

4.8.2

Tabulated list of adverse reactions

The frequencies of Adverse Drug Reactions (ADRs) reported with Ciproxin are summarised

in the table below. Within each frequency grouping, undesirable effects are presented in

order of decreasing seriousness. Frequencies are defined as:

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 be estimated, are listed under “not known”

System Organ

Class

Common

Uncommon

Rare

Very Rare

Not Known

Infections and

Infestations

Mycotic

superinfections

Antibiotic

associated colitis

(very rarely with

possible fatal

outcome)

Blood and

Lymphatic

System

Disorders

Eosinophilia

Leukopenia

Anaemia

Neutropenia

Leukocytosis

Thrombocytopenia

Thrombocytaemia

Haemolytic

anaemia

Agranulocytosis

Pancytopenia

(life-

threatening)

Bone marrow

depression

(life-

threatening)

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System Organ

Class

Common

Uncommon

Rare

Very Rare

Not Known

Immune System

Disorders

Allergic reaction

Allergic oedema /

angiooedema

Anaphylactic

reaction

Anaphylactic

shock (life-

threatening)

Serum

sickness-like

reaction

Metabolism and

Nutrition

Disorders

Decreased

appetite and

food intake

Hyperglycaemia

Hypoglycaemia

Psychiatric

Disorders

Psychomotor

hyperactivity /

agitation

Confusion and

disorientation

Anxiety reaction

Abnormal dreams

Depression

(potentially

culminating in self-

injurious

behaviour, such

as suicidal

ideations /

thoughts and

attempted or

completed

suicide)

Hallucinations

Psychotic

reactions

(potentially

culminating in

self-injurious

behaviour,

such as suicidal

ideations /

thoughts and

attempted or

completed

suicide)

Nervous System

Disorders

Headache

Dizziness

Sleep disorders

Taste disorders

Par- and

Dysaesthesia

Hypoaesthesia

Tremor

Seizures

(including status

epilepticus)

Vertigo

Migraine

Disturbed

coordination

Smell disorders

Hyperesthesia

Intracranial

hypertension

(pseudotumour

cerebri)

Peripheral

neuropathy

polyneuropathy

Eye Disorders

Visual

disturbances

Visual colour

distortions

Ear and

Labyrinth

Disorders

Tinnitus

Hearing loss

Hearing

impaired

Cardiac

Disorders

Tachycardia

prolongation,

ventricular

arrhythmia,

torsades de

pointes *

Vascular

Disorders

Vasodilatation

Hypotension

Syncope

Vasculitis

Respiratory,

Thoracic and

Mediastinal

Disorders

Dyspnoea

(including

asthmatic

condition)

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System Organ

Class

Common

Uncommon

Rare

Very Rare

Not Known

Gastrointestinal

Disorders

Nausea

Diarrhoea

Vomiting

Gastrointestinal

and abdominal

pains

Dyspepsia

Flatulence

Pancreatitis

Hepatobiliary

Disorders

Increase in

transaminases

Increased

bilirubin

Hepatic

impairment

Jaundice

Hepatitis (non-

infective)

Liver necrosis

(very rarely

progressing to

life-threatening

hepatic failure)

Skin and

Subcutaneous

Tissue

Disorders

Rash

Pruritus

Urticaria

Photosensitivity

reactions

Blistering

Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-

Johnson

syndrome

(potentially life-

threatening)

Toxic epidermal

necrolysis

(potentially life-

threatening)

Acute

generalised

exanthematous

pustulosis

(AGEP)

Musculoskeletal,

Connective

Tissue and Bone

Disorders

Arthralgia

Myalgia

Arthritis

Increased muscle

tone and cramping

Muscular

weakness

Tendonitis

Tendon rupture

(predominantly

Achilles

tendon)

Exacerbation of

symptoms of

myasthenia

gravis

Renal and

Urinary

Disorders

Renal

impairment

Renal failure

Haematuria

Crystalluria

Tubulointerstitial

nephritis

General

Disorders and

Administration

Site Conditions

Injection

site

reaction

Unspecific pain

Feeling unwell

Fever

Oedema

Sweating

(hyperhidrosis)

Gait

disturbance

Investigations

Increase in

blood alkaline

phosphatase

Abnormal

prothrombin level

Increased

amylase

International

Normalised

Ratio (INR)

increased (in

patients

treated with

Vitamin K

antagonists)

These events were reported during the postmarketing period and were observed predominantly

among

patients with further risk factors for QT prolongation (see section 4.4 Special warnings

and precautions for use’).

For Ciproxin Solution for Infusion only.

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In isolated instances, some serious adverse drug reactions may be long-lasting (> 30 days)

and disabling; such as tendinitis, tendon rupture, musculoskeletal disorders, and other

reactions affecting the nervous system including psychiatric disorders and disturbance of

senses.

The following undesirable 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, Confusion and disorientation,

Hallucinations, Par- and dysaesthesia, Seizures, Vertigo, Visual

disturbances, Hearing loss, Tachycardia, Vasodilatation, Hypotension,

Transient hepatic impairment, Jaundice, Renal failure, Oedema

Rare

Pancytopenia, Bone marrow depression, Anaphylactic shock,

Psychotic reactions, Migraine, Smell disorders, Hearing impaired,

Vasculitis, Pancreatitis, Liver necrosis, Petechiae, Tendon rupture

4.8.3

Additional information on special populations

4.8.3.1

Pediatric population

The incidence of arthropathy (arthralgia, arthritis), mentioned above, is referring to data

collected in studies with adults. In children, arthropathy is reported to occur commonly (see

section 4.4 Special warnings and precautions for use).

4.8.4

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals are asked to report any suspected adverse reactions to

https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

In the event of acute, excessive oral overdosage, reversible renal toxicity has been

reported in some cases.

Apart from routine emergency measures, it is recommended to monitor renal function,

including urinary pH and acidify, if required to prevent crystalluria. Patients should be kept

well hydrated. Calcium or magnesium containing antacids may reduce the absorption of

ciprofloxacin in overdoses.

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

dialysis.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

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5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Ciprofloxacin is a synthetic broad spectrum fluoroquinolone antibacterial agent (ATCCODE: J

01 MA 02).

5.1.1

Mechanism of action

Ciprofloxacin is effective in vitro against a wide range of Gram-negative and Gram-

positive

organisms. The bactericidal action of ciprofloxacin results from inhibition of

bacterial type II

topoisomerases (DNA gyrase and topoisomerase IV), which are

required for bacterial DNA

replication, transcription, repair, and recombination.

5.1.2

Mechanism of Resistance

In vitro resistance to ciprofloxacin is commonly due to mutations in bacterial topoisomerases

DNA gyrase through multiple-step mutations. Single mutations may result in reduced

susceptibility rather than clinical resistance, but multiple mutations generally result in clinical

resistance to ciprofloxacin and cross-resistance across the fluoroquinolone class.

Resistance mechanisms that inactivate other antibiotics such as permeation barriers

(common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to

ciprofloxacin. Plasmid-mediated resistance encoded by the qnr gene has been reported.

Resistance

mechanisms that inactive penicillins, cephalosporins, aminoglycosides,

macrolides, and tetracyclines may not interfere with the antibacterial activity of ciprofloxacin

and there is no known cross-resistance between ciprofloxacin and other classes of

antimicrobials. Organisms

resistant to these drugs may be susceptible to ciprofloxacin.

The minimum bactericidal concentration (MBC) generally does not exceed the minimal

inhibitory

concentration (MIC) by more than a factor of 2.

In vitro Susceptibility to Ciprofloxacin

The prevalence of acquired resistance may vary geographically and with time for selected

species and local information of resistance is desirable, particularly when treating severe

infections. As necessary, expert advice should be sought where the local prevalence of

resistance is such that utility of the agent, in at least some types of infections, is

questionable.

The bacterial genus and species listed below have been shown to commonly be susceptible

to ciprofloxacin in vitro:

Aerobic Gram-Positive Microorganisms

Bacillus anthracis

Staphylococcus aureus (methicillin-susceptible)

Staphylococcus saprophyticus

Streptococcus spp.

Aerobic Gram-Negative Microorganisms

Aeromonas spp.

Brucella spp.

Citrobacter koseri

Francisella tularensis

Haemophilus ducreyi

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Haemophilius influenzae

Legionella spp.

Moraxella catarrhalis

Neisseria meningitidis

Pasteurella spp.

Salmonella spp.

Shigella spp.

Vibrio spp.

Yersinia pestis

Anaerobic microorganisms

Mobiluncus

Other Microorganisms

Chlamydia trachomatis

Chlamydia pneumoniae

Mycoplasma hominis

Mycoplasma pneumoniae

The following microorganisms show varying degrees of susceptibility to ciprofloxacin:

Acinetobacter baumann, Burkholderia cepacia, Campylobacter spp., Citrobacterfreudii,

Enterococcus faecalis, 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., Propionibacterium

acnes.

The following microorganisms are considered inherently resistant to ciprofloxacin:

Staphylococcus aureus (methicillin-resistant) and Stenotrophomonas maltophilia,

Actinomyces,

Enteroccus faecium, Listeria monocytogenes, Mycoplasma genitalium,

Ureaplasma urealitycum,

Anaerobic microorganisms (Except Mobiluncus,

Peptostreptococus, Propionibacterium acnes)

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 disease if the treatment is made up to the decrease

of the number of spores in the organism under the infective dose.

The recommended use in human subjects is based primarily on in vitro susceptibility and on

animal experimental data together with limited human data. Two month treatment duration

adults with oral ciprofloxacin given at the following dose, 500 mg bid, is considered as

effective to prevent anthrax infection in humans. The treating physician is referred to

national and /or

international consensus documents regarding treatment of anthrax.

The mean serum concentrations of ciprofloxacin associated with a statistically significant

improvement in survival in the rhesus monkey model of inhalational anthrax are reached or

exceeded in adult and paediatric patients receiving oral and intravenous regimens (see

section 4.2 Dose and method of Administration).

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of

11 LD

(~5.5 x 10

) spores (range 5-30 LD

) of B. anthracis was conducted. The minimal

inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was

0.08 μg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at

191001 Ciproxin DS

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expected T

(1 hour post-dose) following oral dosing to steady state ranged from 0.98 to

1.69 μg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from

0.12 to 0.19 μg/mL. Mortality due to anthrax for animals that received a 30-day regimen of

oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared

to the placebo group (9/10) [p = 0.001]. The one ciprofloxacin-treated animal that died of

anthrax did so following the 30-day drug administration period.

5.2

Pharmacokinetic properties

5.2.1

Absorption

5.2.1.1

Film-coated tablets

Following oral administration of single doses of 250 mg, 500 mg, and 750 mg of Ciproxin

film- coated tablets, ciprofloxacin is absorbed rapidly and extensively mainly from the small

intestine,

reaching maximum serum concentrations 1-2 hours later.

Mean Ciprofloxacin Serum Concentrations (mg/L)

after Oral Administration [Time from tablet intake]

Time (h)

250 mg

500 mg

750 mg

12.0

The absolute bioavailability is approximately 70-80%. Maximum serum concentrations (C

and total areas under serum concentration vs. time curves (AUC) increased in proportion to

dose.

5.2.1.2

Oral Suspension

The pharmacokinetics of Ciproxin oral suspension 5% and 10% are virtually identical to

those of

tablets.

5.2.1.3

Solution for Infusion

Following an intravenous infusion of Ciproxin the mean maximum serum concentrations

were

achieved at the end of infusion. Pharmacokinetics of ciprofloxacin were linear over

the dose range up to 400mg administered intravenously.

Mean Ciprofloxacin Serum Concentrations (mg/l)

after Intravenous Administration

[Time from start of infusion (in hours)]

Time (h)

200mg i.v.

(30 min inf.)

0.50

0.75

1.40

1.00

1.00

1.50

0.70

2.50

0.50

4.50

0.30

8.50

0.10

12.50

0.10

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Comparison of the pharmacokinetic parameters for a twice a day and three times a day

intravenous dose regimen indicated no evidence of drug accumulation for ciprofloxacin and

its metabolites.

A 60-minute intravenous infusion of 200 mg ciprofloxacin or the oral administration of 250

mg ciprofloxacin both given every 12 hours produced an equivalent area under the serum

concentration time curve (AUC).

5.2.2

Distribution

The protein binding of ciprofloxacin is low (20-30%), and the substance is present in plasma

largely in a non-ionised form. Ciprofloxacin can diffuse freely into the extravascular space.

The large steady-state volume of distribution of 2-3 L/kg body weight shows that

ciprofloxacin penetrates into tissues resulting in concentrations which clearly exceed the

corresponding serum

levels.

5.2.3

Biotransformation

Small concentrations of 4 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 3 display 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.

5.2.4

Elimination

Ciprofloxacin is largely excreted unchanged both renally and, to a smaller extent, non-renally.

Excretion of Ciprofloxacin (% of dose)

Oral Administration

Urine

Faeces

Ciprofloxacin

44.7

25.0

Metabolites (M

11.3

Intravenous Administration

Urine

Faeces

Ciprofloxacin

61.5

15.2

Metabolites (M

Renal clearance is between 0.18-0.3 L/h/kg and the total body clearance between 0.48-0.60

L/h/kg. Ciprofloxacin undergoes both glomerular filtration and tubular secretion.

Non-renal clearance of ciprofloxacin is mainly due to active transintestinal secretion as well

metabolisation. 1% of the dose is via the biliary excreted route. Ciprofloxacin is present

in the bile

in high concentrations.

Children

In a study in children, C

and AUC were not age-dependent. No notable increase in

AUC upon multiple dosing (10 mg/kg/TID) was observed. In 10 children with

severe sepsis, less

than 1 year of age C

was 6.1 mg/L (range 4.6 – 8.3 mg/L) after a

1-hour intravenous infusion

at a dose level of 10 mg/kg; and 7.2 mg/L (range 4.7 – 11.8

mg/L) for children between 1 and 5 years of age. The AUC-values were 17.4 mg*h/L

(range 11.8 – 32.0 mg*h/L) and 16.5 mg*h/L (range 11.0 – 23.8 mg*h/L) in the respective

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age groups. These values are within the range reported for adults at therapeutic doses.

Based on population pharmacokinetic analysis of paediatric patients with various

infections, the predicted mean half-life in children is approx. 4 –5 hours and the

bioavailability of the oral suspension approx. 60%.

5.3

Preclinical safety data

The acute toxicity of ciprofloxacin after oral administration can be classified as very low.

Depending on the individual species, the LD

after intravenous infusion is 125-290 mg/kg.

Species

Mode of administration

LD

50

(mg/kg)

Mouse

p.o.

Approx. 5000

p.o.

Approx. 5000

Rabbit

p.o.

Approx. 2500

Mouse

i.v.

Approx. 290

i.v.

Approx. 145

Rabbit

i.v.

Approx. 125

i.v.

Approx. 250

5.3.1

Chronic Toxicity

5.3.1.1

Subacute tolerability studies over 4 weeks

Oral administration

Doses up to and including 100 mg/kg were tolerated without damage by rats. Pseudoallergic

reactions due to histamine release were observed in dogs.

Parental administration

In the highest-dose group in each case (rats 80 mg/kg and monkeys 30 mg/kg), crystals

containing ciprofloxacin were found in the urine sediment. There were also changes in

individual renal tubules,

with typical foreign-body reactions due to crystal-like precipitates.

The tubular changes observed should not (as e.g. in the case of aminoglycosides) be

interpreted as a primary toxic effect of ciprofloxacin, but as secondary inflammatory foreign-

body reactions due to the precipitation of a crystalline complex in the distal renal tubule

system (cf. also the subchronic and chronic tolerability studies).

5.3.1.2

Subchronic Toxicity Studies over 3 months

Oral administration

All doses up to 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).

Parental administration

Although the changes in the renal tubules observed in rats were in some cases very slight,

they were present in every dose group. In monkeys they were found only in the highest-dose

group (18 mg/kg) and were associated with slightly reduced erythrocyte counts and

haemoglobin

values.

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5.3.1.3

Chronic tolerability studies over 6 months

Oral administration

Doses up to and including 500 mg/kg and 30 mg/kg were tolerated without damage by rats

and monkeys, respectively. Changes in the distal renal tubules were again observed in

some monkeys in the highest-dose group (90 mg/kg).

Parental administration

In monkeys slightly elevated urea and creatinine concentrations and changes in the distal

renal

tubules were recorded in the highest-dose group (20 mg/kg).

5.3.2

Carcinogenicity

In carcinogenicity studies in mice (21 months) and rats (24 months) 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 carcinogenic potential at any

dose level.

5.3.3

Mutagenicity

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin.

Test results are listed below:

-

Salmonella: Microsome Test (Negative)

-

E. coli: DNA Repair Assay (Negative),

-

Mouse Lymphoma Cell Forward Mutation Assay (Positive)

-

Chinese Hamster V79 Cell HGPRT Test (Negative),

-

Syrian Hamster Embryo Cell Transformation Assay (Negative)

-

Saccharomyces cerev.: Point Mutation Assay (Negative), Mitotic Crossover and Gene

Conversion Assay (Negative)

-

Rat Hepatocyte Primary Culture DNA Repair Assay (UDS) (Positive)

Thus, two of the eight tests were positive, but results of the following four in vivo test

systems gave negative results:

-

Rat Hepatocyte DNA Repair Assay

-

Micronucleus Test (Mice)

-

Dominant Lethal Test (Mice)

-

Chinese Hamster Bone Marrow

Although two of the eight in vitro assays (i.e. the Mouse Lymphoma Cell Forward Mutation

Assay and the Rat Hepatocyte Primary Culture DNA Repair Assay [UDS]) were positive, all

of the in vivo test systems covering all relevant endpoints gave negative results.

In summary, ciprofloxacin poses no significant mutagenic potential. This assessment is

confirmed by the negative outcome of the long-term carcinogenicity studies in mice and rats.

191001 Ciproxin DS

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5.3.4

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 a characteristic damage pattern. Kidney damage, cartilage

damage in

weight-bearing joints of immature animals, and eye damage may be

encountered.

5.3.5

Renal tolerability

The crystallisation observed in the animal studies occurred preferentially under pH

conditions

that do not apply in man.

Compared to rapid infusion, a slow infusion of ciprofloxacin reduces the danger of crystal

precipitation.

The precipitation of crystals in renal tubules does not immediately and automatically lead to

kidney damage. In the animal studies damage occurred only after high doses, with

correspondingly high levels of crystalluria. For example, although they always caused

crystalluria,

even high doses were tolerated over 6 months without damage and without

foreign-body reactions occurring in individual distal renal tubules.

Damage to the kidneys without the presence of crystalluria has not been observed. The

renal damage observed in animal studies must 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.

5.3.6

Articular tolerability studies

As with other gyrase inhibitors, ciprofloxacin causes damage to the large, weight-bearing

joints in immature animals.

The extent of the cartilage damage varies according to age, species, and dose; the damage

be reduced by 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 therapeutic dose) caused articular changes after two weeks

of treatment, which

were still observed after 5 months. At therapeutic doses, no effects were

observed.

5.3.7

Studies aimed at excluding cataractogenic effects

On the basis of the investigations it may be stated from a toxicological point of view that

Ciproxin treatment does not involve any risk of cataract induction, particularly because in

parental administration maximal bioavailability can be assumed and the duration of

administration was 6

months.

5.3.8

Retina tolerability studies

Ciprofloxacin binds to the melanin containing structures including the retina. Potential

effects of ciprofloxacin on the retina were assessed in various pigmented animal species.

Ciprofloxacin

treatment had no effect on the morphological structures of the retina and on

electroretinographic findings.

191001 Ciproxin DS

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6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

6.1.1

Film-coated tablets

Microcrystalline cellulose

Maize starch

Poly (1-vinyl-2-pyrrolidone) crosslinked

Highly dispersed silicon dioxide

Magnesium stearate

Methylhydroxypropylcellulose

Macrogol 4000

Titanium dioxide (E171)

6.1.2

Suspension

Copolymer of ethyl acrylate

Methyl methacrylate

Magnesium stearate

Methylhydroxypropylcellulose

Polysorbate

Polyvidone

Lecithin

Sucrose

Strawberry flavour

Medium chain triglycerides

Water

6.1.3

Infusion solution

Lactic acid

Sodium chloride

Hydrochloric acid

Water for injection

6.2

Incompatibilities

Ciproxin IV solution

The Ciproxin infusion solution is compatible with physiological saline, Ringer solution and

Ringer

lactate solution, 5% and 10% glucose solutions, 10% fructose solution, and 5%

glucose solution

with 0.225% NaCl or 0.45% NaCl. When Ciproxin infusion solutions are

mixed with compatible infusion solutions, they should be administered shortly after

admixture for microbiological and

light sensitivity reasons.

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Unless compatibility with other infusion solutions/drugs has been confirmed, the infusion

solution

must always be administered separately. The visual signs of incompatibility are e.g.

precipitation, clouding, and discolouration. Only clear solutions are to be used

Incompatibility appears with all infusion solutions/drugs that are physically or chemically

unstable

at the pH of the solution (e.g. penicillin’s, heparin solutions), especially in

combination with solutions adjusted to an alkaline pH (pH of the ciprofloxacin infusion

solutions: 3.9-4.5).

Oral suspension

No additions should be made to the mixed final ciprofloxacin suspension.

6.3

Shelf life

Ciproxin 250, 500, 700 film-coated tablets: 60 months

Ciproxin 50 mg/mL, 100 mg/mL oral suspension:

-

Microcapsule: 36 months

-

suspension diluent: 24 months

Shelf life of the reconstituted oral suspension: 14 days

The ready-to-use oral suspension utilizing these individual components is stable only for 14

days when stored either at ambient temperatures up to 30 °C, or in a refrigerator. After this

time, the reconstituted oral suspension should not be taken. Protect the reconstituted oral

suspension from freezing.

Ciproxin 2 mg/mL (with 0.9% NaCl) Infusion solution: 48 months

6.4

Special precautions for storage

Ciproxin Suspension

Microcapsule: Stored below 25 °C.

Suspension diluent: Stored below 25 °C. Protect from freezing. Avoid inverted storage.

For storage conditions after reconstitution of the medicine, see section 6.3 Shelf life.

Ciproxin IV solution

Protect from light. Do not refrigerate or freeze.

At cool storage temperatures precipitation may occur, which will re-dissolve at room

temperature. It is therefore recommended not to store the infusion solution in a refrigerator.

Since the infusion solution is photosensitive, the infusion bottles should be removed from

the box

only immediately before use. In daylight conditions complete efficacy is

guaranteed for a period of 3 days.

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6.5

Nature and contents of container

Ciproxin 250, 500, 700 film-coated tablets: Foil, Strips of 14

Ciproxin 50 mg/mL, 100 mg/mL oral suspension: bottle, PET

Ciproxin 2 mg/mL (with 0.9% NaCl) Infusion solution: glass bottle

6.6

Special precautions for disposal and other handling

6.6.1

Instructions for use / handling

Ciproxin Suspension

The small bottle contains the active substance, the large bottle contains the suspension

fluid.

Open both bottles.

Reconstitution:

-

Childproof cap: Press down according to instructions on the cap while turning to the left.

-

Pour the microcapsules completely into the large bottle with the suspension fluid. Do not

pour water into the suspension!

-

Reclose the large bottle properly according to the instructions on the cap and shake

vigorously for about 15 seconds. The suspension is now ready to use.

Taking the ready-to-use suspension.

Take the prescribed amount of suspension by using the measuring spoon. Do not chew the

microcapsules present in the suspension, simply swallow them. A drink of water may be

taken afterwards. Reseal the bottle properly after use according to the instructions on the

cap. The ready- to-use suspension is stable for 14 days when stored in a refrigerator or at

ambient temperatures below 30°C. After treatment has been completed, discard any surplus

suspension. Shake vigorously each time before use for approx. 15 seconds

The graduated measuring spoon with the markings 1/2 is equivalent to 2.6 mL contains 2.5

mL of final suspension and 1/1 is equivalent to 5.2 mL contains 5.0 mL of final suspension.

The graduated measuring spoon must be used for measuring the required prescribed

amount of Ciproxin Suspension 5 % or 10%.

After use the graduated measuring spoon should be cleaned under running water with

detergent rinsed with water and dried thoroughly afterwards.

Ciproxin IV solution

For glass bottles: For ease of use the infusion vial stopper should be penetrated in the

central ring. Penetration of the outer ring may result in damage to the vial stopper.

6.6.2

Special precautions for use

Ciproxin Suspension

Each consists of two individual components, Microcapsules and Suspension diluent. These

should not be used after the expiration date has been reached.

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Occasionally a slight yellow layer is observed on the surface of the sugar in the suspension.

This has no influence on the pharmaceutical quality of the product.

The ready-to-use oral suspension utilizing these individual components is stable only for 14

days when stored either at ambient temperatures up to 30 °C, or in a refrigerator. After this

time, the reconstituted oral suspension should not be taken. Protect the reconstituted oral

suspension from freezing.

7.

MEDICINE SCHEDULE

Prescription Medicine

8.

SPONSOR

Bayer New Zealand Limited

3 Argus Place

Hillcrest

North Shore

Auckland 0627

Free Phone 0800 229 376

9.

DATE OF FIRST APPROVAL

4 February 1988

10. DATE OF REVISION OF THE TEXT

1 October 2019

Summary table of changes

Section changed

Summary of new information

Update to the new Data Sheet format

Addition of statement: ‘Consideration should be given to available official

guidance on the appropriate use of antibacterial agents’

Additional safety warnings fluoroquinolones associated with disabling and

potentially persistent adverse reactions involving different body systems

Rephrasing of a statement related to psychiatric reactions and cardiac

disorders

Addition of “Agomelatine” to paragraph ‘Cytochrome P450’

Addition of interaction with “Zolpidem” and “Agomelatine”

Referencing of specific terms ‘arthralgia, arthritis’ from the ADR table in

section

Addition of cleaning advice for the spoon used for ciprofloxacin oral

suspension

2.1, 2.2, 2.3

Information updated to correspond with product labels and Medsafe

product details

Addition of information regarding missed doses

New headings for precautions relating to ‘Myasthenia gravis’, ‘Tendinitis

and tendon rupture’, ‘Seizures’, ‘Psychiatric reactions’ and ‘Peripheral

neuropathy’

Addition of risk factors for tendon disorders

Addition of precaution regarding ‘Dysglycaemia’ and ‘Aortic aneurysm and

dissection’

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Reference to Tizanidine removed from sentence regarding Cytochrome

P450

concurrent

medications

because

concurrent

contraindicated

Conversion of information on concomitant use with Oral antidiabetic

agents from an ‘interaction’ into a ‘precaution’ in Section 4.4

Addition of statement regarding potential for long-lasting adverse effects

Update cleaning advice for measuring spoon

1.0, 4.2, 4.4, 4.5,

4.8, 5.1, 6.6, 8.0

Multiple editorial changes

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