Ciprofloxacin

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Ciprofloxacin hydrochloride 582 mg equivalent ciprofloxacin 500 mg;  
Available from:
Multichem NZ Limited
INN (International Name):
Ciprofloxacin hydrochloride 582 mg (equivalent ciprofloxacin 500 mg)
Dosage:
500 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Ciprofloxacin hydrochloride 582 mg equivalent ciprofloxacin 500 mg   Excipient: Colloidal silicon dioxide Hypromellose Macrogol 4000 Magnesium stearate Maize starch Microcrystalline cellulose Purified talc Purified water Sodium starch glycolate Titanium dioxide
Units in package:
Blister pack, PVC/Al (not marketed), 7 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Dr Reddy's Laboratories Limited
Therapeutic indications:
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.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/Al - 7 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/Al - 10 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/Al - 14 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/Al - 20 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/Al - 28 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/Al - 56 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/Al - 100 tablets - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-7296a
Authorization date:
2004-07-15

Ciprofloxacin (Ethics)

Ciprofloxacin hydrochloride Ph Eurequivalent to 250 mg, 500 mg and 750 mg

Ciprofloxacin

GENERALINFORMATION

Name of the Medicinal Product

Ciprofloxacin Tablets

Qualitative and QuantitativeComposition

Film-coated tablets

Ciprofloxacin 250:

1 tablet contains ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin.

Ciprofloxacin 500:

1 tablet contains ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin.

Ciprofloxacin 750:

1 tablet contains ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin.

PHARMACEUTICALFORM

Film-coated tablet:

250 mg:

White to creamish-white, round, biconvex film coated tabletswith CPR 250

embossed on one side and ‘BL’ on the other.

500 mg:

White to creamish-white caplet shaped film coated tablets with CPR 500embossed

and with scoreline on one side and ‘BL’ on the other.

750 mg:

White to creamish-white capsuleshaped film coated tabletswith CPR 750 embossed

on one sideand ‘BL’ on the other.

CLINICALPARTICULARS

INDICATIONS

Adults

Uncomplicated and complicated infections causedby ciprofloxacin sensitive

pathogens:

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

biliary tract,peritonitis).

Infections ofthe skin and soft tissue.

Infections ofthe bones and joints.

Sepsis.

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

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 followingshow varying degreesof sensitivity:

Neisseria, Gardnerella,Flavobacterium, Alcaligenes, Streptococcusagalactiae,

Enterococcus faecalis, Streptococcus pyogenes,Streptococcus pneumoniae,

Viridans group Streptococci, Mycoplasmahominis, Mycobacteriumtuberculosis, and

Mycobacteriumfortuitum.

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.

Children

Cystic fibrosis

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

Adults

Unless otherwise prescribed, the following guideline doses are recommended:

Recommended Dosage

Respiratory tract infection

(according toseverity and organism)

2 x 250-500 mg

Urinary tract infections:

- acute, uncomplicated

- cystitis inwomen

(before menopause)

- complicated

1-2 x 250 mg

single dose250 mg

2 x 250-500 mg

Gonorrhoea

- extragenital

- acute, uncomplicated

1 x 250 mg

single dose250 mg

Diarrhoea 1-2 x 500 mg

Other infections

(see Indications) 2 x 500 mg

-Particularly severe, life-threatening

infections, i.e.Streptococcal pneumonia

-Recurrentinfections in cysticfibrosis

-Bone and joint infections

-Septicaemia

-Peritonitis

In particularwhenPseudomonas,

Staphylococcus orStreptococcusis

2 x 750 mg

Inhalational anthrax(post-exposure)

Drug administration should begin as

soon as possible aftersuspected or

confirmed exposure 2 x 500 mg

Elderly

Elderly patients should receive a dose as low as possibledepending on the severity

of their illness and the creatinine clearance.

Children

Cystic Fibrosis

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

dose 1500mg).

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

of ciprofloxacin.

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

cavity,

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.

Children

Cystic Fibrosis

For acute pulmonary exacerbation ofcystic fibrosis associated with P. aeruginosa

infectioninpaediatric 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 duetoE. coli, the duration

of treatment is 10-21 days.

Renal & Hepatic impairment:

Adults

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.

Children

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

CONTRAINDICATIONS

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

occur.

SPECIALWARNINGSAND 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, ciprofloxacin shouldbe used incombination with an

appropriate antibacterialagent.

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

testing.

Cardiac disorders

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,

uncorrected hypokalemia).

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

limited.

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”.

Hypersensitivity:

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

required.

Gastrointestinal System:

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.

Musculo-Skeletal System:

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.

Nervous System:

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.

Cytochrome P450:

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

interaction

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

blockers.

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.

Omeprazole

Concomitant administration of ciprofloxacin and omeprazole results inaslight

reduction ofC

and AUC of ciprofloxacin.

Theophylline

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

reduced.

Other xanthine derivatives

On concurrent administration of ciprofloxacin and caffeine orpentoxifylline

(oxpentifylline) containingproducts, raised serum concentrations of thesexanthine

derivatives were reported.

NSAID

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.

Cyclosporin

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

augment its

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).

Glibenclamide

In particularcases,concurrent administration ofciprofloxacinand glibenclamide can

intensify theaction of glibenclamide (hypoglycaemia).

Methotrexate

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

Metoclopramide accelerates the absorption of ciprofloxacinresulting ina shorter time

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

of ciprofloxacin.

Tizanidine

In a clinicalstudy in healthy subjects, there was an increasein tizanidineserum

concentrations (C

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

CONTRAINDICATONS).

Duloxetine

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

concomitantadministration.

Ropinirole

In a clinicalstudy it was shown that concomitantuse of ropinirole with ciprofloxacin, a

moderate inhibitor of theCYP450 1A2 isozyme, resulted inincreases inthe C

and

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.

Lidocaine

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

administration.

Clozapine

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.

Sildenafil

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

Pregnancy

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

women.

Animal studies have not shown any evidenceof teratogeniceffects (malformations).

Lactation

Ciprofloxacin is excretedin breastmilk. Due to the potential risk of articular damage,

ciprofloxacinshould notbe used during breast-feeding (seePRECLINICAL SAFETY

DATA).

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 EFFECTS

Adverse Reactions based on all clinical studieswith ciprofloxacin sortedby CIOMS III

categories offrequency are listed below (n = 51721 patients,data lock point: 15 May

2005).

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”.

System Organ

Class Common UncommonRare Very Rare Not Known

Infections and

Infestations Mycotic

superinfections Antibiotic

associated colitis

(veryraraelywith

possible fatal

outcome )

Blood and

Lymphatic

System

Disorders Eosinophilia Leukopenia

Anaemia

Neutropenia

Leukocytosis

Thrombocytopenia

Thrombocytaemia Haemolytic

anaemia

Agranulocytsosis

Pancytopenia

(life-threatening)

Bone marrow

depression(life-

threatening)

Immune System

Disorders Allergicreaction

Allergicoedema/

angiooedema Anaphylactic

reaction

Anaphylactic

shock (life-

threatening)

Serum sickness-

like reaction

Metabolism and

Nutrition

Disorders Anorexia Hyperglycaemia

Psychiatric

Disorders Psychomotor

hyperactivity/

agitation Confusion and

disorientation

Anxiety reaction

Abnormal dreams

Depression

Hallucinations Psychotic

reactions

Nervous System

Disorders Headache

Dizziness

Sleep disorders

Taste disorders Par- and

Dysaesthesia

Hypoaesthesia

Tremor

Seizures

Vertigo Migraine

Disturbed co-

ordination

Smell disorders

Hyperesthesia

Intracranial

hypertension Peripheral

neuropathy

and

polyneuropathy

Eye Disorders Visual

disturbances Visual colour

distortions

Ear and

Labyrinth

Disorders Tinnitus

Hearing loss Hearing

impaired

Cardiac

Disorders Tachycardia QT

prolongation,

ventricular

arrhythmia,

torsadesde

pointes*

Vascular

Disorders Vasodilatation

Hypotension

Syncope Vasculitis

Respiratory,

Thoracic and

Mediastinal

Disorders Dysponea

(including

asthmatic

condition)

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

(veryrarely

progressing to

life-threatening

hepaticfailure)

Skin and

Subcutaneous

Tissue

Disorders Rash

Pruritis

Urticaria Photosensitvity

reactions

Unspecific

blistering Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-

Johnson

syndrome

(potentially life-

threatening)

Toxic epidermal

necrolysis

(potentially life-

Musculoskeletal,

Connective

Tissue andBone

Disorders Arthralgia Myalgia

Arthritis

Increased muscle

tone andcramping Muscular

weakness

Tendonitis

Tendon rupture

(predominantly

Achilles tendon)

Exacerbation of

symptomsof

myasthenia

Renal and

Urinary

Disorders Renal

impairment Renal failure

Haematuria

Crystalluria

Tubulointerstitial

nephritis

General

Disorders and Unspecific pain

Feeling unwell Oedema

Sweating Gait disturbance

Administrations

Site Disorders Fever(hyperhidrosis)

Investigations Increase in

blood alkaline

phosphatase Prothrombin level

abnormal

Increased

amylase

* 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,

oedema

Rare Pancytopenia, bone marrow depression, anaphylactic shock,

psychotic reactions, migraine, smelldisorders, hearing impaired,

vasculitis, pancreatitis, liver necrosis, petechiae,tendon rupture

Overdose

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

absorption ofciprofloxacin.

Only a smallamount of ciprofloxacin(< 10 %) is removed fromthe bodyafter

haemodialysis or peritoneal dialysis.

PHARMACODYNAMIC PROPERTIES

Pharmacodynamic properties

Ciprofloxacin is a synthetic broad spectrum antibacterial agent (ATCCODE: J 01 MA

02).

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

to ciprofloxacin.

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

Bacillus anthracis

Staphylococcus aureus (methicillin-susceptible)

Staphylococcus saprophyticus

Streptococcus spp.

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

Anaerobic microorganisms

Mobiluncus

Other Microorganisms

Chlamydia trachomatis

Chlamydia pneumoniae

Mycoplasma hominis

Mycoplasma pneumoniae

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,

Peptostreptococus ,Propionibacteriumacnes).

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

period.

PHARMACOKINETIC PROPERTIES

Absorption

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

later.

Mean Ciprofloxacin Serum Concentrations (mg/L) after

Oral Administration

(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

12.0 0.20.40.5

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.

Distribution

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.

Metabolism

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.

Excretion

Ciprofloxacin is largelyexcreted 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 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

secretion.

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.

Children

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.

PRECLINICALSAFETYDATA

Theacute toxicityof ciprofloxacinafter oral administrationcan be classified as very

low.

Species LD

50 (mg/kg)

Mouse Approx. 5000

Rat Approx. 5000

Rabbit Approx. 2500

Chronic Toxicity

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).

Carcinogenicity

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.

Reproduction toxicology

Fertility studies in rats

Fertility, theintrauterineand postnatal development of the young, and thefertility of

F1 generation were not affected by ciprofloxacin.

Embryotoxicity studies

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.

Mutagenicity

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

MicronucleusTest (Mice)

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

negative results.

In summary, ciprofloxacin poses nosignificant mutagenic potential. Thisassessment

is confirmedby the negative outcome of the long-term carcinogenicity studies in mice

and rats.

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.

Renal tolerability

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.

PHARMACEUTICALPARTICULARS

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.

Storage

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).

MedicineClassification

Prescription Medicine

Name andAddress

Multichem NZ Limited

8 Apollo Drive

Rosedale

North Shore City 0632

Auckland

Telephone:09 488 0330

Date of Preparation

24 August 2010

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