Amsalyo 75 mg Pulver till koncentrat till infusionsvätska, lösning

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

18-06-2018

Produktens egenskaper Produktens egenskaper (SPC)

18-06-2018

Aktiva substanser:
amsakrin
Tillgänglig från:
Eurocept International B.V.
ATC-kod:
L01XX01
INN (International namn):
amsacrine
Dos:
75 mg
Läkemedelsform:
Pulver till koncentrat till infusionsvätska, lösning
Sammansättning:
amsakrin 75 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Injektionsflaska, 5 st
Bemyndigande status:
Godkänd
Godkännandenummer:
56309
Tillstånd datum:
2018-06-14

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

26-04-2018

Produktens egenskaper Produktens egenskaper - engelska

26-04-2018

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

14-06-2018

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Package leaflet: Information for the patient

Amsalyo 75 mg powder for concentrate for solution for infusion

Amsacrine

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

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Amsalyo is and what it is used for

2. What you need to know before you use Amsalyo

3. How to use Amsalyo

4. Possible side effects

5. How to store Amsalyo

6. Contents of the pack and other information

1. What Amsalyo is and what it is used for

This

medicine

anticancer

(cytostatic)

agent.

used

combination

with

other

chemotherapeutic (anticancer) agents to treat a form of cancer of the white cells in your blood, acute

myeloid leukaemia. It prevents the growth of certain cells.

Amsalyo is mainly indicated in case of recurrence or failure of conventional treatments.

2. What you need to know before you use Amsalyo

Do not use Amsalyo

if you are allergic (hypersensitive) to amsacrine or any of the other ingredients of this medicine

listed in section 6.

if your bone marrow does not produce enough blood cells following the administration of other

chemotherapy products and/or radiation therapy.

during breast-feeding.

Warnings and precautions

Talk to your doctor before taking Amsalyo:

Your doctor will take special care if any of the following conditions apply to you.

this medicine can cause a decrease in the production of white blood cells and platelets where

severe infections and haemorrhages may occur. Your doctor will check this by blood samples

and reduce the dose and interrupt treatment if necessary.

there is a risk of kidney impairment, this will be monitored by blood samples.

if you suffer from kidney or liver impairment your doctor will adjust the dose for you.

your doctor will keep you under observation for allergic reactions when you receive this

medicine.

if your blood potassium or magnesium levels are too low (hypokalaemia/hypomagnesemia), it

will be adjusted before you get this medicine.

the rhythm of your heart will be checked, as some patients are at risk of arrhytmia.

inform your doctor if you suffer from porphyria (group of rare inherited blood disorders).

Contraception in males and females

See section Pregnancy, breast-feeding and fertility

Other medicines and Amsalyo

Tell your doctor or pharmacist if you are taking, have recently taken or may take any other medicines.

A large number of medicines can interact with Amsalyo and significantly alter their effect.

Vaccination should be avoided during treatment with this medicine, ask your doctor for further

information.

Medicines where the effect can be altered include:

Other medicines used in the treatment of cancer

Methotrexate, used in the treatment of e.g. cancer or rheumatoid arthritis

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding think you may be pregnant or are planning to have a baby, ask

your doctor for advice before taking this medicine.

Pregnancy

This medicine should be given during pregnancy only if absolutely necessary. If you become pregnant

during treatment, tell your doctor immediately. The benefit of treatment must be outweighed against

the risk to the unborn baby.

Contraception

If you are a woman of child-bearing age, you must use an effective contraceptive method during

treatment and for 3 months after stopping the treatment.

man,

must

take

appropriate

precautions,

including

effective

contraceptive method, so as not to conceive a child during the amsacrine treatment period or during

the 6 months after stopping the treatment.

Breast-feeding

You must not breast-feed during treatment

with Amsalyo.

Fertility

Amsalyo can have a negative impact on fertility.

Driving and using machines

Some of the side effects listed in this information have an effect on the ability to drive and use

machines. If you experience side effects such as e.g. dizziness, visual disturbances or confusion you

should not drive or use machines.

3. How to use Amsalyo

The dose is calculated by your doctor depending on your general condition and other concomitant

treatment you are receiving. It is given as a slow infusion into the vein (intravenous infusion).

If you use more Amsalyo than you should

As the infusion will be given under supervision of a doctor, it is unlikely that you will be given more

than necessary. However, if you have concerns about the dose of your medicine discuss them with

your doctor.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or nurse immediately:

If after the treatment you feel sick and vomit, have a fever, infection or if you notice bleeding or

bruises, as this product may reduce the white blood cells and platelet levels in your blood.

Very common side effects (affect more than 1 in 10 patients)

Low blood pressure;

Feeling sick, vomiting or diarrhoea;

Abdominal pain;

Inflammation of the mouth;

Red spots on the skin(purpura);

Local inflammation of the vein into which the infusion was given;

Increased liver enzymes levels.

Common side effects (affect 1 in 10 out of 100 patients)

Infection;

Reduced platelet levels in blood, increasing the risk of haemorrhaging;

Low blood potassium levels (hypokalaemia);

Mood changes (emotional lability);

Epileptic fits;

Heart function impairment, irregular heart rhythm and congestive heart failure;

Breathing difficulties (dyspnoea);

Gastrointestinal bleeding;

Hepatitis, jaundice, liver impairment;

Hair loss;

Hives and skin rashes;

Blood in urine;

Fever;

Local irritation at the injection site, tissue death (necrosis), inflammation of the skin.

Rare side effects (affect 1 in 10 out of 10000 patients)

Reduction in red and white blood cells (anaemia and increasing risk of infection);

Allergic reactions, severe allergic reactions (anaphylactic reactions), oedema;

Weight loss or gain;

Lethargy

and confusion;

Headache;

Reduced sensitivity (hypoaesthesia);

Dizziness;

Numbing (peripheral neuropathy);

Heart rhythm disorders and other changes of the heart function;

Increased blood levels of bilirubin, urea, alkaline phosphates and creatinine;

Visual disturbances;

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet.

You can also report side effects directly via the national reporting

system listed in Appendix V*. By reporting side effects you can help provide more information on the

safety of this medicine.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Amsalyo

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the vial. The expiry date refers to the

last day of that month.

Do not store above 30°C.

After preparing (reconstitution) the product must be used immediately.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Amsalyo contains

The active substance is 75 mg amsacrine.

The other ingredient is lactic acid.

What Amsalyo looks like and contents of the pack

This medicine is available as a powder for concentrate for solution for infusion. Powder in a 50 ml vial

(brown glass) with a stopper. Box of 5 vials.

Marketing authorisation holder

EUROCEPT INTERNATIONAL BV

TRAPGANS 5

1244 RL ANKEVEEN

THE NETHERLANDS

Manufacturer

THISSEN LABORATORIES

2-6 RUE DE LA PAPYREE

21420 BRAINE L’ALLEUD

BELGIUM

This leaflet was last revised 26 April 2018

---------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Posology

Treatment should be supervised by a physician experienced in the management of patients with AML.

Before treatment is started the potassium level in serum must be controlled and corrected. A serum

potassium level >4 mEq/L prior to administration is recommended. Amsacrine is given in combination

with other cytostatic drugs.

Numerous dose levels and dosing schedules exist and depend on concomitant therapy, patient and

disease characteristics, bone marrow reserve and hematoxicity, and response to therapy. Refer to the

protocol by which the patient is being treated and to applicable guidelines. Dosing schedules reported

for induction treatment with combination chemotherapy typically include doses of 90 to 150 mg/m2

per day, for three to five consecutive

days. For consolidation

treatment,

lower doses may be

considered.

Method of administration

Like for all cytotoxic agents, the preparation and handling of this product require a set of precautions

that guarantee the protection of the operator and his/her environment, under the safety conditions

required for the patient.

The following is required in addition to the usual precautions to preserve the sterility of preparations

for injection:

wear a long-sleeve tight cuff laboratory coat, in order to prevent any projection of the solution

on the skin,

also wear a disposable surgical mask and wrap-around safety eyeglasses,

wear disposable PVC gloves, not latex, after aseptically washing the hands,

prepare the solution on a work liner,

stop the infusion in case of injection outside the vein,

dispose of any material used for the preparation of the solution (syringes, compresses, liners,

vial) in a container reserved for this purpose,

destroy the toxic waste,

handle excreta and vomit with care.

Pregnant women must avoid handling cytotoxic agents.

After introducing 50 ml of water for injections in the vial containing the lyophilisate, it is essential to

mix the vial gently, without shaking, and allow to rest for approximately 15 minutes. If necessary,

repeat until obtaining a clear intense orange solution. For the stability of the reconstituted solution see

section 5: “How to store Amsalyo”.

The solution thus prepared, should only be injected by IV route, as an infusion.

To prepare the infusion, remove 50 ml of the 500 ml isotonic glucose serum bag and replace them by

the reconstituted amsacrine solution.

Solutions other than glucose, like isotonic saline solution, must not be used during preparation (risk of

precipitation of amsacrine).

This medicinal product must not be mixed with other medicinal products.

The administration is performed exclusively as an intravenous infusion over no less than 60 minutes,

to prevent any local irritation (risk of phlebitis). Stop the infusion in case of injection outside the vein.

In case of daily or continuous 24 hour infusion, it is recommended to insert a central catheter to

prevent the risk of veinitis.

In case of extravasation, the administration will be interrupted immediately.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Amsalyo 75 mg powder for concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 75 mg amsacrine.

After reconstitution, each ml of solution contains 1.5 mg amsacrine.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

Red-orange lyophilized powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Salvage therapy of refractory/relapsed acute myeloid leukaemia (AML) in adults, in combination with

other chemotherapeutic agents.

4.2

Posology and method of administration

Posology

Treatment should be supervised by a physician experienced in the management of patients with AML.

Before treatment is started the potassium level in serum must be controlled and corrected. A serum

potassium level >4 mEq/L prior to administration is recommended. Amsacrine is given in

combination with other cytostatic drugs.

Numerous dose levels and dosing schedules exist and depend on concomitant therapy, patient and

disease characteristics, bone marrow reserve and hematoxicity, and response to therapy. Refer to the

protocol by which the patient is being treated and to applicable guidelines. Dosing schedules reported

for induction treatment with combination chemotherapy typically include doses of 90 to 150 mg/m2

per day, for three to five consecutive days. For consolidation

treatment, lower doses may be

considered.

Renal impairment

Caution is advised when administering amsacrine to patients with renal impairment, see section 5.2.

In patients with mild-renal dysfunction (GFR 60–89 ml/min/1.73 m

), no starting dose

adjustment is

recommended.

In patients with moderate or severe renal impairment (GFR <59 ml/min/1.73 m

), a

starting dose reduction by approximately 20-30% should be considered. Subsequent dose adjustments

may be needed based on clinical toxicity.

Hepatic impairment:

Caution is advised when administering amsacrine to patients with hepatic impairment, see section 5.2.

In patients with mild liver dysfunction no dose adjustment is necessary. In patients with moderate or

severe hepatic impairment, a starting dose reduction by approximately 20-30% should be considered.

Subsequent dose adjustments may be needed based on clinical toxicity.

Elderly

No relevant information regarding the effect of age on the pharmacokinetics or tolerability

amsacrine is available.

Paediatric population

Amsacrine is not authorised for use in the paediatric population. No relevant information regarding

the effect of age on the pharmacokinetics or tolerability of amsacrine is available.

Treatment control

During the induction phase the patients should be kept under close observation and laboratory

monitoring in a hospital. Transfusions of erythrocytes and platelets should be available. Potassium

level in serum, ECG and hepatic and renal function should be controlled regularly.

Method of administration

Administration is performed exclusively as an intravenous infusion in at least 60 minutes to prevent

local irritation (risk of phlebitis).

In case of daily or continuous infusion over 24 hours, the placement of a central catheter is advised to

prevent the risk of veinitis.

In the case of extravasal administration it is recommended to rinse with a small amount of glucose

solution 50 mg/mL after which the body part should be immediately cooled down. The infusion shall

be stopped and started in a different vessel.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3

Contraindications

Hypersensitivity to amsacrine or acridine derivates or to any of the excipients listed in section

6.1;

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

Breast-feeding.

4.4

Special warnings and precautions for use

Bone marrow suppression

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

Infections and haemorrhages 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.

Hyperuricaemia

Amsacrine can induce hyperuricaemia 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. The hepatic monitoring

should include serum bilirubin, transaminases (GOT and GPT) and alkaline phosphatase. Laboratory

tests of liver function are recommended before (preferentially 24 hours) and regularly during the

administration

amsacrine.

addition,

serum

potassium

should

>4

mEq/L

prior

administration.

Adverse reactions

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

problems and epileptic insults (epileptic seizures related to the use of amsacrine, can be treated

according to standard regimen). 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

hypokalaemia are at increased risk of ventricular fibrillation. The risk of developing arrhythmia can

be minimized by ensuring a normal serum potassium level immediately, prior to and during amsacrine

administration.

Hypokalaemia should be corrected prior to amsacrine administration.

Transient hypomagnesemia may contribute to the risk of cardiac arrhythmia. It is recommended to

correct serum magnesium levels prior to amsacrine administration.

Porphyria

Amsacrine has been suggested as possibly porphyrinogenic in the Drug Database for Acute Porphyria.

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.

patients

risk

tumour

lysis

syndrome

(TLS)

(e.g.

elevated

pre-treatment

uric

acid,

compromised renal function or use of nephrotoxic drugs), pre-treatment evaluation is recommended.

Laboratory tests of renal function are recommended before (preferentially 24 hours) and during the

administration of amsacrine.

4.5

Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions:

Vaccines

Concomitant influenza or pneumococcal vaccination and immunosuppressive therapy have been

associated with impaired immune response to the vaccine. In general, all types of live vaccines should

be avoided during treatment with amsacrine.

Other cytotoxic agents:

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

Pharmacokinetic interactions

Effect of other medicinal products on the pharmacokinetics of amsacrine

The effect of other medicinal products on the pharmacokinetics of amsacrine has not been studied.

Amsacrine is extensively metabolised, but the identity of the catalysing enzymes and transporters are

unknown. If possible, concomitant use of strong enzyme inhibitors or inducers should be avoided.

Effects of amsacrine on the pharmacokinetics of other medicinal products

It has not been studied whether amsacrine could act as an enzyme inhibitor or inducer. Thus, other

medicinal products should be used with caution together with amsacrine.

Studies in animals indicate that amsacrine may inhibit the metabolism of methotrexate resulting in

increased methotrexate exposure, but the clinical relevance of this observation is not known.

4.6

Fertility, pregnancy and lactation

Pregnancy

Data from the use of amsacrine in pregnant women are not available to judge possible harmfulness.

However, harmful pharmacological effects during pregnancy are possible.

Studies in animals have shown teratogenicity and other reproductive toxicity (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.

The patient should be informed of the potential hazard to the foetus.

Contraception in males and females

Due to the mechanism of action of amsacrine and possible adverse effects on the foetus, women of

childbearing potential have to use effective contraception during and up to 3 months after treatments

and males during and up to 6 months after treatment.

Breastfeeding

It is unknown whether amsacrine is excreted in human milk. Breast-feeding is contraindicated during

treatment with amsacrine.

Fertility

Reversible azoospermia in humans has been described. Although there is not conclusive data, some

reports suggest that amsacrine can affect fertility in females.

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.

4.8

Undesirable effects

The most common adverse reactions are nausea and/or vomiting, anaemia, 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 haemorrhages. 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 reaction are presented according to MedDRA system organ class 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, haemorrhage

Rare

Anaemia, granulocytopenia, leukopenia

Immune system disorders

Rare

Hypersensitivity, anaphylactic reaction, oedema

Metabolism and nutrition disorders

Common

Hypokalaemia

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, hypoaesthesia, dizziness, peripheral 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,

abnormal,

ejection

fraction

decreased

Vascular disorders

Very common

Hypotension

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Gastrointestinal disorders

Very common

Nausea, vomiting (mild to moderate), diarrhoea, abdominal pain, stomatitis

Common

Gastrointestinal bleeding

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

Haematuria

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

Sometimes paired with hypokalaemia

especially in paediatric patients, pre-treated with anthracyclines

Fatal or life-threatening, usually in patients with hypokalaemia

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)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows

continued

monitoring

benefit/risk

balance

medicinal

product.

Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V*.

4.9

Overdose

specific

antidote

known

case

overdosage.

Treatment

should

symptomatic

supportive.

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

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

Vigorous symptomatic treatment may be necessary for severe mucositis, vomiting or diarrhoea.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic

group:

Antineoplastic

immunomodulating

agents,

other

antineoplastic

agents

ATC code: L01XX01

Amsalyo contains amsacrine which is a synthetic acridine derivative with cytostatic effect. The

substance is a strong tissue irritant. The mechanism of action is not totally clarified but is ascribed to

the ability of the substance to bind to DNA. Amsacrine inhibits the synthesis of DNA, while the

synthesis of RNA is unaffected. It has been shown in cell cultures that cells during division are two to

four times more sensitive than resting cells. The dose limiting toxcicity is due to bone marrow

depression, therefore Amsalyo is especially suitable in the treatment of acute leukaemia. In clinical

studies

no cross resistance

with

anthracycline

antibiotics

seen.

Amsalyo can

given in

combination with cytarabine.

5.2

Pharmacokinetic properties

Distribution

Intravenous infusion of 90 mg/m

over 1 hour results in a maximal plasma concentration of 4.8

micrograms/ml. The degree of plasma protein binding is approximately 97%, and the apparent volume

of distribution 70-110 L/m

Biotransformation

Amsacrine is extensively metabolised in the liver,

but the identity of catalysing enzymes is largely

unknown. The major route of metabolism of amsacrine is oxidation to the reactive quinoen diimine

intermediate followed by conjugation with GSH at the C-5`- and C-6`- postitions of the anilino ring.

Elimination

Excretion

occurs to a high extent via the bile mainly as 5´- and 6`-GSH metabolites,

and as

metabolites in urine

.

The elimination is biphasic with a terminal halflife of 6-9 hours. A limited

fraction of the dose (≈10%) is excreted unchange in the urine. The rest of the dose is excreted as

metabolites in bile and urine. The total plasma clearance rate is 200–300 mL/min per m

.Within 72

hours approximately 40% of the given dose is found in the urine, as metabolites or as unchanged

substance.

Renal and hepatic impairment

Increased halflife is seen in patients with impaired liver function. Urinary excretion of unchanged

amsacrine over 72 h, typically around 12% of the dose, has been reported to decrease to only 2% in

patients with renal impairment and increase to 20% in patients with hepatic impairment. After

administration of [

C]amsacrine, the total amount of radiolabel excreted in urine was 35% in patients

with normal organ function, 49% in patients with liver impairment and 2–16% in patients with renal

impairment.

5.3

Preclinical safety data

Amsacrine is known to produce its toxic effects mainly due to its myelosuppressive properties.

Repeated administration also causes gastrointestinal and mucosal adverse effects in animals.

Because Amsacrine interferes with DNA synthesis, it has potent genotoxic and cytotoxic properties,

and the substance is categorised as a class 2B carcinogen to humans by WHO and IARC. Amsacrine

is slightly genotoxic in both non-human and human mammalian cells. Carcinogenesis studies of

Amsacrine in rats indicate an increased incidence of small intestinal adenocarcinomas and in female

rats significantly increased incidences of mammary tumours.

Amsacrine has been shown to induce aneuploidy and killing of differentiating spermatogonia in mice,

and to be embryotoxic, fetotoxic and teratogenic in rats. These results provide a basis for genetic

counselling of patients under Amsacrine therapy and recommendation for contraception in both males

and females.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactic acid

6.2

Incompatibilities

Solutions other than glucose may not be used during preparation

of the medicinal product as

described in section 4.2, since amsacrine is incompatible with chloride ions.

This medicinal product must not be mixed with other medicinal products.

6.3

Shelf life

3 years.

After reconstitution: the physical and chemical stability of the product has been demonstrated for five

days at 25°C. However, from a microbiological point of view, the product must be used immediately.

If the product is not used immediately, the storage times and conditions after reconstitution and before

use are solely the responsibility of the user.

6.4

Special precautions for storage

Do not store above 30°C.

6.5

Nature and contents of container

Powder in a 50 ml vial (type I brown glass) with a stopper (bromobutyl); box of five.

6.6

Special precautions for disposal and other handling

The following is required in addition to the usual precautions to preserve the sterility of preparations

for injection:

wear a long-sleeve tight cuff laboratory coat, in order to prevent any projection of the solution

on the skin,

also wear a disposable surgical mask and wrap-around safety eyeglasses,

wear disposable PVC gloves, not latex, after aseptically washing the hands,

prepare the solution on a work liner,

stop the infusion in case of injection outside the vein,

dispose of any material used for the preparation of the solution (syringes, compresses, liners,

vial) in a container reserved for this purpose,

destroy the toxic waste,

handle excreta and vomit with care.

Pregnant women must avoid handling cytotoxic agents.

After introducing 50 ml of water for injectable preparation into the vial containing lyophilisate, it is

essential to mix the vial gently, without shaking, and let it stand for approximately 15 minutes. If

necessary, repeat until a clear solution and an intense orange colour is obtained. For stability of

reconstituted solution see section 6.3.

The solution prepared should only be injected IV, in the form of an infusion. To prepare the infusion,

remove 50 ml of the 500 ml isotonic glucose serum bag and replace with the reconstituted amsacrine

solution.

Salt isotonic saline should not be used (risk of precipitation of amsacrine).

Cytostatics should be handled in accordance with national requirements.

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

Eurocept International BV

Trapgans 5

1244 RL Ankeveen

The Netherlands

8.

MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

To be completed nationally

10.

DATE OF REVISION OF THE TEXT

26 April 2018

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