MILRINONE 1 MG / ML SOLUTION FOR INJECTION/INFUSION - patient leaflet, side effects, dosage

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Ifyouhaveanyfur­therquestions, I askyourdoctor, nurseorpharmactst Thismedicinehas been prescribed foryou only. Do not pass iton to others. It may harm them, even iftheirsigns of illness arethesameasyours. Ifyougetanysi­deeffects,tal­ktoyourdoctor,nur­seor pharmacist.This includes any possiblesideeffects not listed in this leaflet. Seesection4.

What is in this leaflet:

• 1. What Milrinone isand what it is used for

• 2. Whatyou need to know beforeyou aregiven Milrinone

• 3. Howyouwillbe­givenMilrinone

• 4. Possiblesi­deeffects

• 5. Howtostore­Milrinone

• 6. Contents ofthe packand other information

1. what milrinone is and what it is used for

The nameofyour medicine is Milrinone 1mg/ml Solution for injection/infu­sion(referred­toasMilrinonet­hroughoutthis leaflet).Itcon­tainsa medicinecalled­milrinone. Thisbelongs to a group of medicines called phosphodiesterase inhibitors. It works by making your heart muscle contract morestrongly and your blood vessels becomewider. This means blood can flow moreeasily making your heart pump blood moresuccessfully.

Milrinone can be used in adults for:

• Short-term treatmentofse­verecongestive heart failure (wherethe heartcannotpum­penoughbloodtot­herestof the body) when other medicines have notworked
• Treatmentafte­raheartoperati­onforwhenyourhe­artis having difficulty pumping blood around your body

Milrinone can be used in children for

• shortterm treatment (up to35 hours) ofseverecongestive heartfailure(whe­rethe heartcannotpum­penoughbloodto the rest of the body) when other medicines have not worked
• shortterm treatment (up to35 hours) ofacute heartfailure aftera heart operation i.e. when your heart is having difficulty pumping blood around your body.

2. what you need to know before you are given milrinone

You should not be given Milrinone if:

• you areallergic (hypersensitive) to milrinoneorany ofthe other ingredients ofthis medicine (listed in Section 6). Signs ofan allergic reaction include: a rash, swallowing or breathing problems, swellingofyour lips,face, throat ortongue
• you have lost body fluids andare severely dehydrated.

Do not have this medicine ifany oftheaboveapply toyou. If you are notsure, talktoyourdoctor, nurse or pharmacist before having Milrinone.

Warnings and precautions

Talktoyourdoc­tor,nurseorphar­mackt beforeyouaregiven milrinoneifyou:

• are having orhavejust had a heart attack
• havesevere heart valve problems such as narrowing, thickening orblockageofy­ourheartvalves
• have uneven oruncontrolled fist heartbeats. You mayako be experiencing pounding in yourchest, light-headedness, faintingandshor­tness in breath
• have low blood pressurewhich may makeyou feel dizzy, light-headedorfaint
• have previously taken watertablets (diuretics) which caused you to have heart problems
• have low levels of potassium in your blood. Yourdoctor may do bloodteststochec­kthis
• havekidneyproblems

Ifyouarenotsu­reifanyofthea­boveapplytoyou­,talktoyour doctor, nurseor pharmacist before having Milrinone.

Thefollowing should beconsidered in addition towarningsand precautions described foradults.

Children and adolescents

Beforegiving Milrinone,you­rdoctorwillchec­kalotof parameters such as heart rhythm and blood pressure. He/she

INFORMATION FOR THE HEALTHCARE PROFESSIONAL

Milrinone 1mg/ml Solution for injection/infusion

Pleaserefertot­heSummaryofPro­ductCharacteris­tics(SmPC) forfurtherdeta­ilsonthkproduct

Qualitative and Quantitative Composition

Each 10mlampoulecontains 10 mg milrinone. Each mlof solutioncontainsl mgmilrinone.

Excipientwith known effect:

Sodium (this medicinal productcontains less thanl mmol sodium (23 mg) perdose)

Pharmaceutical Form

Solution for injection/infusion.

Clear, colourlessto pale yellowsolution, practically free from particles.

ThepHofthesolu­tionis3.2–4.0and theosmolality is 261—319m0sm/Kg.

Therapeutic Indications

MilrinoneInjec­tionisindicated­fortheshort-term treatmentof severecongesti­veheartfailure­unresponsiveto­conventional maintenance therapy, and forthe treatmentofpatients with acuteheartfai­lure,including lowoutputstates­following cardiac surgery.

In paediatric population milrinone is indicated fortheshort-term treatment (upto 35 hours) ofsevere congestive heartfailure unresponsiveto­conventionalma­intenancethera­py(glycosides, diuretics,vaso­dilatorsand/o­rangiotensin convertingenzyme (ACE) inhibitors), and fortheshort-term treatment (up to35 hours) of paediatric patients with acute heart failure, including lowoutputstates­following cardiac surgery.

Posology and method of administration Forintravenou­sadministrati­on.

Adults: Milrinone Injection should begiven as a loading doseof 50pg/kg administered overa period of 10 minutes usually followed by a continuous infusion atadosagetitrated between 0375pg/kg/min and 0.75pg/kg/min according to haemodynamican­dclinicalrespon­se,butshould notexceed 1.13mg/kg/daytotal dose. For instructions on dilution ofthe product beforeadminis­tration and a guideto maintenance infusiondelivery rates,seethein­formationunder “Special precautions fordkposal and other handling".

Solutions ofdifferentcon­centrations may be used according to patientfluidre­quirements.The­durationofthe­rapyshould depend upon the patient's response. In congestive cardiac failure, patients have been maintained on the infusion for up to will order blood tests aswell.

The infusion will notstartifyou­rchild's heart rhythm and blood pressureis notstable.

Pleasetellyou­rdoctor ifyourchild:

• haskidneyproblems
• isa preterm infantor has a low birth weight
• has a certain heart problem named Patent Ductus Arteriosus: a connection between two major blood vessels (aorta and pulmonaryartery) whichpersiststhou­ghitshouldbeclo­sed.

Inthese cases,yourdoc­torwill decideifyourchil­dwillbe treated with Milrinone.

Other medicines and Milrinone

Pleasetellyou­rdoctor,nurse­orpharmacisti­fyouaretaking or have recently taken any other medicines. This includes medicines you buy withouta prescription, including herbal medicines. This is because Milrinonecan affectthe way some other medicines work. Also some medicines can affecttheway Milrinoneworks.

• Inparticular,te­llyourdoctor,nur­seorpharmacis­tifyouare taking: digoxin(usedfor­heartproblems)
• watertablets(di­uretics)
• medicines used to treat high blood pressureorangina (chest pain)suchasam­lodipine,nife­dipineorfelodi­pine.

Pregnancy and breast-feeding

Ifyou are pregnantorbreast-feeding, thinkyou may be pregnantorare­planningtohave­ababy,askyourdoc­tor,nurse or pharmacistforadvice before taking this medicine.

Milrinone contains sodium

This medicinal productcontains less than 1mmol sodium (23mg) perdose.

3. how you will be given milrinone

Milrinonewillalways begiven byyourdoctoror­nurse.Thisk because it needs to begiven as an injection. It isadministered into a vein.

Having this medicine

• This medicine is usually given ina'drip' after being diluted using either0.45%sodium chloride infusion, 0.9% sodium chloride infusion or 5%glucose infusion
• Ifyou feel the effectofyour medicine is too weakortoo strong, tell yourdoctoror nurse

How much will be given to you

• Yourdoctorwill decide how much medicineyou should have basedon your body weight
• Ifyou have problems with your kidneys, you may begiven a lowerdose

Adults and the elderly

• Yourdoctorshould giveyou a first dose of 50 micrograms for every kilogram ofyourweightovera period of 10 minutes
• This is then followed by a smallerdose between 0.375 and 0.75microgram­sforeverykilo­gramofbodyweig­htper minute,as needed
• The medicine is usually given for2to3days, but it may be givenforupto5days
• Ifyou are having this medicineaftera heart operation, itwill usually only begiven for upto12 hours

Use in children and adolescents

• Yourdoctorshou­ldgiveyourchil­dafirstdoseran­ging between 50and 75 micrograms forevery kilogram ofhis weight, overa period of30to 60 minutes.
• This is then followed by a dose ranging from 0.25to 0.75 micrograms forevery kilogram ofhis/herweight per minute accordingtoyou­rchild'srespon­setothetreatmen­tand occurrenceofsi­deeflects.Mil­rinonecanbegi­venforupto 35 hours.

During infusion, yourchild will beclosely monitored: your doctorwillchec­kalotofparame­terssuchas heartrhjrthmand blood pressure and blood will betaken toevaluatethe response to therapy and occurrence of side effects.

If you receive more Milrinone than you should

Itisunlikelyt­hatyourdoctoror­nursewillgive­youtoomuch of thismedicine. Yourdoctorand nursewillchec­kyourprogress and the medicinethaty­ouaregiven.Al­ways askifyouarenot surewhy you aregetting a doseof medicine.The following effects may happen ifyou havetoo much Milrinone:feeling dizzy, light-headedness andfainting (dueto low blood pressure) and an uneven heartbeat.

If you miss a dose of Milrinone

Yourdoctorornur­sewill have instructionson­whentogiveyou this medicine. It is unlikelythatyou will not begiven the medicineas it hasbeen prescribed. However,ifyoudo thinkyou havemksedadose,te­llyourdoctoror­nurse.

• 5 days, although the usual period is48to 72 hours. In acute states following cardiac surgery, it is unlikely that treatment need be maintained for morethan 12 hours.

RenalImpairment: Dosage adjustment required. Data obtained from patients with severe renal impairment butwithout heart failure have demonstrated that the presence of renal impairmentsig­nificantlyincre­ases theterminaleli­mination half-life of milrinone. For patients with clinical evidenceof renal impairment, the loading dose is notaffected, butthe infusion rate should beadjusted according to haemodynamic response. Recommended maintenance infusionratesa­reprovidedunder “Special precautionsfor­disposal and other handling".

Elderly: Experiencesofar­suggests that nospecial dosage recommendations are necessary.

Paediatric population:

• In published studies selected doses for infantsand children were: Intravenous loading dose: 50to 75 pg/kg administered over 30to60minutes.
• Intravenous continuous infusion: To be initiated on the basis of hemodynamic responseand the possibleonsetof undesirableeffects between 0.25to0.75 pg/kg/min fora period upto35 hours.

Inclinicalstudieson lowcardiac outputsyndrome­ininfantsand childrenunder6y­earsofageafter­correctivesur­geryfor congenitalhear­tdisease 75 pg/kg loading doseover60 minutes followed bya0.75 pg/kg/mi­ninfusionfor35 hourssignificantly reducedthe rkkofdevelopmen­toflowcardiacou­tputsyndrome.

Results of pharmacokinetic studies (see section 5.2oftheSmPC) haveto betaken intoconsideration.

Renal impairment:

Duetolackofdata the useofmilrinonek­notrecommende­din paediatric population with renal impairment (forfurther informationple­aseseesection4­.4oftheSmPC).

Patent ductus arteriosus:

Ifthe useof milrinone is desirable in preterm orterm infants at rkkof/with patent ductus arteriosus, thetherapeutic need must beweighed against potential risks (seesections 4.4,4.8,5.2, and 5.3oftheSmPC).

Pharmaceutical Particulars

List of excipients

(S)-Lactic Acid

Anhydrous Glucose WaterforInjections Sodium Hydroxide (for pH adjustment) LacticAcid (for pH adjustment)

If you stop having Milrinone

Keep having Milrinone until yourdoctortelk you tostop. Do not stop having Milrinonejust becauseyoufeel better. Ifyoustop, yourillness may getworse.

Tests

Yourdoctorornur­sewilluseanelec­trocardiogram (ECG)to check howwell your heart works. They will alsocarry out blood testsandchecky­ourbloodpressu­reandpulserate.

Ifyou haveany furtherquestions on the useofthis medicine, askyourdoctoror­nurse.

4. possible side effects

Likeall medicines, this medicine can causesideeffects, although noteverybody gets them.

• Stop having Milrinone and tell your doctor straight away if: You have an allergic reaction. Thesigns may include: a rash, swallowing or breathing problems, swelling ofyour lips, face, throatortongu­e,fainting or losing consciousness. The chances ofthis happening are very rare

Tell a doctor or nurse straight away if you notice any of the following side effects:

Common (affects lessthanl inlOpeople)

• Uneven,increa­sedorfesthear­tbeats. Youmayakoexperience poundinginyou­rchestfeellig­ht-headed,feintor­shortofbreath

Uncommon (affectslessthan­linlOOpeople)

• Ventricularfi­brillation — aseriousheartrhyt­hmproblem. Signs ofthis includevery fast, uneven orforceful heartbeat (palpitations),diz­zinessand lossofconsciou­sness. You mayalso feel sick, havecold sweats, shortnessofbreath and chest pain
• Thrombocytopenia — a blood problem. Signs ofthisarethat you may bruise moreeasily than usual
• Chestpain

Very rare (affects less thanlin 10,000 people)

• Torsades de Pointes—a serious heart rhythm problem. Signs ofthis includevery fest, uneven orforceful heartbeat (palpitations),diz­zinessand lossofconsciou­sness. Youmay alsofeel sick,havecold sweats, shortnessofbreath, unusual palecomplexio­nandchest pain
• Difficulty breathing, wheezing ortightness in thechest

Tell a doctor or nurse as soon as possible if you notice any of the following side effects:

Common (affects lessthanl inlOpeople)

• Low blood pressure. Signsofthis includefeeling dizzy, lightheaded orfainting. Ifyou also noticesigns likeafastor unevenheartbe­atorchest pain thiscouldbeamo­reserious sideeffect (seeabove)
• Headache

Uncommon (affectslessthan­linlOOpeople)

• Feelingshaky
• Low levels of potassium in yourblood. Signsofthis are tiredness,con­fusion,muscle­weaknessandmus­clecramps. This may bedue to low levels ofpotassium in your body.

Tell a doctor or nurse if any of the following side effects gets serious or lasts longer than a few days

Very Rare (affects less than l in lO,OOO people)

• Skinrashesinclu­dingatthesite­oftheinjection

Uncommon (affectslessthan­linlOOpeople)

• A blood test may show changes in the way the liver isworking

Talktoyourdoc­tor,nurseorphar­mackt ifanyoftheside­effects gets serious or lasts longerthan a fowdays, or ifyou notice any side effects not listed in this leaflet.

In addition to side effects observed in adults, thefollowing were reported in children and adolescents:

Additional side effects in children and adolescents

Frequency not known:

• Bleedingintot­hefluid-filledareas(ven­tricles)surrou­ndedby the brain (intraventricular haemorrhage)
• A heart problem known as Patent Ductus Arteriosus: a connection between two major blood vessels (aorta and pulmonaryarttery) whkhpersktsthough itshould beclosed. This can cause excess fluid in the lungs, bleedings, destruction ofthe bowel orpartofthe bowel and possibly befetal
• Changes in the way the kidneys areworking ifyou already havelowbloodpres­sure.

Moreover, comparedto adults,decrease in the numberof platelets in the blood seems tooccur moreoften in children and the riskofthisside effect is increased with the duration ofthe Milrinone infusion. Heart rhythm troublesseem to occur less often in children than in adults.

Reporting of side effects

Ifyou getanysideeffec­ts,talktoyourdoc­tor,pharmacktor

Incompatibilities

Furosemideor bumetanide should not beadminktered in intravenous lines containing Milrinone Injection since precipitation occurs on admixture. Sodium Bicarbonate Intravenous infusion should not be usedfordilution.

In theabsence ofcompatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life

3 years forthe unopened product.

After dilution

Chemicaland physical in-use stability has been demonstrated for48 hours at 5°Cwhen diluted with O.45%sodium chloride infusion, O.9% sodium chloride infusion or 5% glucose infusion. From a microbiological pointofview, the productshould be used immediately. If not used immediately, in-use storage times and conditions priorto usearethe responsibility ofthe userand would normally not be longerthan 24 hours at2to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Special precautions for storage

Store below 25°C. Do notfreeze.Store in theoriginal package. Forstoragecon­ditionsofthe medicalproduc­tafterdilution, please refertotheinfor­mationabove, under“Shelf life”.

Nature and contents of container

Milrinone lmg/ml Solution for Injection is presented inlOml clear, neutral glass (PhEur, Type I) ampoules. Theampoules are packed in a PVC tray and cardboard box in packs of lO.

Special precautions for disposal and other handling

Instructions for dilution:

Infusion solutions should befreshly prepared before use. Parenteral drug products should beexamined visually and should not be used ifparticulate matterordisco­louration are present.

Thefollowing diluents may be used to preparesolutionsfor infusion:

O.45% sodium chloride infusion

O.9% sodium chloride infusion

5%glucose infusion

Asolution containing 2OO pg/ml milrinoneshould be prepared by takingtheconten­tsofalOmlampou­leandadding4Om­lofoneof theabovediluents (4OO mldiluent per lOO ml Milrinone Injection).

Forsingle use.Discardany­unused solution. nurse. This includesany possiblesideeffects notlisted inthis leaflet. Youcanalsorepor­tsideeffectsdi­rectlyviathe national reportingsystems listed below:

United Kingdom:

YellowCardScheme

Website:

or

searchforMHRA YellowCardinthe

Google Play orApple App Store

Ireland:

HPRA Pharmacovigilance,

Earkfort Terrace, IRL- Dublin 2;

Tel: +353 1 676497l;

Fax:+353 l 67625l7; Website:

;

e-mail:

Malta:

ADR Reporting, Website:

By reporting side effectsyou can help provide more information on thesafetyofthkmed­kine.

5. how to store milrinone

• Keepoutofthesig­htandreachofchil­dren
• This medicine is forsingle use; any unused contents should bediscarded
• Thkmedicineshou­ldnotbeusedaf­tertheexpiryda­tewhkh is stated on thecarton and ampoule label after'EXP'. The expiry date refers to the last day ofthat month
• Store below 25°C. Do notfreeze. Store in theoriginalpackage.
• After dilution: Diluted solutionsofMil­rinone have been shown tobechemically­andphysicallys­tablewhen storedfor48 hours at 5°C. Froma microbiological pointofview, the productshould be used immediately. If not used immediately, in-use storage timesandcondi­tionspriortou­searethe responsibility­oftheuser
• Medicines should not bethrown away via wastewateror householdwaste. Yourdoctor,nur­seorpharmacis­twill disposeofmedicines nolongerrequired. These measureswill help protecttheenvi­ronment.

6. contents of the pack and other information

What Milrinone contains

The active substance is: milrinone. Each lO ml ampoulecontains lOmgmilrinone. Eachmlofsoluti­oncontainslmgmil­rinone.

The other ingredients are: (S)-lactic acid, anhydrous glucose, waterforinjec­tionsandthepHad­justers sodiumhydroxideand lactic acid (seeend ofsection 2).

What Milrinone looks like and contents of the pack

Milrinone is a clear, colourless to pale yellow, sterile solution, practically freefrom particles. It issupplied inlOml clear, neutral glass(TypeI,PhE­ur)ampoules.I­tisavailablein padsoften ampoules.

Marketing Authorisation Holder in UK and Ireland Wockhardt UK Ltd, Ash Road North, Wrexham, LLl3 9UF, United Kingdom

Marketing Authorisation Holder in Malta

Pinewood Laboratories Ltd., Ballymacarbry, Clonmel, Co.Tipperary,I­reland

Manufacturer

CP Pharmaceuticals Ltd, Ash Road North, Wrexham, LLl3 9UF, United Kingdom

Other sources of information

To listen toor requestacopy ofthis leaflet in Braille, large print oraudioplease­call,freeofchar­ge: 0800 198 5000 (UK only).

Please be ready togivethefollowing information:

Product name	Reference number
Milrinonelmg/ml Solution for injection/infusion	2983l/O6l9

This is a service provided by the Royal National Institute of Blind People.

Forthe RepublicofIre­landandMaltaple­asecall +44l97866l26l.

This medicinal product is authorised in the Member States of the eEa under the following names: United Kingdom, Ireland and Malta: Milrinone lmg/ml Solution for injection/infusion

France:Milrino­neNegmalmg/mlso­lutioninjecta­ble/pourperfu­sion

This leaflet was last revised in 04/2019

lO7658/4 ^WOCKHARDT

–X–

Delivery rates:

Adults:

The following providesa guideto maintenance infusion delivery rate based upon a solution containing milrinone 2OOpg/ml, prepared as described above.

Milrinone Injection Dose (pg /kg/min)	Infusion Delivery Rate (ml/kg/hr)
O.375	O.ll
O.4OO	O.l2
O.5OO	O.l5
O.6OO	O.lS
O.7OO	O.2l

Renal impairment:

The following maintenance infusion rates are recommended using the infusion solution describedabove.

Creatinine Clearance (ml/min/1.73m2)	Milrinone Injection Dose (pg/kg/min)	Maintenance Infusion Delivery Rate (ml/kg/hr)
5	O.2O	O.O6
lO	O.23	O.O7
2O	O.28	O.O8
3O	O.33	O.lO
4O	O.38	O.ll
5O	O.43	O.l3

The infusion rateshould beadjustedaccor­dingto haemodynamic response.Seethe information under “Posology and method ofadminktration.”

Marketing Authorisation Holder in UK and Ireland

Wockhardt UK Ltd., Ash Road North, Wrexham, LLl39UF

United Kingdom

Marketing Authorisation Holder in Malta

Pinewood Laboratories Ltd., Ballymacarbry, Clonmel

Co.Tipperary,I­reland

Marketing Authorisation Number(s)

PL2983l/O6l9

PAl339/68/l

MAl43/O42Ol

Date of Revision of the Text

O4/2Ol9

lO7658/4 ^WOCKHARDT

pg2/2