AMSIDINE 50 Mg/Ml Concentrate and solvent for solution for infusion

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
AMSACRINE
Available from:
NordMedica A/S
ATC code:
L01XX01
INN (International Name):
AMSACRINE
Dosage:
50 Mg/Ml
Pharmaceutical form:
Concentrate and solvent for solution for infusion
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Other antineoplastic agents
Authorization status:
Authorised
Authorization number:
PA1828/001/001
Authorization date:
2012-08-17

PATIENT INFORMATION LEAFLET

Amsidine 50 mg/mlInjection

Amsacrine ConcentrateforInfusion

READ ALL OF THISLEAFLETCAREFULLY BEFORE YOU START USING

THISMEDICINE.

Keep thisleaflet.Youmay need to read itagain.

Ifyou haveanyfurther questions, ask your doctor orpharmacist.

Ifanyofthesideeffectsbecomeserious,orifyounoticeanysideeffectsnotlistedinthisleaflet,please

tellyour doctoror pharmacist.

Inthisleaflet:

1.WhatAmsidine Injectionis and whatitis used for

2.Before youare given AmsidineInjection

3.How Amsidine Injectionis given

4.Possible side effects

5.How tostoreAmsidine Injection

6.Further information

1.WHAT AMSIDINE INJECTION ISAND WHATITISUSED FOR

Amsidine Injection is one ofa group ofmedicines called antineoplastic(anticancer) agents.

Itis usedto treatacuteleukaemia,a formofcancer ofthewhitecells in yourblood.

2.BEFOREYOU RECEIVEAMSIDINEINJECTION

Youshouldnot be given AmsidineInjectionif:

Youknowthatyouareallergictoamsacrineortoanyoftheotheringredients(seesection6ofthis

leaflet)

Youarealreadyreceivingothertreatmentsforcancer,includingradiation,whichhaveaffectedyour

bonemarroworyou havereceived treatments inthepast(your doctorwill advise you)

Youare under12yearsold.

Youare breastfeeding

Speakto your doctorbeforeyouare given thisinjection ifanyofthese applytoyou.

BeforeyouaregivenAmsidineInjection,yourdoctorwilltakespecialcareifanyofthefollowing

situationsapplytoyou.Makesureyourdoctorisawareofthesesituationsifitisnotalready

obvious:

Youhave everhadakidneyorliver disease

Youhave anyproblemwithyour heart

Youhave aproblem withyour nervous systemor brain

Youhave been told thatthepotassiumlevel inyour blood is too low

Youhave pre-existingbone marrowdepression

Youhave a raised uric acid level.

Speakto your doctor beforeyouare given thisinjection ifanyofthese applytoyou.

Takingor receivingother medicines:

Tellyourdoctorbeforeyouaregiventhismedicineifyouaretakingorhaverecentlytakenanyother

medicines, including medicinesobtainedwithouta prescription.

SomemedicinescaninteractwithAmsidineInjectionwhichcansignificantlyaltertheireffects.These

drugs include:

Vaccines suchas Common Influenzaand Pneumonia Vaccine.

Other medicinesor radiation usedin the treatmentofcancer.

Thereis a potentialfor interactionwith otherproteinbindingdrugs.

Ifyouarealreadytakingoneofthesemedicines,speaktoyoudoctorbeforeyoureceiveAmsidine

Injection.

Pregnancyand breast-feeding

Men aswellas women should use effective contraception.

Tellyourdoctorbeforeyouaregiventhismedicineifyouareorthinkyoumaybepregnantorare

planning to become pregnant,or are breast-feeding.

Donotusethis medicine inthe first3 monthsofpregnancy.

Thismedicineshouldnotbegivenduringpregnancyespeciallyduringthefirstthreemonthsof

pregnancy.Youmustspeaktoyourdoctoraboutthepossibleeffectsthismedicinemighthaveonyour

babybeforeyouare given thismedicine.

Youshould nottakethis medicine ifyou arebreast-feeding.Youshould avoidbecoming pregnantfor at

leastthree monthsafter yourtreatmentwith Amsidine hasstopped.

Men

Amsidineaffects sperm.Youshould avoid fatheringachild foratleastsix months afteryourtreatment

hasstopped.

Drivingand using machines

AmsidineInjectionshouldnotaffectyourabilitytodriveorusemachinery.However,ifyouexperience

anyside effect s afterhavingtheinjection ask yourdoctor’s adviceifyoucan drive.

3.HOWAMSIDINEINJECTION ISGIVEN

Youwill be inhospitalwhen you aregiven Amsidine Injection.

AdoseofAmsidinewillbedissolvedinasugarsolutionandslowlyinjectedintoaveinover60-90

minutes.Thisisknownasaninfusionandwillbeperformedunderthesupervisionofadoctor

experienced in cancer treatment.

Thedosewillbecalculatedbyyourdoctoraccordingtoyourageandthesurfaceareaofyourbody

(normally90mg persquaremetre).

Youwill be givenone infusion a dayfor5-8 days.

Blood monitoringshould be done forallpatients treated with Amsidine. Closemonitoring ofthe blood

levelsshouldbe done including thecomplete blood counts,

urine testsand insomecases blood Amsidinemonitoringalong with liverand kidneyfunctiontests to

detectanyproblems.

Followingthisinitialdosingperiod,furtherdoseswillbegivenevery3 –4weeks,dependingonthe

numberofyourbloodcells.Thissecondcourseoftreatmentwillgenerallybeonethirdoftheoriginal

dose andwill eitherbegiven allon one dayordividedup over 3days.

IfAmsidineInjectiondecreasesthenumberofyourbloodcellstoomuch,itmaybenecessaryforyour

doctor togiveyoua blood transfusion.

Ifyou haveanyfurther questions on the useofthisproduct,askyour doctor.

Ifyou think youhave been given more AmsidineInjectionthanyou should have

Astheinjectionwillbeadministeredunderthesupervisionofadoctor,itisunlikelythatyouwillbegiven

morethanisnecessary.However,ifyouhaveanyconcernsaboutthedoseofyourmedicinediscuss

themwith yourdoctor.

4.POSSIBLE SIDEEFFECTS

LikeallmedicinesAmsidineInjectioncansometimescauseside-effects,althoughnoteverybodygets

them.

Allmedicinescancauseallergicreactionsalthoughseriousallergicreactionsarerare.Any

suddenwheeziness,difficultyinbreathing,swellingoftheeyelids,faceorlips,rashoritching

(especiallyaffecting yourwholebody) shouldbe reportedto adoctor immediately.

Amsidine canmake you more likelytocatch infections. Ifyouthink you havean infection,a

sore throat,fever,chills, orachinessduringtreatmentyoushould tell yourdoctor immediately.

The side-effects reportedwithAmsidineare as follows:

Tell yourdoctorstraight awayifyounotice anyofthefollowing side effects:

VeryCommon –(affectsmore than 1in 10people)

Feeling sick (nausea) orvomiting

Diarrhoea

Abdominalpain

Ulcers inthe mouth

On investigation,ifthere is an increasein liverenzymes

Inflammationoftheveinsatthe site oftheinjection

Common –(Affects morethan 1in10people)

Increaseor decreaseinblood cell counton investigation

Increasedriskofbruisingor bleeding.

Reduced potassium levels in the blood

Emotional instability

Epilepsy(Fits)

HeartProblems(racing heart,heart failure)

Breathlessness

Yellowing ofthe skin or whites oftheeyes caused byliveror blood problems

Hair Loss

Skin rash

Raiseditchyred welts onthesurface ofthe skin

Blood in the urine

Fever

Skin Irritation,black discolouration andredness and swellingatthe injectionsite

Purpura

Infection

Rare –(affectsless than1 in 1,000 people)

Reduction in red blood cells which can make theskin pale andcauseweakness orbreathlessness

Increaseor decreaseinweight

Confusion

Headache,dizziness

Reducedsense oftouch

On urineexamination,high levelsofproteins maybe seen

On blood examination,high levelsofsome enzymes maybe seen

Granulocytopenia,leukopenia

Notcreatingurine (ofthekidney) (anuria)

Sudden insufficiëntkidneyfunction(kidneyinsufficiency)

NotKnown –(cannot be estimated fromthe available data)

Bone marrow failure

Cardiac arrest

Painfulswellingofthejoints(Gout)maybeseeninsomecasesduetoincreaseinuricacidlevelsinthe

blood.

Ifyou develop sign ofseriousallergic reaction,youmustcontact you doctor immediately.

Ifyougetanyofthesesideeffects,orifyounoticeanysideeffectsnotlistedinthisleaflet,pleasetell

your doctoratonce.

Certain other unwantedeffectscan onlybe detected byyour doctor, these include blood disorders,and

changes in liverandkidneyfunction

Althoughtheabovelistofpossiblesideeffectsappearsdaunting,acuteleukaemiaisaseriousdisease

whichrequires aggressivetreatment.

5.HOWTO STORE AMSIDINEINJECTION

The storage ofAmsidine Injection will notbe yourresponsibility.

However,keepinadryplaceanddonotstoreabove25°C.Keepintheoutercartoninordertoprotect

from light.

Keep outofthe reach andsightofchildren.

DonotuseAmsidine Injection afterthe expirydate whichisstated on thevialandoutercarton.

Ifonlypartused,discardtheremainingsolution.

6.FURTHERINFORMATION

What Amsidine Injectioncontains

The activesubstanceis amsacrine.

The other ingredients areN,N, Dimethylacetamide,L-lactic acid and water for injection.

What Amsidine Injectionlookslike and contents of pack

AmsidineInjectioncomesastwotypesofsmallglassbottles.Onesmallsealedclearglassbottle(vial)

containstheactive ingredient,whichis75mg ofamsacrine.

Italsocontainsaninactiveingredient,whichisN,N,dimethylacetamidein1.5mlasaclearbright

orange/red liquid.

Asecond glassbottle (vial) contains13.5mlofa solution ofL-lacticacid inWaterforInjection.

Marketingauthorization holder

NordMedicaA/S

JægersborgAllé 164,DK.2820 Gentofte,Denmark.

Manufacturer

EuroceptBV,Trapgans 5,NL-1244 RLAnkeveen,The Netherlands.

.

Amsidine 50mg/mlInjection is a trade mark.

Thisleafletwaslast approved inDecember2015.

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amsidine 50mg/ml Concentrate and Solvent for Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 75mg amsacrine in 1.5ml (50mg per ml).

Each solvent vial contains 13.5ml of Lactic Acid and water for injection to give a concentration of 0.0353M L-Lactic

acid.

Each ml of the combined solution of the concentrate when diluted with the solvent contains 5mg amsacrine per ml

For a full list of exipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate and solvent for solution for Infusion.

Concentrate is a clear, bright orange/red coloured solution and solvent for infusion is clear colourless solution.

The pH of the combined solution is 3.5 - 4.5.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Amsidine is indicated for the induction and maintenance of remission in acute leukaemia of adults. It is effective in

patients refractory to the anthracycline antibiotics used singly or in combination with other chemotherapeutic agents,

and in patients who were formerly treated with maximum cumulative doses of these antibiotics.

4.2 Posology and method of administration

Intravenous infusion

Amsidine must be diluted in 500ml 5% Dextrose Injection BP and infused over 60 to 90 minutes. Phlebitis or pain at

the injection site may occur at doses greater than 70 mg/m

. (NOTE: DO NOT USE OTHER DILUENTS. AMSIDINE

IS INCOMPATIBLE WITH SALINE). Care must be taken that no extravasation occurs which might produce severe

irritation or

necrosis. Caution in the handling and preparation of

the solution should be exercised,

and the use of

polyethylene gloves is recommended. If the solution of Amsidine contacts the skin or mucosae,

immediately wash

thoroughly with soap and water.

Adults

Induction of remission phase

The usual dosage of Amsidine in the induction phase is 90mg/m

every day for five consecutive days (total dose 450

mg/m

per course of treatment).

If bone marrow biopsy performed on day six displays over 50% cellularity and the

blasts count is over 30%, the treatment may be extended for an additional three days, bringing the total dose per course

of treatment to 720 mg/m

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More than one course of treatment may be required to achieve induction. Depending on the effectiveness of the first

course in producing myelosuppression, the subsequent courses are given at two-week (if not effective) to four-week (if

effective) intervals. In cases where a hypocellular marrow has not been achieved after the first course of treatment, the

daily dose of Amsidine may be escalated to 120 mg/m

per day for the subsequent courses,

provided that this is not

contra-indicated for reasons of non-myelosuppressive toxicity.

For patients with impaired liver function or impaired renal function, the dose of Amsidine should be decreased by 20-

30% (to 60-75 mg/m

per day).

Maintenance phase

The maintenance dose is about

one third the induction dose,

given either as a single IV infusion or divided in three

daily doses e.g. 150 mg/m

given once every 3-4 weeks or 50 mg/m

per day for three consecutive days, repeated every

3-4 weeks.

Each maintenance course should bring down the granulocyte count to 1,000-1,500/µl and Platelet count to 50,000 -

100,000/µl. The granulocyte and platelet counts should be allowed to recover between the courses to over 1,500/µl abd

100,000/µl respectively; otherwise the subsequent course should be delayed.

Elderly

Elimination may be slower in this group. This should be considered when designing dose schedules for the elderly.

Children under 12 Years

Not recommended.

4.3 Contraindications

Hypersensitivity to amsacrine or acridine derivates;

Hypersensitivity to one of the other ingredients of the product;

Clear bone-marrow-suppression as a result of treatment with cytostatics or radiotherapy;

Lactation.

4.4 Special warnings and precautions for use

Amsacrine should only be used under strict control of a specialised oncologist, with preference in institutions with

experience with this kind of therapies.

Bone Marrow Suppression

Amsacrine can cause severe bone-marrow-depression, thus frequent blood control is necessary. Infections and

hemorrhages can be fatal. With an already existing bone marrow depression caused by drugs, amsacrine should be

administered cautiously and with extra controls. Also if a too strong decrease in white blood cells or blood platelets

occurs, interruption of the amsacrine treatment or decrease of dosage can be necessary. Red blood cells and platelets

should be available for transfusion as well as other facilities for the treatment of bone-marrow-depression.

Hyperuricemia

Amsacrine can induce hyperuricemia secondary to rapid lysis of neoplastic cells. Careful monitoring of blood uric

acid levels is recommended, in particular with regard to possible consequences for renal function. Consideration may

be given to reducing uric acid levels prophylactically, prior to or concurrent with amsacrine treatment.

Patients with Hepatic or Renal Impairment

Toxicity at recommended doses is enhanced by hepatic or renal impairment. Laboratory evaluation of hepatic and

renal function is necessary prior to and during administration. A dose reduction might be considered.

Adverse reactions

The physician should be aware of allergic reactions (anaphylaxia, oedema and skin reactions), GI problems and

epileptic insults (epileptic seizures related to the use of amsacrine, can be treated according to standard regimen.

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Local necrosis can occur with extravasation of amsacrine (see section 4.8). Injection site irritation can be prevented by

diluting amsacrine in a greater volume 5 % glucose and infusion is spread over a larger period of time (minimal 1

hour).

Cardiac function

Careful monitoring of cardiac rhythm is recommended for detection of cardiotoxicity. Patients with hypokalemia are

at increased risk of ventricular fibrillation. The risk of developing arrhythmias can be minimized by ensuring a normal

serum potassium level immediately prior to and during amsacrine administration.

Hypokalemia should be corrected prior to amsacrine administration.

Laboratory Tests

Complete blood counts, liver and renal function tests, and electrolytes should be performed regularly. Electrolytes

should be re-evaluated before each day's treatment.

4.5 Interaction with other medicinal products and other forms of interaction

Vaccines:

Concomitant influenza or pneumococcal vaccination and immunosuppressive therapy have been associated with

impaired immune response to the vaccine.

Other Protein-binding Drugs:

Amsacrine may be displaced from serum albumin, with consequential increase in free drug and toxicity if used with

other highly protein binding drugs.

Other Cytotoxic Agents:

Adverse effects may be potentiated by use with other cytotoxic agents.

4.6 Fertility, pregnancy and lactation

Data on the usage of this compound during pregnancy in patients are not available to judge possible harmfulness.

However based on its pharmacologic activity harmfulness of treatment during pregnancy is possible.

In animal studies teratogenicity and other reproductivity toxicity has been observed (see section 5.3). Based on animal

studies and the mechanism of action of the substance, use during pregnancy is discouraged, especially during the first

trimester.

In every individual case the advantages of treatment should be weighed against the risks to the foetus.

Contraception in males and females

Due to the mechanism of action of amsacrine and possible adverse effects on the foetus, females should use effective

contraception for 3 months after treatments and males for 6 months after treatment.

Fertility

Reversible azospermia in humans has been described.

Lactation

As it is not clear whether amsacrine is excreted in the mother milk, lactation is contraindicated.

4.7 Effects on ability to drive and use machines

No data about this influence are known. In view of reported adverse effects profile patients are advised after

administration of amsacrine to be cautious when driving or using machines.

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4.8 Undesirable effects

The most common adverse reactions are nausea and/or vomiting, anemia, fever and infection. Pain or phlebitis on

infusion has been reported.

All patients treated with a therapeutic dosage of amsacrine show bone marrow depression. Main complications are

infections and hemorrhages. Minimal white blood cells occur on day 5-12, usually followed with complete recovery

on day 25. The pattern of inhibition of blood platelets is similar to that of leucocytes.

In the table below all adverse events are presented according to classification of organ system and frequency, very

common (

1/10); common (

1/100 to <1/10); uncommon (

1/1000 to <1/100); rare (

1/10.000 to <1/1000); not

known (cannot be estimated from the available data).

Infections and Infestations

Common

Infection

Blood and Lymphatic System Disorders

Common

Thrombocytopenia, pancytopenia, hemorrhage

Rare

Anemia, granulocytopenia, leukopenia

Immune system disorders

Rare

Hypersensitivity, anaphylactic reaction, oedema

Metabolism and Nutrition Disorders

Common

Hypokalemia

Rare

weight decreased, weight increased

Not known

Hyperuricaemia

Psychiatric Disorders

Common

Affect lability

Rare

Lethargy, confusion

Nervous System Disorders

Common

Grand mal seizure

Rare

Headache, hypoesthesia, dizziness, periferal neuropathy

Eye disorders

Rare

Visual disturbances

Cardiac disorders

Common

Cardiotoxicity, arrhythmia, congestive heart failure

Rare

Atrial fibrillation, sinus tachycardia, ventricular fibrillation

ventricular arrhythmias, cardiomyopathy, bradycardia, ECG

abnormal, ejection fraction decreased

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Sometimes paired with hypokalemia

especially in paediatric patients, pretreated with antracyclines

fatal or lifethreathening, usually in patients with hypokalemia

Mucosa of mouth and tractus digestivus are frequently effected ranging in severity from mild to life-threatening.

Total oral mucosa can be affected; recovery takes several weeks.

related to the concentration of amsacrine infused (see section 4.4)

4.9 Overdose

No specific antidote is known in case of overdosage. Treatment should be symptomatic and supportive.

Not known

Cardiac arrest

Vascular Disorders

Very common

Hypotension

Common

Hemorrhage

Respiratory, Thoracic and Mediastinal Disorders

Common

Dyspnea

Gastrointestinal Disorders

Very common

Nausea, vomiting (mild to moderate), diarrhea, abdominal pain,

stomatitis

Hepatobiliary Disorders

Common

Hepatitis, jaundice, hepatic insufficiency (see section 4.2)

Skin and Subcutaneous Tissue Disorders

Very common

Purpura

Common

Alopecia, urticaria and rash

Renal and Urinary Disorders

Common

Hematuria

Rare

Anuria, proteinuria, acute renal insufficiency

General Disorders and Administration site Conditions

Very common

Infusion site phlebitis

Common

Pyrexia,

Injection site irritation, necrosis, skin inflammation

Investigation

Very common

Hepatic enzymes increased (see section 4.4).

Rare

Blood bilirubin increased, blood urea increased, blood alkaline

phosphatase increased, blood creatinine increased

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Hemorrhage and infection, resulting from bone marrow hypoplasia or aplasia, may require intensive supportive

treatment with red cell, granulocyte or platelet transfusions and appropriate antibiotics.

Vigourous symptomatic treatment may be necessary for severe mucositis, vomiting or diarrhea.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Amsidine is a sterile antitumour chemotherapeutic agent for intravenous infusion. Although not completely clarified,

the mode of action of amsacrine is related to its property of binding the DNA through intercalation and external

(electrostatic) forces. Amsacrine inhibits the synthesis of DNA while the RNA may not be directly affected. An

additional mode of action, involving modification of cell membrane function, has been suggested.

5.2 Pharmacokinetic properties

Amsidine is administered by intravenous infusion. Amsidine has a low lipid solubility, and a relatively high molecular

weight, so that it is unlikely that it would cross the blood-brain barrier. Amsidine distributes well in the body, except to

the brain and CSF, and is therefore inactive against cerebral tumours.

Studies have shown that the plasma concentration time profiles of Amsidine in man are best described using a three

compartment

open model. The

terminal

half-life

found to be

prolonged in patients

with severe

hepatic

dysfunction. Work in animals has shown that

after biotransformation in the liver,

the metabolites of Amsidine are

finally excreted in the bile by an active transport mechanism. The majority of Amsidine is excreted in its metabolised

form. Studies in man have shown that 20% of the administered drug (free and metabolised) was eliminated in the urine

within the first 8 hours, and a total of about 42% within 72 hours in one patient with normal renal function.

5.3 Preclinical safety data

No additional data of relevance.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Concentrate

N,N Dimethylacetamide

Solvent

L-lactic Acid

Water for Injection

6.2 Incompatibilities

Amsidine is incompatible with saline. Amsidine in solution reacts with plastic syringes.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened: Amsacrine concentrate vial: - 2 years

Unopened: Solvent vial: - 2 years

Once opened and diluted with Amsidine solvent: Chemical and physical in-use stability of the reconstituted and diluted

drug has been demonstrated for 8 hours when stored below 25

C and protected from sunlight. Unused solution should

be discarded.

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From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the

product should be used immediately after first opening or following reconstitution. If not used immediately, in-use

storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 25

Store in the original pack in order to protect from light and moisture.

6.5 Nature and contents of container

Concentrate vial - 2ml clear Type I, Ph. Eur. neutral glass vial containing 1.5ml amsacrine solution.

Solvent vial - 20ml clear Type I, Ph. Eur. neutral glass vial contains 13.5ml of 0.0353M L-lactic acid.

Each carton contains 6 vials of concentrate and 6 vials of solvent.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from

such medicinal product and other handling of the product

Amsidine should be handled in accordance with local hospital guidelines for handling cytotoxic drugs. Any unused

product or waste material should be disposed of in accordance with local requirements.

Preparation of the medicinal product: 1.5ml of the drug solution is withdrawn from the concentrate vial and added to

the solvent vial. The diluted concentrate is further diluted with 500ml of 5% Dextrose Injection BP solution. The

concentration when diluted with 500ml of 5% Dextrose solution is 0.146mg Amsacrine per ml.

Use immediately once diluted further with 500ml of 5% Dextrose Injection BP.

Appearance of the diluted solution: The diluted solution is clear deep orange red solution.

Dextrose 5% Injection BP must be used for dilution of Amsidine. Other diluents should not be used.

Caution in handling and preparation of the solution should be excercised, and the use of polyethylene gloves is

recommended (see patient information leaflet). If the solution of Amsidine contacts the skin or mucosae, immediately

wash thoroughly with soap and water.

Glass syringes must be used as Amsidine in solution reacts with plastic syringes.

Do not use the solution if the contents are discoloured in any way or contains particles in it.

7 MARKETING AUTHORISATION HOLDER

NordMedica A/S

Jaegersborg

Alle 164

DK-2820

Gentofte

Denmark

8 MARKETING AUTHORISATION NUMBER

PA1828/001/001

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9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 March l984

Date of last renewal: 05 March 2009

10 DATE OF REVISION OF THE TEXT

August 2017

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