Ribomustin™ 25 mg/100 mg Solution

RIBOMUSTIN is a medicine which is used for the treatment of certain types of cancer (cytotoxic medicine).

RIBOMUSTIN is used alone (monotherapy) or in combination with other medicines for the treatment of the following forms of cancer:

• chronic lymphocytic leukaemia
• non-Hodgkin lymphoma which was not treated before, in combination treatment with rituximab or which had not, or only shortly, responded to prior rituximab treatment (monotherapy)
• multiple myeloma.

You should not receive RIBOMUSTIN

• if you are hypersensitive (allergic) to bendamustine hydrochloride or to mannitol
• during pregnancy or if you are breastfeeding your baby
• if you have severe liver damage (damage to the functional cells of the liver)
• if you have yellowing of the skin or whites of the eyes caused by liver or blood problems (jaundice)
• if you have severely disturbed bone marrow function (bone marrow depression) and serious changes in the number of white blood cells and platelets in your blood (white blood cells and/or thrombocyte values drop to < 3 x 10 9 /ℓ or < 75 x 10 9 /ℓ, respectively)
• if you have had major surgical operations less than 30 days before starting treatment
• if you have an infection, especially one accompanied by a reduction in white blood cells (leukopenia)
• in combination with yellow fever vaccines or other live attenuated vaccines.
• If you have an irregular heart rhythm
• If you are taking any medicines that may cause you to have an irregular heart rhythm

Warnings and precautions

You must take special care with RIBOMUSTIN:

• if you get severe allergic or hypersensitivity reactions: You should pay attention to infusion reactions after your first cycle of therapy.
• if you have a reduced capability of the bone marrow to replace blood cells: You should have your full blood count checked before starting treatment with RIBOMUSTIN, before each subsequent course of treatment and in the intervals between courses of treatment.
• if you have any infections which may include TB (tuberculosis): You should contact your doctor if you have signs of infection, including fever or lung symptoms.
• if you get skin reactions during treatment with RIBOMUSTIN: These reactions may get worse with later courses.
• if you have an existing heart disease (e.g. heart attack, chest pain, disturbed heart rhythm).
• Anti-nausea medicine should be given to help control the nausea and vomiting
• if you notice blood in your urine or a reduced amount of urine: When your disease is very severe, your body may not be able to clear all the waste products from the dying cancer cells. This is called tumour lysis syndrome and can cause kidney failure and heart problems within 48 hours of the first dose of RIBOMUSTIN. Your doctor will be aware of this and may give you medicines to help prevent it.
• If you have or had Hepatitis-B virus
• If you are a man receiving treatment with RIBOMUSTIN, you should not father a child during your treatment and for up to 3 months afterwards. Before starting treatment, you should seek advice on storing your sperm cells because of the possibility of permanent infertility. (see Pregnancy and breastfeeding).

If you are a woman of childbearing age you should use highly effective form of contraception for at least 6 months after treatment.

Unintentional injection into the tissue outside blood vessels (extravasal injection) may cause local tissue damage. Your doctor will treat this.

Other medicines and RIBOMUSTIN

Always tell your healthcare provider if you are taking any other medicine. (This includes all complementary or traditional medicines.)

If RIBOMUSTIN is used in combination with medicines which inhibit the formation of blood in the bone marrow, the effect on the bone marrow may be intensified.

You should not be given live attenuated (weakened) vaccines if you are being treated with RIBOMUSTIN. RIBOMUSTIN may lessen the effectiveness of live-virus vaccination. Additionally, RIBOMUSTIN increases the risk of an infection after vaccination with live vaccines (e.g. viral vaccination).

If you use RIBOMUSTIN in combination with medicines which alter your immune response (ciclosporin or tacrolimus), the effect may be intensified.

You will not be expected to give yourself RIBOMUSTIN. It will be given to you by a person who is qualified to do so.

RIBOMUSTIN is administered into a vein over 30 - 60 minutes in various dosages, either alone (monotherapy) or in combination with other medicines.

Treatment should not be started if your white blood cells (leukocytes) have fallen to counts below 3 x 10 9 /ℓ and/or your blood platelets have fallen to counts below 75 x 10 9 /ℓ. Your doctor will determine these values at regular intervals.

Impaired liver or kidney function

Depending on how well your liver or kidneys function, it may be necessary to adjust your dose. Your attending doctor will decide whether a dosage adjustment is necessary.

How it is administered

Treatment with RIBOMUSTIN will be undertaken only by doctors experienced in cancer therapy. Your doctor will give you the exact dose of RIBOMUSTIN and use the necessary precautions.

Your attending doctor will administer the solution for infusion. The solution is administered into a vein as a short-term infusion over 30 – 60 minutes.

Duration of use

There is no time limit laid down as a general rule for treatment with RIBOMUSTIN. Duration of treatment depends on your disease and your response to treatment.

If you are at all worried or have any questions regarding treatment with RIBOMUSTIN, please speak to your doctor.

If you are given too much RIBOMUSTIN

Since a healthcare provide will administer RIBOMUSTIN, he/she will control the dosage. However, in the event of overdosage, your doctor will manage the overdosage.

If you forget to use RIBOMUSTIN

Since a healthcare provider will administer RIBOMUSTIN, it is unlikely that a dose will be missed.

RIBOMUSTIN can have side effects. Not all side effects reported for RIBOMUSTIN are included in this leaflet. Should your general health worsen or if you experience any untoward effects while taking RIBOMUSTIN, please consult your healthcare provider for advice.

Tissue death (necrosis) has been less frequently observed following unintentional injection into the tissue outside blood vessels (extravascular). A burning sensation where the infusion needle is inserted may be a sign of injection into tissue outside the blood vessels. This can cause pain and poorly healing skin defects.

RIBOMUSTIN can cause impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone-marrow function increases the risk of infection.

Frequent:

• Low counts of white blood cells (disease-fighting cells in your blood)
• Decrease in the red cells of the blood (haemoglobin: a protein in red blood cells that carries oxygen throughout the body)
• Low counts of platelets (colourless blood cells that help blood clot)
• Low counts of neutrophils (a common type of white blood cells important for fighting off infections)
• Infections including TB
• Hypersensitivity reactions such as allergic inflammation of the skin (dermatitis), rash (urticaria)
• Fatigue
• Feeling sick (nausea)
• Vomiting
• Fever
• Mucosal inflammation
• Bleeding (haemorrhage)
• Increased blood level of creatinine (a chemical waste product that is produced by your muscle)
• Increased blood level of urea (a chemical waste product)
• A rise in liver enzymes AST/ALT (which may indicate inflammation or damage to cells in the liver)
• A rise in the enzyme alkaline phosphatase (an enzyme made mostly in the liver and bones)
• A rise in bile pigment (a substance made during the normal breakdown of red blood cells)
• Low potassium blood levels (a nutrient that is necessary for the function of nerve and muscle cells, including those in your heart)
• Impaired function (dysfunction) of the heart
• Palpitations
• Low or high blood pressure (hypotension or hypertension)
• Impaired lung function
• Disturbed metabolism caused by dying cancer cells releasing their contents into the bloodstream
• Reduction in red blood cells which can make the skin pale and cause weakness (anaemia)
• Diarrhoea
• Constipation
• Dehydration
• Sore mouth (stomatitis)
• Loss of appetite
• Hair loss
• Skin changes
• Missed periods (amenorrhoea)
• Pain
• Insomnia
• Chills.

Less frequent:

• Accumulation of fluid in the heart sac (escape of fluid into the pericardial space)
• Infection of the blood (sepsis)
• Acute leukaemia
• Severe allergic hypersensitivity reactions (anaphylactic reactions)
• Signs similar to anaphylactic reactions (anaphylactoid reactions)

Keep out of the reach and sight of children.

Storage conditions: Store at or below 25 °C. Keep the vial in the outer carton to protect the contents from light.

Note on shelf-life after opening or preparing the solution

Solutions for infusions prepared according to the directions listed are stable in polyethylene bags at 25 °C for 3,5 hours, and in a refrigerator, they are stable for 2 days. RIBOMUSTIN contains no preservatives. The solutions should therefore not be used after these lengths of time.