AZITHROMYCIN ACTAVIS 500 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
AZITHROMYCIN DIHYDRATE
Available from:
Actavis Group PTC ehf
INN (International Name):
AZITHROMYCIN DIHYDRATE
Dosage:
500 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Authorised
Authorization number:
PA1380/138/002
Authorization date:
0000-00-00

PACKAGE LEAFLET:INFORMATION FOR THE USER

Azithromycin Actavis 250 mg, film-coated tablets

Azithromycin Actavis 500 mg, film-coated tablets

Azithromycin

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

- Keep this leaflet. You mayneed to read it again.

- If youhave anyfurtherquestions, ask your doctor orpharmacist.

- This medicine has been prescribed for you only.Donot pass it on toothers. It mayharmthem,

even if their signs of illness are the sameas yours.

- If youget any side effects, talk toyour doctor or pharmacist. This includes anypossible side

effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Azithromycin Actavis is and what it is used for

2. Whatyouneed to know before you takeAzithromycinActavis

3. How to take Azithromycin Actavis

4. Possible side effects

5. How to store Azithromycin Actavis

6. Contents of the pack and other information

1. What Azithromycin Actavis is and what it is used for

Azithromycinbelongs toa groupof medicines calledmacrolide antibiotics. Antibiotics are used to

treat infections caused bymicro-organisms like bacteria.

Azithromycin is used for the treatment of certain infections caused by bacteria that are sensitive to it,

such as:

- chest, throat or nasal infections (such asbronchitis,pneumonia, tonsillitis, sore throat

(pharyngitis) andsinusitis)

- ear infections

- skin and softtissue infections, with exceptionof infected burn wounds e.g. - infection of

the tube thatcarries urine fromthe bladder (urethra) or the neck of the womb(cervix) caused

byChlamydia trachomatis(bacteria)

2. What you need to know before you take Azithromycin Actavis

Do not takeAzithromycin Actavis if:

- you are allergicto azithromycin dihydrate, erythromycin or anymacrolide or ketolide

antibiotic

- you are allergic to anyof the other ingredients of thismedicine (listed in section6).

Warnings and precautions

Talk withyour doctoror pharmacistbefore taking Azithromycin Actavis if:

- youhave severe liver or kidneyproblems

- youhave severe heart problems or problemswith your heart beat such as long QT syndrome

(shown on an electro-cardiogramor ECGmachine)

- your blood levels of potassiumormagnesiumare too low

- youdevelop signs of another infection

- you are taking anyergotderivatives suchas ergotamine (to treat migraine) as thesemedicines

shouldnot betaken together with azithromycin (see section “Taking other medicines”)

- youhave a certain type ofmuscle weakness calledmyasthenia gravis

- youhave nervous (neurological) or mental (psychiatric) problems.

Othermedicines and Azithromycin Actavis:

Tell your doctor ifyou are taking, have recentlytakenor might take anyother medicines.

Tell your doctor or pharmacist if you are taking any ofthe followingmedicines:

- antacids - used for heartburn and indigestion.Azithromycin Actavis should be taken at least 1

hour before or2 hours after the antacid

- ergotamine - (used for migraine) shouldnot be taken at the sametime as serious side effects

maydevelop(with numbness or tinglingsensations in the limbs,muscle cramps,headaches,

convulsions,abdominal or chest pain)

- cholesterol lowering medicines (statins)

- warfarin or similarmedicines - used to thinthe blood.AzithromycinActavis can thin the blood

even more.

- cisapride - (used to treat stomach problems) should not be taken atthe sametime as thismay

cause severeheart problems (shown on anelectro-cardiogramor ECGmachine).

- terfenadine - (used to treat hayfever) shouldnot be taken at the same time as thismaycause

severe heart problems (shown on an electro-cardiogramor ECGmachine).

- zidovudine ornelfinavir - used to treat HIVinfections. Taking nelfinavir with Azithromycin

Actavismaymean that you get more of the side effects listed in thisleaflet.

- rifabutin - used to treat tuberculosis (TB)

- quinidine - used to treat heart rhythmproblems

- cyclosporin-used to stopyour bodyrejecting an organ transplant.Your doctorwill regularly

check your blood levels ofcyclosporinand maychange yourdose.

Tell your doctor or pharmacist if you are taking any ofthe followingmedicines. Azithromycin

Actavis can make the effects of these othermedicines stronger. Your doctor may changeyour dose:

- alfentanil - a painkiller used e.g. duringoperations

- theophylline -used for breathingproblems suchasasthma and chronic obstructive pulmonary

disease (COPD).

- digoxin - usedto treat heart problems

- astemizol - used to treat hay fever

- pimozide - used to treat mental health problems

Azithromycin Actavis with food anddrink

This medicine can be taken with or without food.

Pregnancy, breast-feeding and fertility

If you are pregnant orbreast-feeding, thinkyou maybepregnant orare planning tohave a baby, ask

your doctor orpharmacist for advice before taking thismedicine.

There is insufficient information available about the use of azithromycinduring pregnancy.Therefore

you shouldnot use Azithromycin during pregnancy,unless explicitly advised byyour doctor.

Azithromycin is partiallypassed through the mother’smilk, therefore Azithromycin should notbe

used ifyou are breast-feeding.

Driving andusing machines

There are no data available about the influence ofazithromycin onthe abilitytodrive or operate

machines. However azithromycin tablets maycausedizzinessand seizures somake sure you are not

affected before drivingor operating machinery.

Azithromycin Actavis contains lactose

If youhave been told byyour doctor that you have anintolerance to somesugars, contact your doctor

before takingthis medicinal product.

3. How to take Azithromycin Actavis

Alwaystake this medicineexactlyasyour doctoror pharmacist has toldyou. Check with yourdoctor

or pharmacist ifyouare not sure.

For adults and young people with abody weight of 45 kg or over:

500 mgonce daily during three dayswitha total doseof 1500 mg. Your doctormaydecide to

prescribe the total dose of1500 mgduring a periodof5 days, with500 mgthe first dayand 250 mg

on days2to5.

For infections of the neck of the wombandurethra caused by Chlamydia trachomatis:

One dose of 1000 mg, to betaken one time.

Children andadolescents under 45 kg:

The tablets are not recommended. Young people witha bodyweight of less than 45 kg should use

other forms of this medicine.

Patients withkidney or liver problems:

You should tell your doctorifyouhavekidneyor liverproblems asyourdoctormayneed to alter the

normal dose.

Dosage for elderly:

For elderlythe same dosage as for adults applies.

Administration:

The tablets shouldbe taken with ½ glass of water

If you takemore Azithromycin Actavis than youshould

If youhave taken too much Azithromycin Actavis,contact your doctor, pharmacist or go toyour

nearest hospital at once.

Symptomsofoverdose are loss of hearing, feeling sick or being sick and diarrhoea. In case of

overdosage stomach rinse and admission into hospitalmaybe necessary.

If you forgetto take Azithromycin Actavis

If you forget totake Azithromycin Actavis, takeyourdose as soonas possible. If it is almost time for

the next dose, just skip thatdose and take the next onewhen it is due. If in doubt, please contact your

doctor orpharmacist. If you have to skipa dose, stilltake all of your tablets. This means that you will

finishyour course a daylater.

Do not take a double dose tomake up for a forgotten dose.

If you stop taking Azithromycin Actavis

Never stop the treatment with AzithromycinActavis onyour own,but first discuss this with your

doctor. If theprescribed treatment is not completelyfinished, the infection maycome back again.

If youhave anyfurtherquestions on theuse of this medicine, ask your doctor orpharmacist.

4. Possible sideeffects

Like all medicines, thismedicine can causeside effects, although not everybodygets them.

If youhave anyof the following symptoms of a severe allergic reaction stop taking this medicine and

tell your doctor immediately or go to thecasualtydepartment at your nearest hospital:

- Suddendifficultyinbreathing, speakingand swallowing

- Swelling of the lips, tongue, face and neck

- Extreme dizziness or collapse

- Severe or itchy skin rash, especiallyif thisshows blistering and there is sorenessof the eyes,

mouth or genital organs

If you experience anyof the followingside effects contactyourdoctor as soonas possible:

- Diarrhoea that is serious, lasts a long time or hasblood in it,with stomach pain or fever. This

can be a sign of a serious bowel inflammation. This issomething that can rarelyhappen after

taking antibiotics

- Yellowing ofthe skin or whites of the eyes caused by liver problems

- Inflammation of the pancreas, which causessevere painin the abdomen and back

- Increased or reduced urineoutput, or traces of blood inyour urine

- Skin rash caused by sensitivityto sunlight

- Unusual bruising or bleeding

- Irregular heart beat

These areall serious side effects. Youmayneedurgent medical attention. Serious side effects are

uncommon (mayaffect up to 1 in100 people) orthefrequencycannotbe estimated fromthe available

data.

Other side effects include:

Very common(may affect more than 1 in10people)

- diarrhoea

- abdominal pain

- feeling sick (nausea)

- loose wind (flatulence)

Common(may affect up to1 in 10people):

- lack of appetite (anorexia)

- feeling dizzy

- headache

- sensation of pins and needles or numbness (paraesthesia)

- changes inyour sense of taste

- visual impairment

- deafness

- being sick (vomiting), stomach pain or cramps, lossof appetite, problems digestingyour food

- skin rashes and itching

- joint pain (arthralgia)

- fatigue

- change in thequantityof the white bloodcellsand the concentration of bicarbonatein the blood

Uncommon(may affect up to 1 in100 people):

- thrush (candidiasis) - a fungal infecion

- fungal infection

- bacterial infection

- inflammation of the throat (pharyngitis)

- breathlesness,chest pain, wheeze and cough (respiratorydisorder)

- iflammation of the mucousmembrane inside the nose (rhinitis)

- stomach flu (gastroenteritis)

- inflammation insideyourvagina (vaginitis)

- pneumonia

- reduction in the number of white blood cells

- angioedema

- hypersensitivity

- nervousness

- reduced senseof touch (hypoaesthesia)

- feeling drowsy (somnolence)

- having difficultysleeping (insomnia)

- ear disorder

- spinning sensation (vertigo)

- hearing loss or ringing inyour ears

- palpitations

- hot flushes

- shortness of breath

- nosebleed

- inflammation of the liningof the stomach (gastritis)

- constipation

- difficulty swallowing

- swollen abdomen

- dry mouth

- belching

- mouth ulcer

- increased salivaryflow

- liver problems such as hepatitis

- allergic skin reactions suchas being sensitive to sunlight, red, flaking and swollen skin

- severe formof skin flushing

- inflammation of the skin (dermatitis)

- dry skin

- increased sweating

- pain, swelling and reduced motion inyour joints (osteoarthritis)

- muscle pain

- back pain

- neck pain

- increase in bloodurea levels

- painful ordifficult urination

- pain in the upper back (renal pain)

- spotting

- testicular disorder

- urticaria

- chest pain

- face swelling

- fever

- pain, numbness,muscle weakness, burningor tingling sensation (peripheral pain)

- swelling (oedema)

- general feeling of being unwell (malaise)

- weakness (asthenia)

- change in liver enzymelevels and blood levels

- post procedural complications

Rare(may affect up to 1 in1,000 people):

- feeling agitated, feeling ofunreality to the self and own feeling

- abnormal hepatic function

- allergic skin reactions

- swelling of the hands, feet, lips, genitals or throat (angioneurotic oedema)

- kidney problems

Not known(frequency cannot be estimated from the available data)

- gut (colon) infection(pseudomembranous colitis)

- reduced number of red blood cells due todestruction(haemolytic anaemia); reduction in

number of platelets (thrombocytopenia)

- anaphylactic reaction

- feeling angry,aggressive

- anxiety

- confusion

- hallucinations

- fainting (syncope)

- fits (convulsions)

- feeling hyperactive

- change inyour sense of smell (anosmia, parosmia)

- change inyour sense of taste (ageusia)

- exacerbation or aggravation of muscleweakness(myasthenia gravis)

- rapid (ventricular tachycardia) or irregular heart beat, sometimes being life-threatening,

changes of the heart rhythmfound byanelectro-cardiogram(QT prolongation and torsade de

pointes)

- low blood pressure

- inflammation of the pancreas (pancreatitis)

- your tongue and teeth changes colour

- liver failure

- allergic skin reactions

The following side effectshave been reported in prophylactic treatment againstMycobacterium

Aviumcomplex (MAC):

Very common(may affect more than 1 in10people)

- diarrhoea

- abdominal pain

- feeling sick (nausea)

- loose wind (flatulence)

- abdominal discomfort

- loose stools

Common(may affect up to1 in 10people):

- lack of appetite (anorexia)

- feeling dizzy

- headache

- sensation of pins and needles or numbness (paraesthesia)

- changes inyour sense of taste

- visual impairment

- deafness

- being sick (vomiting), stomach pain or cramps, lossof appetite, problems digestingyour food

- skin rashes and itching

- joint pain (arthralgia)

- fatigue

Uncommon(may affect up to 1 in100 people):

- reduced senseof touch (hypoaesthesia)

- hearing loss or ringing inyour ears

- palpitations

- liver problems such as hepatitis

- severe formof skin flushing

- allergic skin reactions suchas being sensitive to sunlight, red, flaking and swollen skin

- general feeling of being unwell (malaise)

- weakness (asthenia)

Reporting of side effects

If youget any side effects, talk toyour doctor orpharmacist. This include anypossible side effects not

listed in this leaflet. You can also reportside effects directly(see details below). Byreportingside

effects you can help providemore information on thesafetyof this medicine. Reports maybe made

byfollowingthe links to the online reporting option accessible from the IMB homepage, or by

completing the downloadable report form alsoaccessible fromthe IMB website,which maybe

completedmanually and submitted to the IMB via freepost, to thefollowing address:

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’MalleyHouse

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: + 353 16764971

Fax: + 35316762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie .

5. How to store Azithromycin Actavis

Keep thismedicine out of the sight and reach of children.

Do not use thismedicine after the expiry date which is stated on the carton afterEXP. The expirydate

refers to the last dayofthat month.

PVC/Alu blister: Store below 25°C. Store in the original packaging toprotect frommoisture.

OPA-PVC-Alu/Alu blister: This medicinal product does not require anyspecial storage conditions.

Do not throw awayanymedicines via wastewaterorhouseholdwaste. Ask yourpharmacist how to

throw awaymedicines you no longeruse. Thesemeasures will help protect theenvironment.

6. Contents of the pack andother information

What Azithromycin Actavis contains

- The active substance is: Azithromycin dihydrate.

- Azithromycin Actavis250mgfilm-coated tablets contain250 mgazithromycin (as dihydrate).

- Azithromycin Actavis500mgfilm-coated tablets contain500 mgazithromycin (as dihydrate).

- The other ingredients are:Core: croscarmellose sodium(E468),magnesiumstearate (E 572),

microcrystalline cellulose (E460), siliciumdioxide, (E551),poloxamer, povidone (E1201), talc,

and waterfree lactose. Coating: hypromellose (E464),hydroxypropylcellulose, macrogoland

titaniumdioxide (E171).

What Azithromycin Actavis looks likeand contents of the pack

Film-coated tablet.

AzithromycinActavis 250mgfilm-coated tabletsarewhite to off-white oval, 6.7 x 13.5 mm,

biconvex film-coated tabletsmarked “250”on one sideand plain onthe other side.

AzithromycinActavis 500mgfilm-coated tabletsarewhite to off-white oval, 9.7 x 17.9 mm,

biconvex film-coated tabletsmarked “500”on one sideand plain onthe other side.

250 mgtablets are available in a PVC/Alu and OPA-PVC-Alu/Alublister of 4 and 6 film-coated

tablets.

500 mgtablets are available in a PVC/Alu and OPA-PVC-Alu/Alublister of 2 and 3 film-coated

tablets.

Marketing AuthorisationHolder and Manufacturer

MA holder

Actavis Group PTC ehf.

Reykjavikurvegur 76-78

220 Hafnarfjörður

Iceland

Manufacturer

Actavis hf

Reykjavikurvegur 76-78

220 Hafnarfjörður

Iceland

This medicinal product is authorised in the Member States of the EEA under the following

names:

Netherlands Azitrhomycine Actavis

Austria AzithromycinActavis 500mgFilmtabletten

Bulgaria Azatril

Czech RepublicAzithromycin Actavis 250 /500 mg

DenmarkAzithromycin Actavis

Estonia AzithromycinActavis

Hungary Zitinn 250 /500 mgfilmatbletta

Iceland AzithromycinActavis

Ireland AzithromycinActavis 250/500 mgFilm-coated Tablets

Lithuania AzithromycinActavis 500mgplėvele dengtos tabletės

Latvia AzithromycinActavis 500mgapvalkotās tabletes

Malta Actamycin

Poland AzithromycinActavis

PortugalAzithromycin Sivatca

RomaniaAzatril

Slovakia AzithromycinActavis 250 /500 mg

Sweden AzithromycinActavis

United Kingdom AzithromycinActavis 250 /500mgfilm-coated tablets PL 30306/0387-0388

This leafletwas last revised in May 2013

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AzithromycinActavis500mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

AzithromycinActavis500mgfilm-coatedtabletscontain500mgazithromycin(asdihydrate).

Excipientswithknowneffect:

Eachtabletcontains120mglactoseanhydrous

Forthefulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedTablet

Whitetooff-whiteoval,9.7x17.9mm,biconvexfilm-coatedtabletsmarked“500”ononesideandplainontheother

side.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Azithromycinisindicatedforthefollowingbacterialinfectionsinducedbymicro-organismssusceptibleto

azithromycin(seesections4.4and5.1):

Acutebacterialsinusitis(adequatelydiagnosed)

Acutebacterialotitismedia(adequatelydiagnosed)

Pharyngitis,tonsillitis

Acuteexacerbationofchronicbronchitis(adequatelydiagnosed)

Mildtomoderatelyseverecommunityacquiredpneumonia

Infectionsoftheskinandsofttissuesofmildtomoderateseveritye.g.folliculitis,cellulitis,erysipelas

UncomplicatedChlamydiatrachomatisurethritisandcervicitis

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

AzithromycinActavisshouldbegivenasasingledailydose.Durationofthetreatmentforthedifferentinfection

diseasesisgivenbelow.

Thetabletscanbetakenwithorwithoutfood.

Thetabletsshouldbetakenwith½glassofwater.

Childrenandadolescentswithabodyweightabove45kg,adultsandtheelderly:

Thetotaldoseis1500mg,administeredas500mgoncedailyfor3days.Alternatively,thesametotaldose(1500mg)

canbeadministeredinaperiodof5days,500mgonthefirstdayand250mgonday2to5.

InthecaseofuncomplicatedChlamydiatrachomatisurethritisandcervicitis,thedosageis1000mgasasingleoral

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Childrenandadolescentswithabodyweightbelow45kg:

AzithromycinActavistabletsarenotsuitableforpatientsunder45kgbodyweight.Otherdosageformsareavailable

forthisgroupofpatients.

Elderlypatients

Forelderlypatientsthesamedoseasforadultscanbeapplied.Sinceelderlypatientscanbepatientswithongoing

proarrhythmicconditionsaparticularcautionisrecommendedduetotheriskofdevelopingcardiacarrhythmiaand

torsadesdepointes(seesection4.4).

Patientswithrenalimpairment:

Doseadjustmentisnotrequiredinpatientswithmildtomoderaterenalimpairment(GFR10 -80ml/min)(seesection

4.4).

Patientswithhepaticimpairment:

Doseadjustmentisnotrequiredforpatientswithmildtomoderatehepaticdysfunction(seesection4.4).

4.3Contraindications

Theuseofthisproductiscontraindicatedinpatientswithhypersensitivitytoazithromycin,erythromycin,any

macrolideorketolideantibiotic,ortoanyoftheexcipientslistedinsection6.1.

4.4Specialwarningsandprecautionsforuse

Aswitherythromycinandothermacrolides,rareseriousallergicreactionsincludingangioneuroticoedemaand

anaphylaxis(rarelyfatal),havebeenreported.Someofthesereactionswithazithromycinhaveresultedinrecurrent

symptomsandrequiredalongerperiodofobservationandtreatment.

Sincetheliveristheprincipalrouteofeliminationforazithromycin,theuseofazithromycinshouldbeundertakenwith

cautioninpatientswithsignificanthepaticdisease.Casesoffulminanthepatitispotentiallyleadingtolife-threatening

liverfailurehavebeenreportedwithazithromycin(seesection4.8).Somepatientsmayhavehadpre-existinghepatic

diseaseormayhavebeentakingotherhepatotoxicmedicinalproducts.

Incaseofsignsandsymptomsofliverdysfunction,suchasrapiddevelopingastheniaassociatedwithjaundice,dark

urine,bleedingtendencyorhepaticencephalopathy,liverfunctiontests/investigationsshouldbeperformed

immediately.Azithromycinadministrationshouldbestoppedifseriousliverdysfunctionhasemerged.

Inpatientsreceivingergotderivatives,ergotismhasbeenprecipitatedbycoadministrationofsomemacrolide

antibiotics.Therearenodataconcerningthepossibilityofaninteractionbetweenergotaminederivativesand

azithromycin.However,becauseofthetheoreticalpossibilityofergotism,azithromycinandergotderivativesshould

notbeco-administered(seesection4.5).

Superinfections:

Aswithanyantibioticpreparation,itisrecommendedtopayattentiontosignsofsuperinfectionwithnon-susceptible

micro-organismslikefungi.Asuperinfectionmayrequireaninterruptionoftheazithromycintreatmentandinitiation

ofadequatemeasures.

Clostridiumdifficileassociateddiarrhoea(CDAD)hasbeenreportedwithuseofnearlyallantibacterialagents,

includingazithromycin,andmayrangeinseverityfrommilddiarrhoeatofatalcolitis.Treatmentwithantibacterial

agentsaltersthenormalfloraofthecolonleadingtoovergrowthofC.difficile.

C.difficileproducestoxinsAandBwhichcontributetothedevelopmentofCDAD.HypertoxinproducingstrainsofC.

difficilecauseincreasedmorbidityandmortality,astheseinfectionscanberefractorytoantimicrobialtherapyandmay

requirecolectomy.CDADmustbeconsideredinallpatientswhopresentwithdiarrhoeafollowingantibioticuse.

CarefulmedicalhistoryisnecessarysinceCDADhasbeenreportedtooccurovertwomonthsaftertheadministration

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Inpatientswithsevererenalimpairment(GFR<10ml/min)a33%increaseinsystemicexposuretoazithromycinwas

observed(seesection5.2).

ProlongedcardiacrepolarisationandQTinterval,impartingariskofdevelopingcardiacarrhythmiaandtorsadesde

pointes,havebeenseenintreatmentwithothermacrolides,includingazithromycin(seesection4.8).Thereforeasthe

followingsituationsmayleadtoanincreasedriskforventriculararrhythmias(includingtorsadedepointes)whichcan

leadtocardiacarrest,azithromycinshouldbeusedwithcautioninpatientswithongoingproarrhythmicconditions

(especiallywomenandelderlypatients)suchaspatients:

WithcongenitalordocumentedacquiredQTprolongation.

CurrentlyreceivingtreatmentwithotheractivesubstancesknowntoprolongQTintervalsuchasantiarrhythmics

ofclassesIA(quinidineandprocainamide)andclassIII(dofetilide,amiodaroneandsotalol),cisaprideand

terfenadine;antipsychoticagentssuchaspimozide;antidepressantssuchascitalopram;andfluoroquinolones

suchasmoxifloxacinandlevofloxacin.

Withelectrolytedisturbance,particularlyincasesofhypokalaemiaandhypomagnesaemia.

Withclinicallyrelevantbradycardia,cardiacarrhythmiaorseverecardiacinsufficiency.

Exacerbationsofthesymptomsofmyastheniagravisandnewonsetofmyastheniasyndromehavebeenreportedin

patientsreceivingazithromycintherapy(seesection4.8).

SafetyandefficacyforthepreventionortreatmentofMycobacteriumAviumComplex(MAC)inchildrenhavenot

beenestablished.

Thefollowingshouldbeconsideredbeforeprescribingazithromycin:

AzithromycinActavisisnotsuitablefortreatmentofsevereinfectionswhereahighconcentrationoftheantibioticin

thebloodisrapidlyneeded.

Theselectionofazithromycintotreatanindividualpatientshouldtakeintoaccounttheappropriatenessofusinga

macrolideantibacterialagentbasedonadequatediagnosistoascertainthebacterialetiologyoftheinfectioninthe

approvedindicationsandtheprevalenceofresistancetoazithromycinorothermacrolides.

InareaswithahighincidenceoferythromycinAresistance,itisespeciallyimportanttotakeintoconsiderationthe

evolutionofthepatternofsusceptibilitytoazithromycinandotherantibiotics.

Asforothermacrolides,highresistanceratesofStreptococcuspneumoniaehavebeenreportedforazithromycinin

someEuropeancountries(seesection5.1).Thisshouldbetakenintoaccountwhentreatinginfectionscausedby

Streptococcuspneumoniae.

Inbacterialpharyngitistheuseofazithromycinisrecommendedonlyincaseswherefirstlinetherapywithbeta-

lactamsisnotpossible.

Skinandsofttissueinfections:

Themaincausativeagentofsofttissueinfections,Staphylococcusaureus,isfrequentlyresistanttoazithromycin.

Therefore,susceptibilitytestingisconsideredapreconditionfortreatmentofsofttissueinfectionswithazithromycin.

Infectedburnwounds:

Azithromycinisnotindicatedforthetreatmentofinfectedburnwounds.

Sexuallytransmitteddisease:

IncaseofsexuallytransmitteddiseasesaconcomitantinfectionbyT.pallidiumshouldbeexcluded.

Neurologicalorpsychiatricdiseases:

Azithromycinshouldbeusedwithcautioninpatientswithneurologicalorpsychiatricdisorders.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Antacids:

Inapharmacokineticstudyinvestigatingtheeffectsofsimultaneousadministrationofantacidswithazithromycin,no

effectonoverallbioavailabilitywasseen,althoughpeakserumlevelswerereducedbyapproximately25%.

Azithromycinmustbetakenatleast1hourbeforeor2hoursafterantacids.

Cetirizine:

Inhealthyvolunteers,coadministrationofa5-dayregimenofazithromycinwithcetirizine20mgatsteady-state

resultedinnopharmacokineticinteractionandnosignificantchangesintheQTinterval.

Didanosine(Dideoxyinosine):

Coadministrationof1200mg/dayazithromycinwith400mg/daydidanosinein6HIV-positivesubjectsdidnotappear

toaffectthesteady-statepharmacokineticsofdidanosineascomparedwithplacebo.

Digoxin(P-gpsubstrates):

Concomitantadministrationofmacrolideantibiotics,includingazithromycin,withP-glycoproteinsubstratessuchas

digoxin,hasbeenreportedtoresultinincreasedserumlevelsoftheP-glycoproteinsubstrate.Therefore,if

azithromycinandP-gpsubstratessuchasdigoxinareadministeredconcomitantly,thepossibilityofelevatedserum

concentrationsofthesubstratesshouldbeconsidered.

Zidovudine:

Single1000mgdosesandmultipledosesof600mgor1200mgazithromycinhadlittleeffectontheplasma

pharmacokineticsorurinaryexcretionofzidovudineoritsglucuronidemetabolite.However,administrationof

azithromycinincreasedtheconcentrationsofphosphorylatedzidovudine,theclinicallyactivemetabolite,inperipheral

bloodmononuclearcells.Theclinicalsignificanceofthisfindingisunclear,butitmaybeofbenefittopatients.

AzithromycindoesnotinteractsignificantlywiththehepaticcytochromeP450system.Itisnotbelievedtoundergothe

pharmacokineticdruginteractionsasseenwitherythromycinandothermacrolides.HepaticcytochromeP450induction

orinactivationviacytochrome-metabolitecomplexdoesnotoccurwithazithromycin.

Ergotaminederivatives:

Duetothetheoreticalpossibilityofergotism,theconcurrentuseofazithromycinwithergotderivativesisnot

recommended(seesection4.4).

Pharmacokineticstudieshavebeenconductedbetweenazithromycinandthefollowingdrugsknowntoundergo

significantcytochromeP450mediatedmetabolism.

Astemizole,alfentanil:

Therearenoknowndataoninteractionswithastemizoleoralfentanil.Cautionisadvisedintheco-administrationof

thesemedicineswithAzithromycinbecauseoftheknownenhancingeffectofthesemedicineswhenusedconcurrently

withthemacrolideantibioticerythromycin.

Atorvastatin:

Coadministrationofatorvastatin(10mgdaily)andazithromycin(500mgdaily)didnotaltertheplasmaconcentrations

ofatorvastatin(basedonaHMGCoA-reductaseinhibitionassay).However,post-marketingcasesofrhabdomyolysis

inpatientsreceivingazithromycinwithstatinshavebeenreported.

Carbamazepine:

Inapharmacokineticinteractionstudyinhealthyvolunteers,nosignificanteffectwasobservedontheplasmalevelsof

carbamazepineoritsactivemetaboliteinpatientsreceivingconcomitantazithromycin.

Cisapride:

CisaprideismetabolizedintheliverbytheenzymeCYP3A4.Becausemacrolidesinhibitthisenzyme,concomitant

administrationofcisapridemaycausetheincreaseofQTintervalprolongation,ventriculararrhythmiasandtorsadesde

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Cimetidine:

Inapharmacokineticstudyinvestigatingtheeffectsofasingledoseofcimetidine,given2hoursbeforeazithromycin,

onthepharmacokineticsofazithromycin,noalterationofazithromycinpharmacokineticswasseen.

Coumarin-TypeOralAnticoagulants:

Inapharmacokineticinteractionstudy,azithromycindidnotaltertheanticoagulanteffectofasingle15-mgdoseof

warfarinadministeredtohealthyvolunteers.Therehavebeenreportsreceivedinthepost-marketingperiodof

potentiatedanticoagulationsubsequenttocoadministrationofazithromycinandcoumarin-typeoralanticoagulants.

Althoughacausalrelationshiphasnotbeenestablished,considerationshouldbegiventothefrequencyofmonitoring

prothrombintimewhenazithromycinisusedinpatientsreceivingcoumarin-typeoralanticoagulants.

Cyclosporin:

Inapharmacokineticstudywithhealthyvolunteersthatwereadministereda500mg/dayoraldoseofazithromycinfor

3daysandwerethenadministeredasingle10mg/kgoraldoseofcyclosporin,theresultingcyclosporinC

werefoundtobesignificantlyelevated.Consequently,cautionshouldbeexercisedbeforeconsidering

concurrentadministrationofthesedrugs.Ifcoadministrationofthesedrugsisnecessary,cyclosporinlevelsshouldbe

monitoredandthedoseadjustedaccordingly.

Efavirenz:

Coadministrationofa600mgsingledoseofazithromycinand400mgefavirenzdailyfor7daysdidnotresultinany

clinicallysignificantpharmacokineticinteractions.

Fluconazole:

Coadministrationofasingledoseof1200mgazithromycindidnotalterthepharmacokineticsofasingledoseof800

mgfluconazole.Totalexposureandhalf-lifeofazithromycinwereunchangedbythecoadministrationoffluconazole,

however,aclinicallyinsignificantdecreaseinCmax(18%)ofazithromycinwasobserved.

Indinavir:

Coadministrationofasingledoseof1200mgazithromycinhadnostatisticallysignificanteffectonthe

pharmacokineticsofindinaviradministeredas800mgthreetimesdailyfor5days.

Methylprednisolone:

Inapharmacokineticinteractionstudyinhealthyvolunteers,azithromycinhadnosignificanteffectonthe

pharmacokineticsofmethylprednisolone.

Midazolam:

Inhealthyvolunteers,coadministrationofazithromycin500mg/dayfor3daysdidnotcauseclinicallysignificant

changesinthepharmacokineticsandpharmacodynamicsofasingle15mgdoseofmidazolam.

Nelfinavir:

Coadministrationofazithromycin(1200mg)andnelfinaviratsteadystate(750mgthreetimesdaily)resultedin

increasedazithromycinconcentrations.Noclinicallysignificantadverseeffectswereobservedandnodoseadjustment

isrequired.

Rifabutin:

Coadministrationofazithromycinandrifabutindidnotaffecttheserumconcentrationsofeitherdrug.

Neutropeniawasobservedinsubjectsreceivingconcomitanttreatmentofazithromycinandrifabutin.Although

neutropeniahasbeenassociatedwiththeuseofrifabutin,acausalrelationshiptocombinationwithazithromycinhas

notbeenestablished(seesection4.8).

Sildenafil:

Innormalhealthymalevolunteers,therewasnoevidenceofaneffectofazithromycin(500mgdailyfor3days)onthe

AUCandC

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Terfenadine:

Pharmacokineticstudieshavereportednoevidenceofaninteractionbetweenazithromycinandterfenadine.Therehave

beenrarecasesreportedwherethepossibilityofsuchaninteractioncouldnotbeentirelyexcluded;howevertherewas

nospecificevidencethatsuchaninteractionhadoccurred.

Theophylline:

Thereisnoevidenceofaclinicallysignificantpharmacokineticinteractionwhenazithromycinandtheophyllineareco-

administeredtohealthyvolunteers.Asinteractionsofothermacrolideswiththeophyllinehavebeenreported,alertness

tosignsthatindicateariseintheophyllinelevelsisadvised.

Triazolam:

In14healthyvolunteers,coadministrationofazithromycin500mgonDay1and250mgonDay2with0.125mg

triazolamonDay2hadnosignificanteffectonanyofthepharmacokineticvariablesfortriazolamcomparedto

triazolamandplacebo.

Trimethoprim/sulfamethoxazole:

Coadministrationoftrimethoprim/sulfamethoxazoleDS(160mg/800mg)for7dayswithazithromycin1200mgon

Day7hadnosignificanteffectonpeakconcentrations,totalexposureorurinaryexcretionofeithertrimethoprimor

sulfamethoxazole.Azithromycinserumconcentrationsweresimilartothoseseeninotherstudies.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofazithromycininpregnantwomen.Inreproductiontoxicitystudiesin

animalsazithromycinwasshowntopasstheplacenta,butnoteratogeniceffectswereobserved(seesection5.3).The

safetyofazithromycinhasnotbeenconfirmedwithregardtotheuseoftheactivesubstanceduringpregnancy.

ThereforeAzithromycinActavisshouldonlybeusedduringpregnancyifthebenefitoutweighstherisk.

Breast-feeding

Azithromycinhasbeenreportedtobesecretedintohumanbreastmilkmbuttherearenoadequateandwell-controlled

clinicalstudiesinnursingwomentthathavecharacterizedthepharmacokineticsofazithromycinexcretionintohuman

breastmilk.

Becauseitisnotknownwhetherazithromycinmayhaveadverseeffectsonthebreast-fedinfant,nursingshouldbe

discontinuedduringtreatmentwithAzithromycinActavis.Amongotherthingsdiarrhoea,fungusinfectionofthe

mucousmembraneaswellassensitisationispossibleinthenursedinfant.Itisrecommendedtodiscardthemilkduring

treatmentandupuntil2daysafterdiscontinuationoftreatment.Nursingmayberesumedthereafter.

Fertility

Infertilitystudiesconductedinrat,reducedpregnancyrateswerenotedfollowingadministrationofazithromycin.The

relevanceofthisfindingtohumansisunknown.

4.7Effectsonabilitytodriveandusemachines

Nodataareavailableregardingtheinfluenceofazithromycinonapatient'sabilitytodriveoroperatemachinery.

However,thepossibilityofundesirableeffectslikedizzinessandconvulsionsshouldbetakenintoaccountwhen

performingtheseactivities.

4.8Undesirableeffects

Thetablebelowliststheadversereactionsidentifiedthroughclinicaltrialexperienceandpost-marketingsurveillance

bysystemorganclassandfrequency.Adversereactionsidentifiedfrompost-marketingexperienceareincludedin

italics.Thefrequencygroupingisdefinedusingthefollowingconvention:Verycommon(1/10);Common(1/100to

<1/10);Uncommon(1/1,000to<1/100);Rare(1/10,000to<1/1,000);VeryRare(<1/10,000);andNotknown

(cannotbeestimatedfromtheavailabledata).Withineachfrequencygrouping,undesirableeffectsarepresentedin

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Adversereactionspossiblyorprobablyrelatedtoazithromycinbasedonclinicaltrialexperienceandpost-

marketingsurveillance:

very

common

1/10 common

1/100to<

1/10 uncommon

1/1,000to<

1/100 rare

1/10,000to

<1/1,000 very

rare

<

1/10,000 notknown

frequencycannot

beestimatedfrom

availabledata

Infectionsandinfestations

Candidiasis,

oralcandidiasis,

vaginal

infection,

pneumonia,

fungalinfection,

bacterial

infection,

pharyngitis,

gastroenteritis,

respiratory

disorders,

Pseudomembranous

colitis(seesection

4.4)

Bloodandlymphaticsystemdisorders

Leukopenia,

neutropenia,

eosinophilia Thrombocytopenia,

haemolytic

anaemia

Immunesystemdisorders

Angioedema,

hypersensitivity Anaphylactic

reaction(see

section4.4.)

Metabolismandnutritiondisorders

Anorexia

Psychiatricdisorders

Nervousness,

insomnia Agitation,

depersonalisation Aggression,

anxiety,delirium,

hallucination

Nervoussystemdisorders

Dizziness,

headache,

paraesthesia,

dysgeusia Hypoaesthesia,

somnolence Syncope,

convulsion,

psychomotor

hyperactivity,

anosmia,ageusia,

parosmia,

myastheniagravis

(seesection4.4)

Eyedisorders

Visual

impairment

Earandlabyrinthdisorders

Deafness Eardisorder,

hearing

impaired,

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Cardiacdisorders

Palpitations Torsadesdepointes

(seesection4.4),

arrhythmia(see

section4.4)

including

ventricular

tachycardia.

ElectrodiogramQT

prolonged(see

section4.4)

Vasculardisorders

Hotflush Hypotension

Respiratory,thoracicandmediastinaldisorders

Dispnoea,

epistaxis

Gastrointestinaldisorders

Diarrhoea,

abdominal

pain,

nausea,

flatulence Vomiting,

dyspepsia Gastritis,

constipation,

dysphagia,

abdominal

distension,dry

mouth,

eructation,

mouth

ulceration,

salivary

Pancreatitis,tongue

andteeth

discoloration

Hepatobiliarydisorders

Hepatitis Hepaticfunction

abnormal,

jaundice

cholestatic Hepaticfailure

(whichhasrarely

resultedindeath)

(seesection4.4),

hepatitisfulminant,

hepaticnecrosis,

Skinandsubcutaneoustissuedisorders

Rash,

pruritus Stevens-Johnson

syndrome,

photosensitivity

reaction,

urticaria,

dermatitis,dry

skin,

hyperhidrosis Allergic

reactions

including

angioneurotic

oedema Toxicepidermal

necrolysis,

erythema

multiforme

Musculoskeletalandconnectivetissuedisorders

Arthralgia Osteoarthritis,

myalgia,back

pain,neckpain

Renalandurinarydisorders

Dysuria,renal

pain Renalfailure

acute,nephritis

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AdversereactionspossiblyorprobablyrelatedtoMycobacteriumAviumComplexprophylaxisandtreatmentbasedon

clinicaltrialexperienceandpost-marketingsurveillance.Theseadversereactionsdifferfromthosereportedwith

Reproductivesystemandbreastdisorders

Metrorrhagia,

testicular

disorders

Generaldisordersandadministrationsiteconditions

Fatigue Chestpain,face

oedema,

pyrexia,

peripheralpain,

oedema,

malaise,asthenia

Investigations

Lymphocyte

count

decreased,

eosinophil

count

increased,

blood

bicarbonate

decreased,

basophils

increased,

monocytes

increased,

neutrophils

Aspartate

aminotransferase

increased,blood

bilirubin

increased,blood

ureaincreased,

bloodcreatinine

increased,blood

potassium

abnormal,blood

alkaline

phosphatase

increased,

chloride

increased,

glucose

increased,

platelets

increased,

hematocrit

decreased,

bicarbonate

increased,

abnormal

sodium

Injuryandpoisoning

Postprocedural

complications

SystemOrganClass Adversereaction Frequency

Metabolismand

NutritionDisorders Anorexia Common

NervousSystem

Disorders Dizziness,headache,paraesthesia,

dysgeusia Common

Hypoesthesia Uncommon

EyeDisorders Visualimpairment Common

EarandLabyrinth

Disorders Deafness Common

Hearingimpaired,tinnitus Uncommon

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4.9Overdose

Adverseeventsexperiencedinhigherthanrecommendeddosesweresimilartothoseseenatnormaldoses.

Symptoms

Thetypicalsymptomsofanoverdosewithmacrolideantibioticsincludereversiblelossofhearing,severenausea,

vomitinganddiarrhoea.

Treatment

Intheeventofoverdose,generalsymptomaticandsupportivemeasuresareindicatedasrequired.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antibacterialsforsystemicuse,macrolides.ATCcode:J01FA10.

Azithromycinisamacrolideantibioticbelongingtotheazalidegroup.

ThemoleculeisconstructedbyaddinganitrogenatomtothelactoneringoferythromycinA.Thechemicalnameof

azithromycinis9-deoxy-9a-aza-9a-methyl-9a-homoerythromycinA.Themolecularweightis749.0.

Modeofaction

Azithromycinisanazalide,asub-classofthemacrolideantibiotics.Bybindingtothe50Sribosomalsub-unit,

azithromycinavoidsthetranslocationofpeptidechainsfromonesideoftheribosometotheother.Asaconsequenceof

this,RNA-dependentproteinsynthesisinsensitiveorganismsisprevented.

PK/PDrelationship:

ForazithromycintheAUC/MICisthemajorPK/PDparametercorrelatingbestwiththeefficacyofazithromycin.

Mechanismofresistance:

Resistancetoazithromycinmaybeinherentoracquired.Therearethreemainmechanismsofresistanceinbacteria:

targetsitealteration,alterationinantibiotictransportandmodificationoftheantibiotic.

CompletecrossresistanceexistsamongStreptococcuspneumoniae,betahaemolyticstreptococcusofgroupA,

EnterococcusfaecalisandStaphylococcusaureus,includingmethicillinresistantS.aureus(MRSA)toerythromycin,

azithromycin,othermacrolidesandlincosamides.

Breakpoints

Gastrointestinal

Disorders Diarrhoea,abdominalpain,nausea,

flatulence,abdominaldiscomfort,

loosestools Verycommon

HepatobiliaryDisorders Hepatitis Uncommon

SkinandSubcutaneous

TissueDisorders Rash,pruritus Common

Steven-Johnsonsyndrome,

photosensitivityreaction Uncommon

Musculoskeletaland

ConnectiveTissue

Disorders Arthralgia Common

GeneralDisordersand

AdministrationSite

Conditions Fatigue Common

Asthenia,malaise Uncommon

MICbreakpoint(mg/L)

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Susceptibility:

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

Pathogensforwhichresistancemaybeaproblem:prevalenceofresistanceisequaltoorgreaterthan10%inatleast

onecountryintheEuropeanUnion.

Tableofsusceptibility

Commonlysusceptiblespecies

AerobicGram-negativemicroorganisms

Haemophilusinfluenzae*

Moraxellacatarrhalis*

Othermicroorganisms

Chlamydophilapneumoniae

Chlamydiatrachomatis

Legionellapneumophila

Mycobacteriumavium

Mycoplasmapneumonia*

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicroorganisms

Staphylococcusaureus*

Streptococcusagalctiae

Streptococcuspneumoniae*

Streptococcuspyogenes*

Othermicroorganisms

Ureaplasmaurealyticum

Inherentlyresistantorganisms

AerobicGram-positivemicroorganisms

Staphylococcusaureus–methicillinresistantanderythromycinresistantstrains

Streptococcuspneumoniae–Penicillinresistantstrains

AerobicGram-negativemicroorganisms

Escherichiacoli

Pseudomonasaeruginosa

Klebsiellaspp.

AnaerobicGram-negativemicroorganism

Bacteroidesfragilis-group

*Clinicaleffectivenessisdemonstratedbysensitiveisolatedorganismsforapprovedclinical

Staphylococcusspp. 1 >2

Streptococcusspp.(GroupA,B,C,G) 0.25 >0.5

Streptococcuspneumoniae 0.25 >0.5

Haemophilusinfluenzae 0.125 >4

Moraxellacatarrhalis 0.25 >0.5

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5.2Pharmacokineticproperties

Absorption:

Bioavailabilityofazithromycinafteroraladministrationisapproximately37%.Peakplasmaconcentrationsareattained

after2-3hours.Themeanmaximumconcentrationobserved(C

)afterasingledoseof500mgisapproximately

0.4µg/ml.

Distribution:

Orallyadministeredazithromyciniswidelydistributedthroughoutthebody.

Pharmacokineticstudieshavedemonstratedthattheconcentrationsofazithromycinmeasuredintissuesarenoticeably

higher(upto50timesthemaximumobservedconcentrationinplasma)thanthosemeasuredinplasma.Thisindicates

thattheagentstronglybindstotissues(steady-statedistributionvolumeapprox.31l/kg).

Attherecommendeddosenoaccumulationappearsintheserum.Accumulationappearsintissueswherelevelsare

muchhigherthaninserum.Threedaysafteradministrationof500mgasasingledoseorinpartialdoses

concentrationsof1,3-4,8 µ

g/g,0,6-2,3 µ

g/g,2,0-2,8 µ

g/gand0-0,3 µ

g/mlhavebeenmeasuredinresp.lung,prostate,

tonsilandserum.

Inexperimentalinvitroandinvivostudiesazithromycinaccumulatesinphagocytes.Releaseisstimulatedbyactive

phagocytosis.Inanimalmodelsthisprocesscontributestotheaccumulationofazithromycinintissue.

Bindingofazithromycintoserumproteinsisvariableandvariesfrom52%at0,05mg/lto18%at0,5mg/l,depending

ontheserumconcentration.

Excretion:

Theterminalplasmaeliminationhalf-lifecloselyreflectstheeliminationhalf-lifefromtissuesof2-4days.

Approximately12%ofanintravenouslyadministereddoseisexcretedinunchangedformwiththeurineoveraperiod

of3days;themajorproportioninthefirst24hours.Concentrationsofupto237µg/mlazithromycin,2daysaftera5-

daycourseoftreatment,havebeenfoundinhumanbile.Tenmetaboliteshavebeenidentified(formedbyN-andO-

demethylation,byhydroxylationofthedesosamineandaglyconerings,andbysplittingofthecladinoseconjugate).

Investigationssuggestthatthemetabolitesdonotplayaroleinthemicrobiologicalactivityofazithromycin.

PharmacokineticsinSpecialpopulations:

RenalInsufficiency:

Followingasingleoraldoseofazithromycin1g,meanC

andAUC

0-120 increasedby5.1%and4.2%respectively,

insubjectswithmildtomoderaterenalimpairment(glomerularfiltrationrateof10-80ml/min)comparedwithnormal

renalfunction(GFR>80ml/min).Insubjectswithsevererenalimpairment,themeanC

andAUC

0-120 increased

61%and35%respectivelycomparedtonormal.

Hepaticinsufficiency:

Inpatientswithmildtomoderatehepaticimpairment,thereisnoevidenceofamarkedchangeinserum

pharmacokineticsofazithromycincomparedtonormalhepaticfunction.Inthesepatients,urinaryrecoveryof

azithromycinappearstoincreaseperhapstocompensateforreducedhepaticclearance.

Elderly:

Thepharmacokineticsofazithromycininelderlymenwassimilartothatofyoungadults;however,inelderlywomen,

althoughhigherpeakconcentrations(increasedby30-50%)wereobserved,nosignificantaccumulationoccurred.

Inelderlyvolunteers(>65years)higher(29%)AUCvalueshavebeenmeasuredaftera5daytreatmentthanin

youngervolunteers(<45years).Thesedifferencesarenotregardedasclinicallyrelevant;doseadjustmentistherefore

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Infants,toddlers,childrenandadolescents:

Pharmacokineticshasbeenstudiedinchildrenaged4months–15yearstakingcapsules,granulesorsuspension.At

10mg/kgonday1followedby5mg/kgondays2-5,theC

achievedisslightlylowerthaninadults,with224µg/l

inchildrenaged0.6-5yearsandafter3daysdosing,and383µg/linthoseaged6-15years.Thehalf-lifeof36hinthe

olderchildrenwaswithintheexpectedrangeforadults.

5.3Preclinicalsafetydata

Inanimalstudiesusingexposures40timesthoseachievedattheclinicaltherapeuticdosages,azithromycinwasfound

tohavecausedreversiblephospholipidosis,butasaruletherewerenoassociatedtoxicologicalconsequences.The

relevanceofthisfindingtohumansreceivingazithromycininaccordancewiththerecommendationsisunknown.

ElectrophysiologicalinvestigationshaveshownthatazithromycinprolongstheQTinterval.

Carcinogenicpotential:

Long-termstudiesinanimalshavenotbeenperformedtoevaluatecarcinogenicpotential.

Mutagenicpotential:

Therewasnoevidenceofapotentialforgeneticandchromosomemutationsinin-vivoandin-vitrotestmodels.

Reproductivetoxicity:

Teratogeniceffectswerenotobservedinratreproductivetoxicitystudies.Inrats,azithromycindosagesof100and

200mg/kgbodyweight/dayledtomildretardationinfoetalossificationandinmaternalweightgain.Inperi-and

postnatalstudiesinratsmildretardationsinphysicalandreflexdevelopmentwerenotedfollowingtreatmentwith

50mg/kg/dayazithromycinandabove.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Croscarmellosesodium(E468)

Magnesiumstearate(E572)

Microcrystallinecellulose(E460)

Silicondioxide(E551)

Poloxamer

Povidone(E1201)

Talc

Anhydrouslactose

Coating:

Hypromellose(E464)

Hydroxypropylcellulose

Macrogol

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

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6.4Specialprecautionsforstorage

PVC/Alublisters:Donotstoreabove25°C.Storeintheoriginalpackagingtoprotectfrommoisture.

OPA-PVC-Alu/Alublisters:Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/Alublisterwith2or3tabletsof500mg.

OPA-PVC-Alu/Alublisterwith2or3tabletsof500mg.

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalandotherhandling

Notapplicable.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78,

220Hafnarfjordur,

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/138/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:16thNovember2012

10DATEOFREVISIONOFTHETEXT

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