Bosvate

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Bisoprolol fumarate 5 mg;  
Available from:
Douglas Pharmaceuticals Limited
INN (International Name):
Bisoprolol fumarate 5 mg
Dosage:
5 mg
Pharmaceutical form:
Tablet
Composition:
Active: Bisoprolol fumarate 5 mg   Excipient: Colloidal silicon dioxide Croscarmellose sodium Magnesium stearate Microcrystalline cellulose Sodium starch glycolate
Units in package:
Blister pack, PVC/PVdC-aluminium Sample pack, 10 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Moehs Catalana SL
Therapeutic indications:
Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVdC-aluminium Sample pack - 10 tablets - 3 years from date of manufacture stored at or below 25°C protect from light and moisture - Blister pack, PVC/PVdC-aluminium - 30 tablets - 3 years from date of manufacture stored at or below 25°C protect from light and moisture - Blister pack, PVC/PVdC-aluminium - 90 tablets - 3 years from date of manufacture stored at or below 25°C protect from light and moisture
Authorization number:
TT50-8692a
Authorization date:
2010-11-25

ConsumerMedicineInformation

BOSVATE

Bisoprololfumarate

Bosvate2.5mg,5mg,10mgtablets

Whatisinthisleaflet

PleasereadthisleafletcarefullybeforeyoustartusingBosvateTablets.

ThisleafletanswerssomecommonquestionsaboutBosvateTablets.Itdoesnot

containalltheavailableinformation.Itdoesnottaketheplaceoftalkingtoyour

doctororpharmacist.

Allmedicineshaverisksandbenefits.Yourdoctorhasweighedtherisksofyouusing

BosvateTabletsagainstthebenefitstheyexpectitwillhaveforyou.

Thismedicinehasbeenprescribedforyou.Donotpassitontoothers.Itmayharm

them,eveniftheirsymptomsarethesameasyours.

Ifanyofthesideeffectsgetserious,orifyounoticeanysideeffectsnotlistedinthis

leaflet,pleasetellyourdoctororpharmacist.

Ifyouhaveanyconcernsaboutusingthismedicine,askyourdoctoror

pharmacist.

Keepthisleafletwiththemedicine.Youmayneedtoreaditagain.

WhatBosvateisusedfor

Theactivesubstanceinthismedicineisbisoprololfumarate.Bisoprololfumarate

belongstoagroupofmedicinescalledbeta-blockers.Thesemedicinesworkby

affectingthebody’sresponsetosomenerveimpulses,especiallyintheheart.Asa

result,bisoprololslowsdowntheheartrateandmakestheheartmoreefficientat

pumpingbloodaroundthebody.Heartfailureoccurswhentheheartmuscleisweak

andunabletopumpenoughbloodtosupplythebody'sneeds.

Bisoprololisused:

Totreatstablechronicheartfailure.Itisusedincombinationwithother

medicinessuitableforthiscondition(suchasACE-inhibitors,diuretics,and

heartglycosides).

Intreatmentofcoronaryheartdiseaseandchestpain(anginapectoris)

causedbyshortageofoxygenintheheartmuscle.

Intreatmentofhighbloodpressure(hypertension).

BeforeyouuseBosvate

Whenyoumustnotuseit

DonottakeBosvateTabletsifoneofthefollowingconditionsappliestoyou:

allergic(hypersensitive)tobisoprololfumarateoranyoftheotheringredients

ofbisoprololfumaratetablets.

severeasthmaorseverechroniclungdisease.

severebloodcirculationproblemsinyourlimbs(suchasRaynaud’s

syndrome),whichmaycauseyourfingersandtoestotingleorturnpaleor

blue.

untreatedphaeochromocytoma,whichisararetumouroftheadrenalgland.

metabolicacidosis,whichisaconditionwhenthereistoomuchacidinthe

blood.

DonottakeBosvateTabletsifyouhaveoneofthefollowingheartproblems:

acuteheartfailure.

worseningheartfailurerequiringinjectionofmedicinesintoavein,that

increasetheforceofcontractionoftheheart.

slowheartrate.

lowbloodpressure.

certainheartconditionscausingaveryslowheartrateorirregularheartbeat.

cardiogenicshock,whichisanacuteseriousheartconditioncausinglow

bloodpressureandcirculatoryfailure.

Beforeyoustarttouseit

TakespecialcarewithBosvateTablets:

Ifyouhaveanyofthefollowingconditionstellyourdoctorbeforetakingthis

medicine;heorshemaywanttotakespecialcare(forexamplegiveadditional

treatmentorperformmorefrequentchecks):

diabetes.

strictfasting.

certainheartdiseasessuchasdisturbancesinheartrhythm,orseverechest

painatrest(Prinzmetal’sangina).

kidneyorliverproblems.

lessseverebloodcirculationproblemsinyourlimbs.

lesssevereasthmaorchroniclungdisease.

historyofascalyskinrash(psoriasis).

tumouroftheadrenalgland(phaeochromocytoma).

thyroiddisorder.

Inaddition,tellyourdoctorifyouaregoingtohave:

desensitizationtherapy(forexampleforthepreventionofhayfever),because

bisoprololmaymakeitmorelikelythatyouexperienceanallergicreaction,or

suchreactionmaybemoresevere.

anaesthesia(forexampleforsurgery),becausethismedicinemayinfluence

howyourbodyreactstothissituation.

Takingothermedicines

Pleasetellyourdoctororpharmacistifyouaretakingorhaverecentlytakenany

othermedicines,includingmedicinesobtainedwithoutaprescription.Donottake

thefollowingmedicineswithBosvateTabletswithoutspecialadvicefromyourdoctor:

Certainmedicinesusedtotreatirregularorabnormalheartbeat(ClassI

antiarrhythmicmedicinessuchasquinidine,disopyramide,lidocaine,

phenytoin;flecainide,propafenone).

Certainmedicinesusedtotreathighbloodpressure,anginapectorisor

irregularheartbeat(calciumantagonistssuchasverapamilanddiltiazem).

Certainmedicinesusedtotreathighbloodpressuresuchasclonidine,

methyldopa,moxonodine,rilmenidine.However,donotstoptakingthese

medicineswithoutcheckingwithyourdoctorfirst.

CheckwithyourdoctorbeforetakingthefollowingmedicineswithBosvateTablets;

yourdoctormayneedtocheckyourconditionmorefrequently:

Certainmedicinesusedtotreathighbloodpressureoranginaorabnormal

heartbeat(dihydropyridine-derivativecalciumantagonistssuchasnifedipine).

Certainmedicinesusedtotreathighbloodpressureoranginapectoris

(dihydropyridine-typecalciumantagonistssuchasfelodipineandamlodipine).

Certainmedicinesusedtotreatirregularorabnormalheartbeat(ClassIII

antiarrhythmicmedicinessuchasamiodarone).

Beta-blockingagentsappliedlocally(suchastimololeyedropsforglaucoma

treatment).

CertainmedicinesusedtotreatforexampleAlzheimer’sdiseaseorglaucoma

(parasympathomimeticssuchastacrineorcarbachol)ormedicinesthatare

usedtotreatacuteheartproblems(sympathomimeticssuchasisoprenaline

anddobutamine).

Antidiabeticmedicinesincludinginsulin.

Anaestheticagents(forexampleduringsurgery).

Digitalis,usedtotreatheartfailure.

Non-steroidalanti-inflammatorymedicines(NSAIDs)usedtotreatarthritis,

painorinflammation(forexampleibuprofenordiclofenac).

Anymedicine,whichcanlowerbloodpressureasadesiredorundesired

effectsuchasantihypertensives,certainmedicinesfordepression(tricyclic

antidepressantssuchasimipramineoramitriptyline),certainmedicinesused

totreatepilepsyorduringanaesthesia(barbituratessuchasphenobarbital),or

certainmedicinestotreatmentalillnesscharacterizedbyalossofcontactwith

reality(phenothiazinessuchaslevomepromazine).

Moxisylate,usedfortreatmentraynaudsdisease(poorcirculationwhich

makestoesandfingersnumbandpale.

Mefloquine,usedforpreventionortreatmentofmalaria.

Depressiontreatmentmedicinescalledmonoamineoxidaseinhibitors(except

MAO-Binhibitors)suchasmoclobemide.

HowtouseBosvate

AlwaystakeBosvateTabletsexactlyasyourdoctorhastoldyou.Youshouldcheck

withyourdoctororyourpharmacistifyouarenotsure.BosvateTabletsshouldbe

takeninthemorning,before,withorafterbreakfast.Swallowthetablet/swholewith

somewateranddonotcheworcrushthem.

Thistreatmentshouldbeinitiatedbyaspecialistincardiologyorinternalmedicine.

Childrenunder12yearsandadolescents:BosvateTabletsarenotrecommended

foruseinchildren

Stablechronicheartfailure

Adultsincludingtheelderly:Treatmentwithbisoprololmustbestartedatalow

doseandincreasedgradually.Yourdoctorwilldecidehowtoincreasethedose,and

thiswillnormallybedoneinthefollowingway:

1.25mgbisoprololoncedailyforoneweek

2.5mgbisoprololoncedailyforoneweek

3.75mgbisoprololoncedailyforoneweek

5mgbisoprololoncedailyforfourweeks

7.5mgbisoprololoncedailyforfourweeks

10mgbisoprololoncedailyformaintenance(on-going)therapy.

Themaximumrecommendeddailydoseis10mgbisoprololfumarate.

Dependingonhowwellyoutoleratethemedicine,yourdoctormayalsodecideto

lengthenthetimebetweendoseincreases.Ifyourconditiongetsworseoryouno

longertoleratethedrug,itmaybenecessarytoreducethedoseagainortointerrupt

treatment.Insomepatientsamaintenancedoselowerthan10mgbisoprololmaybe

sufficient.Yourdoctorwilltellyouwhattodo.Ifyouhavetostoptreatmententirely,

yourdoctorwillusuallyadviseyoutoreducethedosegradually,asotherwiseyour

conditionmaybecomeworse.

Renalorliverdisease:

Thedosageshouldbeincreasedverygraduallyandcautiouslyinpatientswith

severekidneyorliverproblems.

Hypertensionandangina

Adultsandtheelderly:Theusualdoseforadultsisonetablet(10mg)daily.Your

doctormaydecidetoincreaseordecreasethisdose.

Renalorliverdisease:Thedosageshouldnotexceed10mgoncedailyinpatients

withseverekidneyorliverproblems.

WhileyouareusingBosvate

Thingsyoumustdo

Ifyouareabouttobestartedonanynewmedicinetellyourdoctorandpharmacist

thatyouaretakingBosvateTablets.

IfyouforgettotakeBosvateTablets:

Ifyouforgettotakeadose,takeitassoonasyourememberitunlessitisnearly

timeforyournextdose.Donottakeadoubledosetomakeupforaforgottendose.

IfyoustoptakingBosvateTablets:

Donotstoptreatmentsuddenlyorchangetherecommendeddosewithouttalkingto

yourdoctorfirst.Ifyouneedtostoptreatment,itmustbedonegradually,toavoid

sideeffects.

Ifyouhaveanyfurtherquestionsontheuseofthisproduct,askyoudoctoror

pharmacist.

Thingstobecarefulof

TakingBosvateTabletswithfoodanddrink:

BosvateTabletsshouldbetakeninthemorning,before,withorafterbreakfast.They

shouldbeswallowedwholewithliquidandshouldnotbechewedorcrushed.

Avoiddrinkingexcessivealcohol,sinceitmayincreasethebloodpressure-lowering

effectofbisoprolol.Avoiddrinkingalcoholaltogether,ifitmakesyoumoredizzyor

morelight-headedthanusual.

Pregnancyandbreast-feeding:

ThereisariskthatuseofBosvateTabletsduringpregnancymayharmthebaby.If

youarepregnantorplanningtobecomepregnant,tellyourdoctor.Heorshewill

decidewhetheryoucantakethismedicineduringpregnancy.Itisnotknown

whetherbisoprololpassesintohumanbreastmilk.Therefore,breastfeedingisnot

recommendedduringtherapywithBosvateTablets.

Drivingandusingmachines:

Yourabilitytodriveorusemachinerymaybeaffecteddependingonhowwellyou

toleratethemedicine.Pleasebeespeciallycautiousatthestartoftreatment,when

thedoseisincreasedorthemedicationischanged,aswellasincombinationwith

alcohol.

Incaseofoverdose

Ifyoutaketoomuch(overdose)

ImmediatelytelephoneyourdoctorortheNationalPoisonsCentre(telephone0800

POISONor0800764766),orgotoaccidentandemergencyatyournearest

hospital.Takethisleafletandanytabletsyoustillhavewithyou.Yourdoctorwill

decidewhatmeasuresarenecessary.

Symptomsofanoverdosemayincludeslowedheartrate,severedifficultyin

breathingfeelingdizzy,ortrembling(duetodecreasedbloodsugar).

SideEffects

Likeallmedicines,BosvateTabletscancausesideeffects,althoughnoteverybody

getsthem.

Topreventseriousreactions,speaktoadoctorimmediatelyifasideeffectissevere,

occurredsuddenlyorgetsworserapidly.Themostserioussideeffectsarerelatedto

theheartfunction:

slowingofheartrate(affectsmorethan1personin10)

worseningofheartfailure(affectslessthan1personin10)

sloworirregularheartbeat(affectslessthan1personin100)

Ifyoufeeldizzyorweak,orhavebreathingdifficultiespleasecontactyourdoctoras

soonaspossible.

Furthersideeffectsarelistedbelowaccordingtohowfrequentlytheymayoccur:

Verycommon: affectsmorethan1userin10

Common: affects1to10usersin100

Uncommon: affects1to10usersin1,000

Rare: affects1to10usersin10,000

Veryrare: affectslessthan1userin10,000

Common(affectslessthan1personin10):

tiredness,feelingweak,dizziness,headache

feelingofcoldnessornumbnessinhandsorfeet

lowbloodpressure

stomachorintestineproblemssuchasnausea,vomiting,diarrhoea,or

constipation.

Uncommon(affectslessthan1personin100):

sleepdisturbances

depression

dizzinesswhenstandingup

breathingproblemsinpatientswithasthmaorchroniclungdisease

muscleweakness,musclecramps.

Rare(affectslessthan1personin1,000):

hearingproblems

allergicrunnynose

reducedtearflow

inflammationoftheliverwhichcancauseyellowingoftheskinorwhitesofthe

eyes

certainbloodtestresultsforliverfunctionorfatlevelsdifferingfromnormal

allergy-likereactionssuchasitching,flush,rash

impairederection

nightmares,hallucinations.

Veryrare(affectslessthan1personin10,000):

irritationandrednessoftheeye(conjunctivitis)

hairloss

appearanceorworseningofscalyskinrash(psoriasis);psoriasis-likerash.

Ifanyofthesideeffectsgetsserious,orifyounoticeanysideeffectsnotlistedinthis

leaflet,pleasetellyourdoctororpharmacist.

AfterusingBosvate

Storage

Keepoutofthereachandsightofchildren.

DonotuseBosvateTabletsaftertheexpirydatewhichisstatedontheblisterand

thecarton.Theexpirydatereferstothelastdayofthatmonth.

Storeintheoriginalpackageinordertoprotectfromlight.Thismedicinalproduct

doesnotrequireanyspecialtemperaturestorageconditions.

Disposal

Medicinesshouldnotbedisposedofviawastewaterorhouseholdwaste.Askyour

pharmacisthowtodisposeofmedicinesnolongerrequired.Thesemeasureswill

helptoprotecttheenvironment.

Productdescription

Whatitlookslike

2.5mg:Whitetooffwhiteroundbiconvextabletswithabreaklineononeside.

5mg:Whitetooffwhiteroundbiconvextabletswithabreaklineononeside.

10mg:Whitetooffwhiteroundbiconvextabletswithabreaklineononeside.

Thetabletscanbedividedintoequalhalves.

Packsizesof30and90tablets.Notallpacksizesmaybemarketed.

Ingredients

Activeingredient(s):

Each2.5mgtabletcontains2.5mgbisoprololfumarate.

Each5mgtabletcontains5mgbisoprololfumarate.

Each10mgtabletcontains10mgbisoprololfumarate.

Inactiveingredients:

Theotheringredientsaremicrocrystallinecellulose,silicacolloidalanhydrous,

croscarmellosesodium,sodiumstarchglycolate(typeA)andmagnesiumstearate.

SponsorDetails

BosvateTabletsaresuppliedinNewZealandby:

DouglasPharmaceuticalsLimited

POBox45027

Auckland0651

NEWZEALAND

ph:(09)8350660

DateofPreparation

Thisleafletwaspreparedon4thApril2012.

1 | P a g e

New Zealand Data Sheet

1.

PRODUCT NAME

Bosvate® 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, 10 mg Tablet

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Bosvate 1.25 mg: each tablet contains 1.25 mg bisoprolol fumarate

Bosvate 2.5 mg: each tablet contains 2.5 mg bisoprolol fumarate

Bosvate 3.75 mg: each tablet contains 3.75 mg bisoprolol fumarate

Bosvate 5 mg: each tablet contains 5 mg bisoprolol fumarate

Bosvate 7.5 mg: each tablet contains 7.5 mg bisoprolol fumarate

Bosvate 10 mg: each tablet contains 10 mg bisoprolol fumarate

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Bosvate 1.25 mg: White to off white round biconvex tablet

Bosvate 2.5 mg: White to off white round biconvex tablet with a break line on one side

Bosvate 3.75 mg: White to off white round biconvex tablet

Bosvate 5 mg: White to off white round biconvex tablet with a break line on one side

Bosvate 7.5 mg: White to off white round biconvex tablet with a break line on one side

Bosvate 10 mg: White to off white round biconvex tablet with a break line on one side.

The 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets can be divided into equal halves.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Treatment of stable chronic heart failure with reduced systolic left ventricular function

in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (for

additional information see section 5.1).

Treatment of chronic, stable angina pectoris.

Treatment of essential hypertension.

4.2.

Dose and method of administration

Stable chronic heart failure

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in

case of intolerance to ACE inhibitors), a beta-blocker, diuretics, and when appropriate cardiac

2 | P a g e

glycosides. Patients should be stable (without acute failure) when bisoprolol treatment is

initiated.

It is recommended that the treating physician should be experienced in the management of

chronic heart failure.

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration

period and thereafter.

Titration Phase

The treatment of stable chronic heart failure with bisoprolol requires a titration phase.

The treatment with bisoprolol is to be started with a gradual uptitration according to the

following steps:

1.25 mg once daily for 1 week, if well tolerated increase to

2.5 mg once daily for a further week, if well tolerated increase to

3.75 mg once daily for a further week, if well tolerated increase to

5 mg once daily for the 4 following weeks, if well tolerated increase to

7.5 mg once daily for the 4 following weeks, if well tolerated increase to

10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart

failure is recommended during the titration phase. Symptoms may already occur within the first

day after initiating the therapy.

Treatment modification

If the maximum recommended dose is not well tolerated, gradual dose reduction may be

considered.

In the case of transient worsening of heart failure, hypotension, or bradycardia reconsideration

of the dosage of the concomitant medication is recommended. It may also be necessary to

temporarily lower the dose of bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the

patient becomes stable again.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt

withdrawal may lead to acute deterioration of the patents condition.

Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.

3 | P a g e

Administration

Bisoprolol tablets should be taken in the morning and can be taken with food. They should be

swallowed with liquid and should not be chewed.

Special population

Renal or liver impairment

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart

failure and with impaired liver or renal function. Up-titration of the dose in these populations

should therefore be made with additional caution.

Elderly

No dosage adjustment is required. It is recommended to start with the lowest possible dose.

Children

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for

children.

Hypertension and Angina pectoris

The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day. In

patients with ischemic heart disease, it is recommended that withdrawal of treatment should be

gradually over 1-2 weeks. In some patients 5 mg per day may be adequate.

Special population

Renal or hepatic impairment

In patients with final stage impairment of renal function (creatinine clearance < 20 ml/min) or

liver function, the dose should not exceed 10 mg bisoprolol once daily.

Elderly

No dosage adjustment is normally required, but 5 mg per day may be adequate in some

patients; as for other adults, dosage may have to be reduced in cases of severe renal or hepatic

dysfunction.

Children under 12 years and adolescents

Bisoprolol is not recommended for use in children due to a lack of experience in children.

4.3.

Contraindications

Bisoprolol is contraindicated in chronic heart failure patients with:

acute heart failure or during episodes of heart failure decompensation requiring i.v.

inotropic therapy

4 | P a g e

cardiogenic shock

second or third degree AV block (without a pacemaker)

sick sinus syndrome

sinoatrial block

bradycardia with less than 60 beats/min before the start of therapy

hypotension (systolic blood pressure less than 100 mm Hg)

severe bronchial asthma or severe chronic obstructive pulmonary disease

late stages of peripheral arterial occlusive disease and Raynaud's syndrome

untreated phaeochromocytoma

metabolic acidosis

hypersensitivity to bisoprolol or to any of the excipients

4.4.

Special warnings and precautions for use

Bisoprolol must be used with caution in:

bronchospasm (bronchial asthma, obstructive airways diseases)

diabetes mellitus with large fluctuations in blood glucose values; symptoms of

hypoglycaemia can be masked

strict fasting

ongoing desensitisation therapy

first degree AV block

Prinzmetal's angina

peripheral arterial occlusive disease (intensification of complaints might happen especially

during the start of therapy)

general anaesthesia

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias

and myocardial ischemia during induction and intubation, and the post-operative period. It is

currently recommended that maintenance beta-blockade be continued peri-operatively. The

anaesthetist must be aware of beta-blockade because of the potential for interactions with

other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the

decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw

beta-blocker therapy before surgery, this should be done gradually and completed about 48

hours before anaesthesia.

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the

following diseases and conditions:

insulin dependent diabetes mellitus (type I)

severely impaired renal function

severely impaired hepatic function

restrictive cardiomyopathy

congenital heart disease

haemodynamically significant organic valvular disease

myocardial infarction within 3 months

5 | P a g e

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class

I antiarrhythmic drugs and with centrally acting antihypertensive drugs is generally not

recommended.

In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms,

bronchodilating therapy should be given concomitantly. Occasionally an increase of the airway

resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have

to be increased.

As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and

the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected

therapeutic effect.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g.

bisoprolol) after carefully balancing the benefits against the risks.

In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-

receptor blockade.

Under treatment with bisoprolol the symptoms of a thyrotoxicosis may be masked.

The initiation of treatment with bisoprolol necessitates regular monitoring. The cessation of

therapy with bisoprolol should not be done abruptly unless clearly indicated (see section 4.2).

4.5.

Interaction with other medicines and other forms of interaction

Combinations not recommended

Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative

influence on contractility and atrio-ventricular conduction. Intravenous administration of

verapamil in patients on beta-blocker treatment may lead to profound hypotension and

atrioventricular block.

Class I antiarrhythmic drugs (e.g. quinidine, disopyramide, lidocaine, phenytoin, flecainide,

propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative

inotropic effect increased.

Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa,

moxonidine, rilmenidine): Concomitant use of centrally acting antihypertensive medicinal

products may worsen heart failure by a decrease in the central sympathetic tonus (reduction of

heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-

blocker discontinuation, may increase risk of “rebound hypertension”.

6 | P a g e

Combinations to be used with caution

Calcium antagonists such as dihydropyridine derivatives with negative inotropic effect (e.g.,

nifedipine): Nifedipine decrease myocardial contractility by affecting the amount of calcium. Its

concomitant use in patients on beta-blocker treatment may increase the risk of hypotension and

reduction of the ventricular pump function with possible development of heart failure in

patients with latent cardiac insufficiency. The negative inotropism of nifedipine may precipitate

or exacerbate heart failure.

Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant

use may increase the risk of hypotension, and an increase in the risk of a further deterioration of

the ventricular pump function in patients with heart failure cannot be excluded.

Class-III antiarrhythmic medicinal products (e.g. amiodarone): Effect on atrio-ventricular

conduction time may be potentiated.

Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of

bisoprolol.

Parasympathomimetic medicinal products: Concomitant use may increase atrio-ventricular

conduction time and the risk of bradycardia.

Insulin and oral antidiabetic medicinal products: Intensification of blood sugar lowering effect.

Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia.

Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension

(for further information on general anaesthesia see section 4.4).

Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of

bisoprolol.

β-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may

reduce the effect of both agents.

Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline):

Combination with bisoprolol may unmask the α-adrenoceptor-mediated vasoconstrictor effects

of these agents leading to blood pressure increase and exacerbated intermittent claudication.

Such interactions are considered to be more likely with nonselective β-blockers. Higher doses of

adrenaline may be necessary for treatment of allergic reactions.

Concomitant use with antihypertensive agents as well as with other medicinal products with

blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines)

may increase the risk of hypotension.

7 | P a g e

Moxisylate: Possibly causes severe postural hypertension.

Combinations to be considered

Mefloquine: increased risk of bradycardia

Monoamineoxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of beta-

blocking agents but also risk of hypertensive crisis.

4.6.

Fertility, pregnancy and lactation

Pregnancy

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the

fetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has

been associated with growth retardation, intrauterine death, abortion or early labour. Adverse

effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If

treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers

are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with

bisoprolol is considered necessary, the uteroplacental blood flow and the fetal growth should be

monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be

considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and

bradycardia are generally to be expected within the first 3 days.

Breast-feeding

It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not

recommended during administration of bisoprolol.

Fertility

No data are available.

4.7.

Effects on ability to drive and use machines

In a study with coronary heart disease patients bisoprolol did not impair driving performance.

However, due to individual variations in reactions to the drug, the ability to drive a vehicle or to

operate machinery may be impaired. This should be considered particularly at start of treatment

and upon change of medication as well as in conjunction with alcohol.

4.8.

Undesirable effects

The following terminologies have been used in order to classify the occurrence of undesirable

effects: Very common ( 1/10), Common ( 1/100, to < 1/10), uncommon ( 1/1,000 to < 1/100),

Rare ( 1/10,000 < 1/1,000), Very rare ( 1/10,000).

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Cardiac disorders:

Very common: bradycardia.

Common: worsening of heart failure.

Uncommon: AV-conduction disturbances

Investigations:

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Nervous system disorders:

Common: dizziness, headache.

Rare: syncope

Eye disorders:

Rare: reduced tear flow (to be considered if the patient uses lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders:

Rare: hearing impairment

Respiratory, thoracic and mediastinal disorders:

Uncommon: Bronchospasm in patients with bronchial asthma or a history of obstructive airways

disease.

Rare: allergic rhinitis.

Gastrointestinal disorders:

Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (itching, flush, rash).

Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon: muscular weakness and cramps

Vascular disorders:

Common: Feeling of coldness or numbness in the extremities, hypotension

Uncommon: orthostatic hypotension.

General disorders:

Common: asthenia, fatigue

Hepatobiliary disorders:

Rare: hepatitis

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Reproductive system and breast disorders:

Rare: Potency disorders.

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

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

4.9.

Overdose

Symptoms

With overdose (e.g. daily dose of 15 mg instead of 7.5 mg) third degree AV-block, bradycardia,

and dizziness have been reported. In general the most common signs expected with overdose of

a beta-blocking agent are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency

and hypoglycaemia. To date a few cases of overdose (maximum: 2000 mg) with bisoprolol have

been reported in patients suffering from hypertension and/or coronary heart disease showing

bradycardia and/or hypotension; all patients recovered.

Treatment

There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol and

patients with heart failure are probably very sensitive. Therefore it is mandatory to initiate the

treatment of these patients with a gradual up-titration according to the scheme given in section

4.2.

If overdose occurs, bisoprolol treatment should be stopped and supportive and symptomatic

treatment should be provided. Limited data suggest that bisoprolol is hardly dialysable. Based on

the expected pharmacologic actions and recommendations for other beta-blocking agents, the

following general measures should be considered when clinically warranted.

Bradycardia: Atropine should be administered intravenously. If the response is inadequate,

isoprenaline or another agent with positive chronotropic properties may be given cautiously.

Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagon

may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with

isoprenaline infusion or transvenous cardiac pacemaker insertion.

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

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Bronchospasm: Bronchodilator therapy such as isoprenaline, beta2-sympathomimetic medicinal

products and/or aminophylline should be administered.

Hypoglycaemia: i.v. glucose should be administered.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective. ATC Code: C07AB07

Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating

and relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of

the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with

metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the

airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond

the therapeutic dose range.

In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) were in NYHA class III and

17% (n = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection

fraction <35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8%

(relative reduction 34%). A decrease in sudden death (3.6% vs. 6.3%, relative reduction 44%) and

a reduced number of heart failure episodes requiring hospital admission (12% vs. 17.6%, relative

reduction 36%) was observed. Finally, a significant improvement of the functional status

according to NYHA classification has been shown. During the initiation and titration of bisoprolol

hospital admission due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation

(4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3%

and 6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in

the bisoprolol group and 15 in the placebo group.

The CIBIS III trial investigated 1010 patients aged 65 years with mild to moderate chronic heart

failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤ 35%, who had not been

treated previously with ACE inhibitors, beta-blockers or angiotensin receptor blockers. Patients

were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an initial 6

months treatment with either bisoprolol or enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol

was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-

first treatment was not proven in the protocol analysis, although the two strategies for initiation

of CHF treatment showed a similar rate of the primary combined endpoint death and

hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1% in the enalapril-first

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group, per-protocol population). The study shows that bisoprolol can also be used in elderly

chronic heart failure patients with mild to moderate disease.

Bisoprolol is also used for the treatment of hypertension and angina. As with other β1-blocking

agents, the mode of action in hypertension is not clear but it is known that bisoprolol markedly

depresses plasma renin levels.

In acute administration in patients with coronary heart disease without chronic heart failure

bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen

consumption. In chronic administration the initially elevated peripheral resistance decreases.

Hence bisoprolol is effective in eliminating or reducing the symptoms.

5.2.

Pharmacokinetic properties

Bisoprolol is absorbed and has a biological availability of about 90% after oral administration.

The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5 l/kg. Total

clearance is approximately 15 l/h. The half-life in plasma of 10-12 hours gives a 24 hour effect

after dosing once daily. Bisoprolol is excreted from the body by two routes. 50% is metabolised

by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50%

is excreted by the kidneys in an unmetabolised form. Since the elimination takes place in the

kidneys and the liver to the same extent a dosage adjustment is not required for patients with

impaired liver function or renal insufficiency. The pharmacokinetics in patients with stable

chronic heart failure and with impaired liver or renal function has not been studied.

The kinetics of bisoprolol are linear and independent of age.

In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher

and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration

at steady state is 64+21 ng/ml at a daily dose of 10 mg and the half-life is 17+5 hours.

5.3.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity. Like other Beta-blocking

agents, bisoprolol caused maternal (decreased food intake and decreased body weight) and

embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring,

retarded physical development) at high doses but was not teratogenic.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Bosvate tablets

contain the following excipients:

Cellulose, Microcrystalline

Silica, Colloidal Anhydrous

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Croscarmellose Sodium

Sodium Starch Glycolate (Type A)

Magnesium Stearate

6.2.

Incompatibilities

Not applicable.

6.3.

Shelf life

1.25 mg tablets: 2 years

2.5 mg, 3.75 mg, 5 mg, 7.5 mg, 10 mg tablets: 3 years.

6.4.

Special precautions for storage

Store below 25°C.

6.5.

Nature and contents of container

Cartons of PVC/PVdC-aluminium blister strips containing 10, 30 or 90 tablets.

Not all strengths or pack sizes may be marketed.

6.6.

Special precautions for disposal and other handling

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

Prescription medicine.

8.

SPONSOR

Douglas Pharmaceuticals Ltd

P O Box 45 027

Auckland 0651

New Zealand

Phone: (09) 835 0660

9.

DATE OF FIRST APPROVAL

Bosvate 1.25 mg, 3.75 mg, 7.5 mg: 12 August 2014

Bosvate 2.5 mg, 5 mg, 10 mg: 29 September 2011

13 | P a g e

10.

DATE OF REVISION OF THE TEXT

7 September 2018

Summary table of changes

Section Changed

Summary of new information

SPC format

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