legal status: prescription only product vi.2 elements for

Risk Management Plan Doxorubicin RMP Version 2.0

The data and conclusions included in this report are confidential and proprietary information of Agila Specialties UK

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Safety concern Routine risk minimisation measures Additional risk minimisation

measures

Section 4.6:

Pregnancy:

Doxorubicin should not be given during

pregnancy. In general cytostatics should

only be administered during pregnancy

on strict indication, and the benefit to the

mother weighed against possible hazards

to the foetus. In animal studies,

doxorubicin has shown embryo-, foeto-

and teratogenic effects.

Section 5.3:

Animal studies from literature show that

doxorubicin affects the fertility, is

embryo- and foetotoxic and teratogenic.

An abbreviated version of this in lay

language is provided in the package

leaflet (PL).

Legal Status: Prescription only product

VI.2 Elements for a public summary

VI.2.1 Overview of disease epidemiology

Breast cancer

Breast cancer is the most frequently observed life-threatening cancer in women and the main cause of

cancer death among women.



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The beginning of the 21st century saw a dramatic decrease in breast cancer incidence in a number of

Westernized countries (e.g., the United Kingdom, France, Australia and United States). In 2008, there

were an estimated 1.38 million new cases of breast cancer worldwide. The 2008 incidence of female

breast cancer ranged from 19.3 cases per 100,000 in Eastern Africa to 89.9 cases per 100,000 in Western

Europe. With early detection and significant advances in treatment, death rates from breast cancer have

been decreasing over the past 25 years in North America and parts of Europe. The incidence rate of

breast cancer increases with age, 95% of new cases occur in women aged 40 years or older. Among

women younger than 40 years, African Americans have a higher incidence. (2)

Neoadjuvant and adjuvant therapy of osteosarcoma

Osteosarcoma is the most common type of bone cancer.

The occurrence of osteosarcoma for allraces and both sexes are 4.0 (3.5–4.6) for the range 0–14

years and 5.0 (4.6–5.6) for the range 0–19 years per year per million persons. Among childhood

cancers, osteosarcoma occurs eighth in terms of the general incidence. It occurs mainly during

adolescence and in older adulthood. The occurrence is higher in males than in females, occurring at

a rate of 5.4 per million persons per year in males vs. 4.0 per million in females, with a higher

incidence in blacks (6.8 per million persons per year) and Hispanics (6.5 per million), than in whites

(4.6 per million). Osteosarcoma commonly occurs in the long bones of the extremities. The most

common sites are the thigh bone (femur), the shinbone (tibia), and the bone of the upper arm

(humerus). Other likely locations are the skull or jaw and the pelvis. (3)

Advanced soft-tissue sarcoma in adults

Soft tissue sarcoma is a type of rare cancer that can occur anywhere in the soft tissues of the body

like fat, muscle, connective tissue, and nerves.

Soft tissue sarcoma is mainly occurring in children rather than adults. It spreads in the whole body

rather than affecting the small area and appears as small painless lump, which further start growing

in size. Soft tissue cancer can be cured as per the early diagnosis is concerned. Relatively 5 years of

survival is possible for the cancer-affected patients but unfortunately very low percentage of patient



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can enjoy their lives more than 5 years. Unluckily there is a chance of recurrence of the soft tissue

cancer in the first two years of the treatment for 70% of patients. (4)

Small-cell lung cancer

Globally, lung cancer is the most frequent malignancy in men and the fifth most common cancer in

women. An estimated 1.6 million new lung cancers are diagnosed worldwide each year. The highest

occurrence rates in males are observed in Central/Eastern and Southern Europe (57 and 49 per 100, 000,

respectively), whereas in women the highest rates are found in Northern Europe (36 per 100, 000). In

the Western world, the proportion of patients with SCLC has decreased to 13%. Virtually all patients

have a history of tobacco use. Therefore, smoking habits are closely linked to incidence, which varies

across different populations. (5)

Hodgkin’s lymphoma

Hodgkin lymphoma is a type of cancer affect the white blood cell called lymphocyte with presence

of specific type of abnormal cell called a Reed-Sternberg cell.

It is one of the most common cancers among older children and adolescents. In the UK, there is a

higher frequency in males compared with females. It is the third most commonly diagnosed cancer

in people aged 15-29 years, and the sixth most commonly diagnosed cancer in children under 15.

Infectious agents may be involved in the manner of the development of the disease. Patients with

HIV infection have a higher frequency compared with the population without HIV infection. It

mainly affects children, with 85% of the cases affecting boys. The lowest incidence is found in

Asians and Pacific Islanders. (6)

Highly malignant non-Hodgkin’s lymphoma

Non-Hodgkin lymphoma is a type of cancer which affects the white blood cells called lymphocytes

without a specific type of abnormal cell called a Reed-Sternberg cell. It accounts for approximately

4% of all cancer diagnoses and ranks seventh in frequency among all cancers. It is more than 5 times

as common as Hodgkin’s disease.



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The incidence varies with race; white people have a higher risk than black and Asian American

people do. In general, the incidence of this cancer is slightly higher in men than in women, with a

male-to-female ratio of approximately 1.4:1.

The 5-year relative survival rate of patients with this cancer is approximately 63%. The survival rate

has steadily improved over the last 2 decades, thanks to improvements in medical and nursing care,

the advent of novel therapeutic strategies (i.e. monoclonal antibodies) and the implementation of

tailored treatment. (7)

Induction and consolidation therapy in acute lymphatic leukaemia

Acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia, is a cancer that starts

from white blood cells called lymphocytes in the the soft inner part of the bones, where new blood

cells are made (bone marrow).

Most ALL cases occur in children, with an incidence of 3 to 4/100,000 in patients 0 to 14 years of

age and approximately 1/100,000 in patients older than 15 years, in the United States. In children,

ALLs represent 75% of all acute leukemias, with a peak incidence at 2 to 5 years of age. This

percentage is much lower in adults. There observed incidence was slightly higher in male and a

significant excess incidence among white children. Exposure to ionizing radiation, pesticides and

solvents has also increased risk for childhood leukemia. (8)

Acute myeloblastic leukaemia

It is a form of myeloid tissue cancer affecting stem cells. The number of new cases of acute myeloid

leukemia in adults in Europe is 5–8 cases/100,000 population /year. The mortality is approx 4–6

cases/100, 000/year. Acute myeloid leukemia (AML) accounts for approximately 25% of all

leukemias in adults in the Western world, and therefore is the most frequent form of leukemia.

Worldwide, the occurrence of AML is highest in the U.S., Australia, and Western Europe. AML is

primarily a disease of later adulthood. Patients newly diagnosed with AML have a median age of 65

years..AML in adults has a slight male predominance in most countries. The development of AML

has been associated with several risk factors. These include age, antecedent hematologic disease,



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and genetic disorders; as well as exposures to viruses as well as radiation, chemical, or other

occupational hazards and previous chemotherapy. (9)

Advanced multiple myeloma

Multiple myeloma is a cancer of plasma cells, a type of white blood cell normally responsible for

producing white blood cells.

It accounts for 10% of all blood cancers. The age-adjusted annual incidence of this cancer is 4.3

cases per 100,000 in white men, 3 cases per 100,000 in white women, 9.6 cases per 100,000 in black

men, and 6.7 cases per 100,000 black women.

The average age of patients with this cancer is 68 years for men and 70 years for women. Only 18%

of patients are younger than 50 years, and 3% of patients are younger than 40 years. The male-to-

female ratio of multiple myeloma is approximately 3:2. The survival rate is ranging from 1 year to

more than 10 years. Average survival in unselected patients with this cancer is 3 years. The 5-year

relative survival rate is around 35%. Survival is higher in younger people and lower in the elderly.

(10)

Advanced or recurrent endometrial carcinoma

Endometrial cancer (also referred to as corpus uterine cancer or corpus cancer) is the most frequently

occurring female genital cancer.

More than one in 20 female cancers in Europe is of the endometrium. Surveillance of incidence rates

is imperative given the rapidly changing profile in the prevalence and distribution of the underlying

determinants. There were increasing trends among postmenopausal women in many Northern and

Western countries. Denmark and possibly France and Switzerland were exceptions, with decreasing

trends in postmenopausal women. In postmenopausal women, changes in reproductive behavior and

prevalence of overweight and obesity may partially account for the observed increases, as well as

hormone replacement therapy use in certain countries. Combined oral contraceptive use may be

responsible for the declines observed among women aged <55 years. Increases in obesity and



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decreases in fertility imply that endometrial cancer in postmenopausal women will become a more

substantial public health problem in the future. (11)

Advanced papillary/follicular thyroid cancer

Papillary thyroid cancer or follicular thyroid cancer is the most common type of thyroid

cancer, representing 75 percent to 85 percent of all thyroid cancer cases.

Thyroid cancers are quite rare, accounting for only 1.5% of all cancers in adults and 3% of all cancers

in children, but the rate of new cases is increasing in the last decades. The highest incidence of

thyroid carcinomas in the world is found among female Chinese residents of Hawaii. Of all thyroid

cancers, 74-80% of cases are papillary cancer. Follicular carcinoma incidences are higher in regions

where incidence of endemic goiter is high.

In contrast to other cancers, thyroid cancer is usually curable. Most thyroid cancers grow slowly and

are associated with a very favorable cure. The mean survival rate after 10 years is higher than 90%

and is 100% in very young patients with minimal disease. (12)

Anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is a form of thyroid cancer, which has a very poor recovery due to

its aggressive behavior and resistance to cancer treatments.

It accounts for less than 2% of all thyroid cancers, it causes up to 40% of deaths from thyroid cancer.

The aggressive nature of ATC makes treatment studies difficult to perform. The overall 5-year

survival rate is reportedly less than 10%, and most patients do not live longer than a few months

after diagnosis. The female-to-male ratio is approximately 3:1. Peak incidence occurs during the

sixth to seventh decades of life. The age range of affected patients reportedly is 15-90 years. (13)

Bladder carcinoma

Bladder cancer is the 9th most common cancer diagnosis worldwide, with more than 330,000 new

cases each year and more than 130,000 deaths per year, with an estimated male: female ratio of



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3.8:1.0. At any point intime, 2.7 million people have a history of urinary bladder cancer.At the initial

diagnosis of bladder cancer, 70% of cases are diagnosed as non-muscle-invasivebladder cancer

(NMIBC) and approximately 30% as muscle-invasive disease. Gary David and colleagues

mentioned that worldwide, bladder cancer is diagnosed in approximately 275,000 people each year,

and about 108,000 die of this disease. (14)

Ovarian carcinoma

Ovarian cancer is the fifth commonest cancer in women in the UK after breast, colorectal, lung and

uterus. Approximately 6,700 new cases of ovarian cancer were diagnosed every year in UK between

2004 and 2007 accounting for approximately 1 in 20 cases of cancer in women. In comparison with

other European countries, the UK is among those with the highest incidence rates of ovarian cancer.

Generally, the highest rates are in the Northern and Eastern European countries of Lithuania, Latvia,

Ireland, Slovakia and Czech Republic. The lowest rates are in Southern European countries of

Portugal and Cyprus.

Globally, ovarian cancer incidence rates increase with advancing age and range from 0.2 among

those aged 0-14 to 29.2 among those aged 75 years and older. Factors that increase the risks of

ovarian cancer include a family history of ovarian or breast cancer, ovulation history and

reproductive status, elevated body mass index, diagnosis of endometriosis and post-menopausal

hormone use. (15)

Wilms’ tumour (in stage II in highly malignant variants, all advanced stages [III – IV])

Wilms tumor, or nephroblastoma, is the most common childhood abdominal cancer. Wilms tumor

appears to be relatively more common in Africa and least common in East Asia. The incidence in

Europe is similar to that reported in North America. Wilms tumor is relatively more common in

blacks than in whites and is rare in East Asians. Estimates suggest 6-9 cases per million person years

in whites, 3-4 cases per million person years in East Asians and more than 10 cases per million

person years among black populations. For patients with bilateral disease, the male-to-female ratio

was 0.60:1. The median age at diagnosis of Wilms tumor is approximately 3.5 years.



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Approximately 80-90% of children with a diagnosis of Wilms tumor survive with current

multimodality therapy. Patients who have tumors with favourable histology have an overall survival

rate of at least 80% at 4 years after the initial diagnosis, even in patients with stage IV disease. (16)

Advanced multiple myeloma

In Europe is 6.0 new cases are reported per 100 000 people each year with a common age of diagnosis

between 63 and 70 years; 4.1 cases are reported to be fatal per 100 000 people each year.

Multiple myelomas are a less frequent cancer site between both sexes. On a worldwide scale, it is

estimated that about 86,000 incident cases occur annually (47,000 males and 39,000 females),

accounting for about 0.8% of all new cancer cases. About 63,000 subjects are reported to die from

the disease each year (33,000 males and 30,000 females), accounting for 0.9% of all cancer deaths.

Geographically, the industrialized regions of Australia/New Zealand, Europe, and North America

have the highest number of new cases. It is estimated that within the population of the USA there is

an almost doubled occurrence of multiple myeloma among the blacks compared to the whites, while

people of Asian origin, especially Chinese and Japanese, experience a much lower incidence. (17)

Advanced neuroblastoma

Neuroblastoma is almost exclusively a disease of children. It is the third most common childhood

cancer, after leukemia and brain tumors, and neuroblastoma accounts for approximately 15 percent

of all pediatric cancer fatalities.

Incidence rates are age-dependent. The average age at diagnosis is 17.3 months, and 40 percent of

patients are diagnosed before one year of age. Neuroblastomas are the most common extracranial

solid malignant tumor diagnosed during the first two years of life, and the most common cancer

among infants younger than 12 months, in whom the incidence rate is almost twice that of leukemia

(58 versus 37 per one million infants). The incidence of neuroblastoma is greater among white than

black infants (ratio of 1.7 and 1.9 to 1 for males and females, respectively), but little if any racial

difference is apparent among older children. Neuroblastoma is slightly more common among boys

compared to girls. (18)



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Ewing sarcoma

Ewing's sarcoma is a primary bone cancer that affects mainly children and adolescents.The annual

incidence of Ewings sarcoma from birth to age 20 years is 2.9 cases per million of the population.

Approximately 10% of patients are aged 20-30 years. Cases occurring later than this are infrequent.

The incidence of these tumors in white people is at least 9 times higher than it is in black people.

The incidence of Ewings sarcoma in females is 2.6 cases per million of the population, compared

with 3.3 cases per million of the population in males.

The incidence of these tumors peaks in the late teenage years. The survival of patients with Ewings

sarcoma depends highly on the initial manifestation of the disease. Approximately 80% of patients

present with localized disease, whereas 20% present with clinically detectable cancer disease, most

often to the lungs, bone, and/or bone marrow. The overall patient survival rate is 60% for patients

with localized disease. (19)

VI.2.2 Summary of treatment benefits

Doxorubicin Agila is indicated for the treatment of the following infections in adults and children:

- Breast cancer

- Bone cancer (osteosarcoma) given before surgery and given following surgery - Cancer found in the soft tissue (advanced soft-tissue sarcoma in adults)

- Lung cancer (small cell lung cancer)

- Cancer of the lymphatic tissue (hodgkin’s and non-hodgkin’s lymphoma)

- Certain cancers of the blood (acute lymphatic or myeloblastic leukaemias) - Cancer of the bone marrow (multiple myeloma)

- Cancer of the lining of the uterus (advanced or recurrent endometrial cancer)

- Cancers of the thyroid (advanced papillary/follicular thyroid cancer, anaplastic thyroid

cancer) - Certain bladder cancers (locally advanced or spreading stage). It is also used intravenously

- (into the bladder) in early (superficial) bladder cancer to prevent recurrence of bladder

cancer after surgery

- Recurrent cancer of the ovaries - A certain childhood kidney cancer (Wilms’ tumour)

- Childhood cancer of the nervous tissue (advanced neuroblastoma).

Clinical studies have shown a wide spectrum of antitumor activity in solid tumor and hematologic

malignancies in adults and children when used as a single cytotoxic agent or in polydrug regimens.



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The most important therapeutic results achieved with doxorubicin in the treatment of various

malignancies are briefly summarized below:

Complete remission rates (CR), have been reported with doxorubicin when administered as a single

cytotoxic agent: 38% in sarcomas, about 40% in endometrial cancer, only poor results (15-20%) in

lung cancer depending on cell type, 5-8% in oesophageal cancer, 22-25% in cancer of the stomach,

25% in hepatocellular carcinoma, less than 5% in colo-rectal cancer and 8-10% in cancer of the

pancreas. In thyroid carcinomas, doxorubicin alone gives an overall objective response rate of

approximately 30%, in squamous cancers of the head and neck an overall response rate of about

20%. Adriamycin-containing regimens have drastically improved the CR rate up to about 75% in

Hodgkin’s disease, 60-82% in acute myeloblastic leukemia, and 70-80% in breast cancer.

VI.2.3 Unknowns relating to treatment benefits

Not known.

VI.2.4 Summary of safety concerns

Important identified risks

Risk What is known Preventability

Heart muscle damage

(Cardiotoxicity)

Before and during treatment

with Doxorubicin Agila the

doctor will have an

electrocardiogram (ECG) test

done, that records heart’s

activity, before the start of

treatment with doxorubicin and

during the whole treatment as

doxorubicin is likely to cause

inflammation of the heart

Yes.

Doxorubicin Agila will NOT be

given to the patient intravenously

(in a vein) in the following

situations:If the patient has

problems with their heart (severe

heart rhythm disorders, reduced

heart function, (previous) heart

attack, inflammation of the

heart). These can be problems



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muscles (cardiomyopathy).

This particularly can occur if

patients have a history of heart

disease, are over 70 or below

15 years of age, have been

previously treated with

doxorubicin (or other related

anthracycline medicines) or

radiation in the chest cavity. A

cumulative dose of 450-550

mg/m2 should not be exceeded,

because at higher doses the risk

of development of heart failure

considerably increases,

particularly in children and in

patients with a history of heart

disease. In children the

maximal cumulative dose is

usually considered 300 mg/m2

(under 12 years of age) to 450

mg/m2 (over 12 years of age).

For infants the maximal

cumulative dosages may be

even lower. Doctor may also

perform other tests to monitor

heart function.

Heart muscle damage

(cardiotoxicity) is reported

that appear quickly but that have

a short but severe action.

The doctor will take special care

while the patient is given

Doxorubicin Agila

If the patient has a history

of heart disease

Before starting the treatment with

doxorubicin, the patient should

inform the physician if they are

having any history of heart

problems.

Inform the doctor if the patient

-has been treated with any other

anthracycline drugs or other

drugs that may harm the heart

such as 5-fluorouracil,

cyclophosphamide or paclitaxel

(anti-cancer medicines) or any

drugs that affect the heart

function (like calcium

antagonists).

-have been treated or are due to

be treated with trastuzumab (anti-

cancer medicine) as the doctor

will need to monitor the patients

heart function.



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very commonly (affects more

than 1 user in 10).

The risk increases if the patient

is treated with radiation

therapy or other medicines

toxic to the heart, if the patient

is elderly (over 60 years) or if

the patient has high blood

pressure.

Effects can occur shortly after

treatment or effects can be seen

several years after treatment.

Heart rhythm disorders

(irregular heartbeat, increased

heart rate, decreased heart

rate), contraction of the

chambers of the heart,

reduction in the amount of

blood pumped to the body by

the heart, deterioration of the

function of the heart muscles

(cardiomyopathy) which can

be life threatening are observed

commonly (affects 1 to 10

users in 100). Isolated cases of

life-threatening irregular heart

beat (arrhythmias), left sided

heart failure, inflammation of

-Have been taking digoxin (for

the heart), the effect of digoxin

may decrease.

During the treatment with

doxorubicin, if the patient

experienced any heart problem,

he / she should immediately

consult the physician.



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the lining surrounding the heart

causing chest pain and the

accumulation of fluid around

the heart (pericarditis),

inflammation of the heart

muscle and sack surrounding

the heart (pericarditis-

myocarditis syndrome), loss of

nerve impulses in the heart

(atrioventricular block, bundle

branch block)

Patch of skin that

contrasts with

surrounding tissue

(Cutaneous lesions)

Accidental administration

outside the vein (extravasation)

can cause severe skin

inflammation (cellulitis),

blistering, inflammation of the

vein involving the formation of

a blood clot

(thrombophlebitis),

inflammation in the glands

characterised by painful, red

streaks below the skin surface

(lymphangitis) and localised

cell death which may require

surgery (including skin grafts).

Sensitivity of the skin to

artificial or natural light

(photosensitivity), flushes

Yes,

The patient should inform the

doctor if they have experienced

any skin reaction during the

treatment with Doxorubicin.

- If the patient has a

stinging or burning sensation at

the place where they have been

injected with doxorubicin, it may

be due to leaking of doxorubicin

out of the vein. If this happens,

please tell the doctor as they will

start treatment from a different

vein and will monitor the affected

area carefully.



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(reddening of the skin) are

reported very commonly

(affects more than 1 user in 10)

Allergic reactions at places

where you were treated with

radiation therapy (so-called

radiation recall reaction) is

reported commonly (affects 1

to 10 users in 100).

Skin rash (exanthema), hives

(urticaria), colouring

(pigmentation) of the skin and

nails, injection site reactions

including itching, rash and pain

are reported rarely (affects 1 to

10 users in 10,000).

-Very Rare:

Swelling and numbness of the

hands and feet (acral

erythemas), blistering

-Tissue damage particularly of

the hands and feet, leading to

redness, swelling, blisters,

tingling or burning sensation

caused by the leakage of the

medicinal product into tissues



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(Palmar-plantar

erythrodysaesthesia syndrome)

Cancer (Secondary

neoplasms)

Blood cancer (Secondary

leukaemia), has been reported

in patients treated with these

types of drugs

(anthracyclines). It is more

common when such drugs are

given in combination with

DNA-damaging anti cancer

drug (anti-neoplastic agents),

when patients have been

heavily pre-treated with drugs

that are harmful to cells

(cytotoxic drugs) or when

doses of the type of drugs

(anthracyclines)are increased.

These leukaemias can have a 1

to 3 year latency period.

Doxorubicin in combination

with other cancer medicines

can cause certain forms of

blood cancer (leukaemia).

These forms of cancer are

noticeable within 1-7 years.

Yes.


doxorubicin, the patient should

inform the doctor if taking any

anti-cancer drug.



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Decreased functioning

of the bone marrow

(Myelosuppression)

Bone marrow damage

(myelosupression) including a

reduction in the number of

white blood cells and platelets,

which makes infections more

likely and increases the risk of

bleeding or bruising are


(affects more than 1 user in

10).

Decreased functioning of the

bone marrow

(myelosuppression) by

doxorubicin is dose-dependent

side effects so dose may be

reduced or drug may withdraw

while experiencing such side

effects.

The common symptoms of

damage to the bone marrow are

fever, infections, blood

poisoning, shock (severe drop

in blood pressure, pallor,

restlessness, weak rapid pulse,

clammy skin, reduced

consciousness) as a result of

blood poisoning (septic shock),

bleeding, lack of oxygen in the

Yes




situations:

-If the patient has decreased

blood cell production, decreased

functioning of the bone marrow

(myelosuppression) or

inflammation of the mouth

(stomatitis) due to previous

treatment with cancer drugs

and/or radiation.

The doctor will take special

care while you are given

Doxorubicin Agila

If the patient has a history of

damage to their bone-marrow


doxorubicin the patient should

inform to physician for having

decreased blood cell production,

decreased functioning of the

bone marrow

(myelosuppression). If there is

serious damage to your bone



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tissues (tissue hypoxia) and

tissue death.

marrow the doctor may reduce,

stop or delay treatment.

Inform the doctor if you have

been treated with drugs affecting

the functions of the bone marrow

such as cytostatic agents (e.g.

cytarabine, cisplatin or

cyclophosphamide),

sulfonamides (for infections),

chloramphenicol (for infections),

phenytoin (for epilepsy),

amidopyrine derivatives (for pain

and inflammation), anti-

retroviral drugs (for AIDS). This

may lead to bone marrow damage

causing a decrease in the number

of blood cells.

Bladder inflammation

(Chemical cystitis)

Following the administration

in the bladder, the following

common side effects may be

observed:

- Difficulty, pain or a burning

sensation when passing water

(urinating)

- Decreased quantity of urine

- Increased frequency of

urinating

Yes


given to you intravesically (in the

bladder) in the following

situations:

- If the cancer has spread to the

wall of the bladder

- If the patient has a urinary tract

infection



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- Cramps of the bladder

- Inflammation in the bladder

which sometimes causes blood

in the urine

Local side effects with

administration into the bladder,

such as bladder inflammation

(chemical cystitis) is reported

- If the patient has a bladder

inflammation

- If there are problems with using

a catheter (a tube inserted in the

bladder to drain urine)

- If the patient has blood in the

urine (haematuria).


doctor while experiencing any

bladder inflammation during the

treatment.

Tell the doctor if you:

- have taken

cyclophosphamide (anti-cancer

medicine), the risk of adverse

events of the bladder

(hemorrhagic cystitis, an

infection of the bladder that

causes sometimes blood in the

urine) increases.

Stomach and intestinal

(Gastrointestinal)

disorders

During treatment patient may

experience severe symptoms of

nausea, being sick and

inflammation in the lining of

the mouth or nose.

Inflammation or ulceration of

the lining of the mouth

Yes,

Before starting the treatment, the

patient should inform the doctor

for any history inflammation,

ulceration or diarrhea before



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(stomatitis), nose or throat

(oesophagitis) e.g. mouth

ulcers and cold sores are


(affects more than 1 user in 10).

Ulcers in the lining of the

mouth, throat, gullet, stomach

or intestines, coloration

(pigmentation) of the mouth

lining are reported very rarely

(affects less than 1 user in

10,000).

-Uncommon: Bleeding of the

stomach or intestines,

abdominal pain, ulcers and

death of tissue cells (necrosis)

of the large intestine with

bleeding and infections, in

particular of the large bowel.

This can occur when

doxorubicin is used together

with cytarabine (an anticancer

medicine)

starting the treatment with

Doxorubicin.


doctor if experiencing any

stomach and intestinal disorder

during the treatment.

Liver damage

(Hepatotoxicity)

Severe liver damage which can

sometimes progress to

permanent damage to normal

Yes




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liver tissue (cirrhosis) with

unknown frequency.

Life threatening liver damage

has been reported in patient

taking or took radio therapy

along with doxorubicin.



situations:

- If the patient has a severe

impaired liver function.

Tell the doctor if you have been

treated with 6-mercaptopurine

(anti-cancer medicine), the risk

of adverse events of the liver is

increased.

If the patient has severe problems

with your kidney function or liver

function, a reduction of the dose

may be necessary.

Before starting the treatment, the

patient should inform the doctor

of having any liver disorder or

history of radiotherapy for cancer

treatment.

The doctor should monitor the

patient’s liver function (by blood

tests). A reduction of the dose

may be necessary in case the

liver function is decreased.

Important potential risks



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Risk What is known

Kidney failure (Renal Failure)

A condition where the kidneys stop functioning properly (acute

kidney failure) has been reported very rarely (affects less than 1

user in 10,000). If the patient gets any of these side effects, they

must talk to their doctor or pharmacist.

Lungs disease affecting the

tissue and space around the air

sacs of the lungs (Interstitial

Lung Disease)

Frequency not known:

Radiation damage (to the skin, lungs, throat, gullet, lining of the

stomach and intestines, heart) that is already healing may

reappear with doxorubicin treatment. If the patient gets any of

these side effects, they must talk to their doctor or pharmacist.

Foetal toxicity Animal studies from the literature show that doxorubicin is

poisonous to embryo and foetus.

If you are a woman, you should not get pregnant during

treatment with doxorubicin or up to 6 months after treatment.’If

you are a man, you should take adequate precautions to ensure

that your partner does notbecome pregnant during your

treatment with doxorubicin or up to 6 months after treatment. If

you are considering becoming parents after the treatment please

discuss with your doctor.

Doxorubicin is not recommended if you are pregnant.

Breast-feeding must be discontinued for the duration of

Doxorubicin Agilatherapy.

Missing information

Risk What is known

Nil



Limited 158

VI.2.5 Summary of risk minimisation measures by safety concern

All medicines have a Summary of Product Characteristics (SmPC) which provides physicians,

pharmacists and other health care professionals with details on how to use the medicine, the risks

and recommendations for minimizing them. An abbreviated version of this in lay language is

provided in the form of the package leaflet (PL). The measures in these documents are known as

routine risk minimisation measures.

This medicine has no additional risk minimisation measures.

VI.2.6 Planned post authorisation development plan

No studies planned

VI.2.7 Summary of changes to the risk management plan over time

Version Date Safety Concern Comment

2.0 Following safety concerns are

added:

Important identified risk:

Cutaneous lesions

Secondary neoplasms

Myelosuppression

Important potential risk:

Renal Failure

Interstitial Lung Disease

Foetal toxicity

RMP Part V: Risk

Minimisation

Measures and Part VI

Summary of the risk

management plan by

productupdated, based

on the Day 120

comments from The

Netherlands



Limited 159

Version Date Safety Concern Comment

Following safety concerns are

deleted:

Important identified risk:

Hypersensitivity

Mutagenesis

Impairment of fertility

legal status: prescription only product vi.2 elements for

Documents