Possible Side Effects

Like all medicines, Bendamustine ACTe can cause side effects, although not everybody gets them. Some of the findings listed below may be found after tests are performed by your doctor.

Tissue decay (necrosis) has been observed very rarely following leakage of Bendamustine ACTe into the tissue outside the blood vessels (extravascular). A burning sensation where the infusion needle is inserted may be a sign of leakage outside
the blood vessels. The consequence can be pain and poorly healing skin defects. The dose-limiting side effect of Bendamustine ACTe is impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone marrow function may lead to low counts of blood cells, which in turn may lead to an increased risk of infection, anaemia or a heightened risk of bleeding.

Very common (may affect more than 1 in 10 people):

• Low counts of white blood cells (disease-fighting cells in your blood)
• Decrease in the red pigment of the blood (haemoglobin: a protein in red bloodcells that carries oxygen throughout the body)
• Low counts of platelets (colourless blood cells that help blood clot)
• Infections
• Feeling sick (nausea)
• Vomiting
• Mucosal inflammation
• Headache
• Increased blood level of creatinine (a chemical waste product that is produced by yourmuscle)
• Increased blood level of urea (a chemical waste product)
• Fever
• Fatigue

Common (may affect up to 1 in 10 people):
• Bleeding (haemorrhage)
• Disturbed metabolism caused by dying cancer cells releasing their contents into the blood stream
• Reduction in red blood cells which can make the skin pale and cause weakness or breathlessness (anaemia)
• Low counts of neutrophils (a common type of white blood cell important to fighting off infections)
• Abnormally low concentration of neutrophils (a type of white blood cell) in the blood leading to increased susceptibility to infection (neutropenia)
• Hypersensitivity reactions such as allergic inflammation of the skin (dermatitis), nettle rash (urticarial)
• 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)
• Disturbed function (dysfunction) of the heart
• Disturbed heart rhythms (arrhythmia)
• Low or high blood pressure (hypotension or hypertension)
• Disturbed lung function
• Diarrhoea
• Constipation
• Sore mouth (stomatitis)
• Loss of appetite
• Hair loss
• Skin changes
• Missed periods (amenorrhoea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy rash (urticarial)

Uncommon (may affect up to 1 in 100 people):
• Accumulation of fluid in the heart sac (escape of fluid into the pericardial space)
• Ineffective production of all blood cells in the bone marrow (the spongy material inside your bones where blood cells are made)
• Acute leukaemia
• Heart attack, chest pain (myocardial infarct)
• Heart failure

Rare (may affect up to 1 in 1,000 people):
• Infection of the blood (sepsis)
• Severe allergic hypersensitivity reactions (anaphylactic reactions)
• Signs similar to anaphylactic reactions (anaphylactic reactions)
• Drowsiness
• Loss of voice (aphonic)
• Acute circulatory collapse (failure of blood circulation mainly from a cardiac origin with failure to maintain the supply of oxygen and other nutrients to the tissues and removing toxins)
• Reddening of the skin (erythema)
• Inflammation of the skin (dermatitis)
• Itching (pruritus)
• Skin rash (macular exanthema)
• Excessive sweating (hyperhidrosis)
• Reduction in your bone marrow function, which may make you feel unwell or show up in your blood tests

Very rare (may affect up to 1 in 10,000 people):
• Primary atypical inflammation of the lungs (pneumonia)
• Breakdown of red blood cells
• Rapid decrease in blood pressure sometimes with skin reactions or rash (anaphylactic shock)
• Disturbed sense of taste
• Altered sensations (paraesthesia)
• Malaise and pain in the limbs (peripheral neuropathy)
• Serious conditions resulting in the blockade of specific receptors in the nervous system
• Disorders of the nervous system
• Lack of coordination (ataxia)
• Inflammation of the brain (encephalitis)
• Increased heart rate (tachycardia)

• Inflammation of the veins (phlebitis)
  • Formation of tissue in the lungs (fibrosis of the lungs)
  • Bleeding inflammation of the gullet (haemorrhagic oesophagitis)
  • Bleeding of stomach or gut
  • Infertility
  • Multiple organ failure

Not known (frequency cannot be estimated from the available data):
• Renal failure
• Liver failure
• Irregular and often rapid heart rate (atrial fibrillation)
• Painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membranes (e.g. mouth and lips), in particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) and/or fever.
• Pneumonitis
• Bleeding from the lungs
There have been reports of tumours (myelodysplastic syndrome, AML, bronchial carcinoma) following treatment with Bendamustine ACTe. No clear relationship with Bendamustine ACTe could be determined.

Contact your doctor or seek medical attention immediately if you notice any of the following side effects (frequency not known):
Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis. These can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms.
Widespread rash, high body temperature, enlarged lymph nodes and other body organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also known as DRESS or drug hypersensitivity syndrome).
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

The following information is intended for healthcare professionals only:
As with all similar cytotoxic substances, stricter safety precautions apply as far as nursing staff and doctors are concerned, due to the potentially genome-damaging and cancer-causing effect of the preparation. Avoid inhalation (breathing in) and contact with the skin and mucous membranes when handling Bendamustine ACTe (wear gloves, protective clothing, and possibly a face mask!). If any parts of the body become contaminated, clean them carefully with soap and water, and flush the eyes with 0.9% (isotonic) saline solution. If possible, it is advisable to work on a special safety work bench (laminar flow) with a disposable absorbing sheet that is impermeable to liquids. Contaminated articles are cytotoxic waste. Please comply with national guidelines on the disposal of cytotoxic material. Pregnant staff must be excluded from working with cytostatics.
The concentrate for solution for infusion has to be diluted with sodium chloride 9mg/ml (0.9%) solution for injection and then administered by intravenous infusion. Aseptic technique is to be used.

1. Preparation of the concentrate

• One vial of Bendamustine ACTe containing 25 mg of bendamustine hydrochloride is first dissolved in

10 ml by shaking

• One vial of Bendamustine ACTe containing 100 mg of bendamustine hydrochloride is first dissolved

in 40 ml by shaking

2. Preparation of the solution for infusion

As soon as a clear solution is obtained (generally after 5 – 10 minutes), the total recommended dose of Bendamustine ACTe is immediately diluted with 0.9% (isotonic) saline solution to obtain a final volume of approximately 500 ml. Bendamustine ACTe must not be diluted with other solutions for infusion or injection. Bendamustine ACTe must not be mixed in an infusion with other substances.

3. Administration
   The solution is administered by intravenous infusion over 30 – 60 min. The vials are for single dose use. Product should be inspected before use. When inspected, visible particles in the solution or discolouration of solution are a sign of deterioration. Deteriorated medicinal product must not be used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Unintentional injection into the tissue outside blood vessels (extravasal injection) should be stopped immediately. The needle should be removed after a short aspiration. Thereafter the affected area of tissue should be cooled. The arm
   should be elevated. Additional treatments like the use of corticosteroids are not of clear benefit.

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