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PACKAGE LEAFLET: INFORMATION FOR THE USER

Hydroxyurea 500 mg capsules, hard

Hydroxycarbamide

Read all of this leaflet carefully before you start taking this medicine.

-    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. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

-    If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1.    What Hydroxyurea is and what it is used for

2.    Before you take Hydroxyurea

3.    How to take Hydroxyurea

4.    Possible side effects

5.    How to store Hydroxyurea

6.    Further information

1. WHAT HYDROXYUREA IS AND WHAT IT IS USED FOR

Hydroxyurea is used for the treatment of patients :

•    with an aggressive white blood cell disease starting at the bone marrow (chronic myeloid leukaemia) in a chronic or accelerated phase of the disease

•    with a surplus of blood platelets (essential thrombocythaemia)

•    with a surplus of certain blood cells (polycythaemia vera) associated with a high risk of vascular occlusion (thrombosis)

Hydroxyurea is a medicine to treat tumour diseases.

2. BEFORE YOU TAKE HYDROXYUREA

Do not take Hydroxyurea

•    if you are hypersensitive (allergic) to hydroxycarbamide or any of the other ingredients of Hydroxyurea. Therapy should be discontinued if hypersensitivity to Hydroxyurea occurs.

•    if the function of the bone marrow is considerably reduced, such as

-    reduced number of white blood cells (less than 2.5 x 10⁹ leukocytes/l)

-    deficiency of blood platelets (less than 100 x 10⁹ thrombocytes/l)

-    severe anaemia.

•    if you are breastfeeding.

•    if you are concomitantly treated with yellow fever vaccine.

Take special care with Hydroxyurea

•    if you suffer from impaired liver and/or kidney function.

Only little experience is available regarding this. Special caution is therefore required during treatment with Hydroxyurea, particularly at the beginning of therapy. The blood values as well as liver and kidney function are to be monitored by a doctor during treatment with Hydroxyurea.

•    if you suffer from anaemia or if it occurs.

Red blood cells can be replaced, if necessary. Their formation from abnormally large precursors is often to be observed only when treatment is started and it resembles the anaemia due to vitamin B₁₂ deficiency. However, this is not attributable to too little vitamin B₁₂ or folic acid.

•    if you notice skin changes.

These require further observation, as certain types of skin cancer can occur in isolated cases.

•    if you notice painful ulcers on the lower legs.

These are usually difficult to treat and can require interruption of treatment. Discontinuation of hydroxycarbamide usually enables the ulcers to slowly heal after some weeks.

•    if you receive long-term treatment in cases of excessive formation of blood cells such as polycythaemia vera and thrombocythaemia.

Another white blood cell cancer can develop. The extent to which this relates to the underlying disease or treatment with hydroxycarbamide is unknown to date.

•    if you experience impaired blood formation in the bone marrow.

A considerable reduction in white blood cells is the first and most common sign. A considerable reduction in blood platelets and anaemia occur less frequently and rarely without preceding leukopenia.

•    if you are given other anticancer drugs or radiotherapy treatment.

•    if you are concomitantly treated with live attenuated vaccines (expected yellow fever vaccines see “Do not take Hydroxyurea”).

The risk of an inflammation of the blood vessels of the skin, including blood vessel ulcerations and deterioration, is increased. Severe skin blood vessel ulcers have been reported in patients with myeloproliferative disease. Hydroxycarbamide should therefore be discontinued if such ulcerations develop. In addition, alternative medicines should be used if necessary.

The following parameters should be observed in the blood count during treatment with Hydroxyurea, even after the optimal dose has been established:

-    content of red blood pigment

-    differentiation of white blood cells

-    number of blood platelets

The control interval must be individualised, but is normally once a week.

It is important to monitor uric acid levels regularly. You should always drink sufficient liquid during treatment with Hydroxyurea.

Appropriate contraceptive measures are to be taken if one partner is treated with Hydroxyurea.

Men undergoing treatment with Hydroxyurea should not father a child during treatment and up to 1 year afterwards. Seek advice on sperm conservation before beginning therapy as hydroxycarbamide therapy can cause transient infertility. If pregnancy is desired, specialized counselling is recommended even after therapy.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

• Other medicines against tumour diseases or radiotherapy

Side effects can be more intense and more common than after administration of Hydroxyurea alone. These side effects include the suppression of blood formation in the bone marrow, stomach and bowel complaints and inflammation in the mouth cavity. Enhancement of inflammatory reddening of the skin caused by previous or concomitant radiotherapy is possible.

Laboratory tests have shown that hydroxycarbamide enhances the toxicity of certain medicines against tumour diseases, e.g. of

-    fluoropyrimidines (e.g. fluorouracil) and

-    cytarabine

It is not clear whether these interactions are additive in their toxicity during use in humans and whether the dose must be adjusted.

•    Medicines against viral diseases (nucleoside analogues, medicines for the treatment of a HIV infection) Conditions such as, inflammation of the pancreas, liver damage, sometimes lethal, and severe peripheral nervous conditions have all been reported. Combination with medicines to treat viral diseases cannot be recommended.

•    Prior or concomitant interferon therapy

The risk of an inflammation of the blood vessels of the skin, including blood vessel ulcerations and deterioration, is increased in patients who receive prior or concomitant interferon therapy.

•    Yellow fever vaccine

There is a risk of generalised vaccinale disease, which can be fatal, therefore concomitant use is contraindicated (see section “Do not take Hydroxyurea”).

•    Live attenuated vaccines (except yellow fever)

There is a risk of systemic, possible fatal disease. This risk is increased if you are already immunosuppressed by your underlying disease. An inactivated vaccine should be used where this exists (poliomyelitis).

•    Ciclosporine, Tacrolimus

Concomitant use is to be taken into consideration because of an excessive immunosuppression with risk of lymphoproliferation.

Pregnancy and breast-feeding

Hydroxyurea may impair the development of your unborn child. You must therefore not use Hydroxyurea during pregnancy. Women of childbearing potential should take contraceptive measures before starting and during treatment with Hydroxyurea. If a patient intends to become pregnant after a therapy with hydroxycarbamide a specialized consultation is recommended.

If a doctor deems the use absolutely necessary during pregnancy, he/she should inform you about the possible risk for your child. If you become pregnant during treatment with Hydroxyurea, inform your doctor without delay, and make use of the possibility of specialized counselling.

You must not use Hydroxyurea while breast-feeding. If treatment is recommended by a doctor, you must stop breast-feeding.

Driving and using machines

Reactivity can be impaired during treatment with Hydroxyurea. In this case, do not drive a car, and do not operate hazardous machines.

3. HOW TO TAKE HYDROXYUREA

Treatment should be conducted only by experienced specialists.

Always take Hydroxyurea exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The capsules should be swallowed as a whole and must not disintegrate within the mouth.

The dosages stated in the following are based on the patient’s actual or ideal weight, whichever is the less. Your doctor determines the number of capsules and the duration of treatment.

•    Aggressive white blood cell disease

(chronic myeloid leukaemia)

Depending on the number of white blood cells, the initial dose is usually 40 mg hydroxycarbamide per kg bodyweight daily.

Your doctor will reduce the dose to 20 mg per kg daily if the number of white blood cells falls below 20 x 10⁹/l. The dose is then adjusted on an individual basis in order to keep the number of white blood cells at 5-10 x 10⁹/l.

If the white blood cells are less than 5 x 10⁹ per litre, the dosage should be reduced, and it should be increased if they are above 10 x 10⁹/l.

If the white blood cells fall below 2.5 x 10⁹/l or the blood platelets below 100 x 10⁹/l, your doctor should interrupt therapy until the values normalize.

An appropriate test time to determine the efficacy of Hydroxyurea is 6 weeks. Your doctor will discontinue therapy if the disease is progressing. If there is a response, therapy can be continued indefinitely.

•    Surplus of blood platelets

(essential thrombocythaemia)

For this disease, the initial dose is usually 15 mg hydroxycarbamide per kg bodyweight daily. This should keep the number of blood platelets below 600 x 10⁹/l without reducing the number of white blood cells below 4 x 10⁹/l.

•    Surplus of certain blood cells

(polycythaemia vera)

In this case, treatment should be started with a dosage of 15-20 mg hydroxycarbamide per kg bodyweight daily. The dose is to be adjusted on an individual basis in order to keep the ratio between red blood cells and blood plasma below 45% and the number of blood platelets below 400 x 10⁹/l.

This can be achieved in most patients with a continuous administered dose of 1 to 2 hard capsules daily on average. If the ratio of red blood cells to blood plasma and the number of blood platelets remain stable, treatment should be continued indefinitely.

Children

As these diseases only rarely occur in children, no dosage schemes can be established at present.

Elderly patients

Elderly patients can have a more pronounced reaction to the effect of hydroxycarbamide and possibly require a lower dosage.

Patients with impaired liver or kidney function

Recommendations cannot be given for these patients as no data exists to date.

If you take more Hydroxyurea than you should

If the dosage taken was several times more than the recommended dosage, the following acute skin and/or mucosal changes may be signs of an overdose:

soreness

•    violet skin rash

•    swellings on palms and soles, followed by scaling of hands and feet

•    sore feet

•    excessive generalised pigmentation

•    severe acute inflammation of oral mucosa

Immediately inform a doctor if an overdose occurs. Immediate treatment consists of stomach irrigation, followed by supportive measures and monitoring of the blood formation.

If you forget to take Hydroxyurea

Do not take a double dose if you have forgotten the previous intake. Go back to your original directions for your next dose. If you are unsure contact your doctor.

If you stop taking Hydroxyurea

Your disease might worsen if therapy is discontinued.

Therapy with hydroxycarbamide may be terminated or interrupted only on the orders of the attending doctor. If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

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

The strength of suppressed blood formation of the bone marrow determines the dosage or whether therapy must be interrupted in rare cases.

Side effects affecting the stomach or the intestine only rarely require dose reduction or cessation of treatment. Side effects can occur with the following frequencies:

Common, occurs in 1 to 10 per 100 users

•    suppressed blood formation in the bone marrow

•    reduced number of white blood cells (you are more prone to catch infections)

•    changes in the red blood count (megaloblastosis)

Possible changes in the red blood count which do not respond to treatment with folic acid or vitamin B_J2 subside when therapy is discontinued.

•    diarrhoea

•    constipation

Uncommon, occurs in 1 to 10 per 1,000 users

•    reduced number of blood platelets (you are more prone to bruising, bleeding)

•    anaemia (feeling tired)

•    nausea, vomiting, loss of appetite

•    inflammation of oral mucosa

•    drug fever

•    chills

•    feeling unwell

•    flaky, knotty inflamed skin, skin rash

•    inflammatory reddening affecting face, arms and legs

•    elevated liver enzymes

•    elevated bilirubin

•    transient disorders of tubular kidney function with increase in uric acid, urea and creatinine in blood

Rare, occurs in 1 to 10 per 10,000 users

•    allergic reactions

•    hair loss

•    rare disorders of nerve function including headache, dizziness, disorientation, hallucinations and fits

•    development of an acute lung reaction with accumulation of liquid in the lung, fever, shortness of breath

•    allergic reactions in the lungs

•    difficult or painful urination (dysuria)

•    Potentially life-threatening metabolic complications that can occur after treatment of cancer leading to increased uric acid level in the blood, which may result in gout or acute renal failure (tumour lysis syndrome)

Very rare, occurs in fewer than 1 per 10,000 users

In isolated cases after maintenance therapy for several years with daily intake of hydroxycarbamide:

•    variable skin changes such as reddening and swelling

•    excessive pigmentation on skin and nails

•    thinning of skin and nails

•    ulcers of the lower legs

•    itching

•    small, rough reddish patches on the skin, which may become skin cancer if not removed (actinic keratosis)

•    skin cancer

•    violet nodules

•    skin scaling

•    impaired kidney function

•    cutaneous ulcers (especially ulcers of the lower legs)

Another white blood cell cancer can develop in patients with excessive formation of blood cells and continuously treated with hydroxycarbamide. It is not known whether this is attributable to the underlying disease or to the treatment with hydroxycarbamide.

Severe stomach complaints such as nausea, vomiting and loss of appetite, which can occur in combination with radiotherapy, can be controlled if administration of hydroxycarbamide is transiently stopped.

Hydroxycarbamide can enhance mucosal inflammations caused by radiation. Inflammatory reddening and excessive pigmentation can occur in pretreated tissue.

Inflammation of the blood vessels of the skin, including blood vessel ulcerations and deterioration, have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. This was reported most often in patients with a history of, or currently receiving, interferon therapy (see “Taking other medicines”).

High doses can cause moderate sleepiness.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE HYDROXYUREA

Keep out of the reach and sight of children.

Do not store above 30 °C.

Do not use the medicine after the expiry date which is stated on the pack. The expiry date refers to the last day of that month.

The medicine should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION What Hydroxyurea contains

•    The active substance is hydroxycarbamide

1 capsule, hard contains 500 mg hydroxycarbamide.

•    The other ingredients are:

Capsule contents

Citric acid anhydrous, disodium hydrogen phosphate anhydrous, magnesium stearate Capsule shell

Gelatin, ferric oxide, yellow, titanium dioxide

What Hydroxyurea looks like and contents of the pack

Capsule, hard with white lower part and yellow upper part

Hydroxyurea 500 mg capsules, hard are available in PVC/PVDC/aluminium-blister packs of 20, 25, 50, 100 and 120 capsules.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer Marketing Authorisation

Hexal AG, Industriestrasse 25, 83607 Holzkirchen, Germany.

Manufacturer

AMAREG GmbH, Donaustaufer Str. 378, 93055 Regensburg, Germany or

Salutas Pharma GmbH, Otto-von-Guericke-Allee 1, 39179 Barleben,

Germany

This leaflet was last approved in 09/2009