BENDAMUSTINE GLENMARK

Package leaflet: Information for the user

Bendamustine Glenmark, 2.5 mg/ml, powder for concentrate for solution for infusion
Bendamustini hydrochloridum
Please read all of this leaflet carefully before 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 symptoms 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.

Contents of the leaflet

1. What Bendamustine Glenmark is and what it is used for
2. What you need to know before using Bendamustine Glenmark
3. How to use Bendamustine Glenmark
4. Possible side effects
5. How to store Bendamustine Glenmark
6. Contents of the pack and other information

1. What Bendamustine Glenmark is and what it is used for

Bendamustine Glenmark is a medicine used in the treatment of certain types of cancer (a cytostatic agent).
Bendamustine Glenmark is used either as a single agent (monotherapy) or in combination with other medicines for the treatment of the following cancers:

• chronic lymphocytic leukaemia when treatment with chemotherapy containing fludarabine is not recommended,
• non-Hodgkin's lymphomas that did not respond or responded only briefly to prior treatment with rituximab,
• multiple myeloma when treatment with thalidomide or bortezomib-containing chemotherapy is not recommended.

2. What you need to know before using Bendamustine Glenmark
When not to use Bendamustine Glenmark:

• if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);
• during breastfeeding; if treatment with Bendamustine Glenmark is necessary during this period, breastfeeding must be discontinued (see section on warnings and precautions during breastfeeding);
• if you have severe liver damage (severe impairment of liver parenchymal cells);
• if you have jaundice (yellowing of the skin or whites of the eyes) caused by liver dysfunction or blood disorders (jaundice);
• if you have severe bone marrow dysfunction (bone marrow suppression) with significant changes in white blood cell and platelet counts;
• if you have undergone extensive surgery within 30 days prior to starting treatment;
• if you have an infection, especially with accompanying low white blood cell count (leukopenia);
• if you have been vaccinated against yellow fever.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Bendamustine Glenmark.

• if you have reduced bone marrow function in producing blood cells. Your doctor will check your white blood cell and platelet counts before starting treatment with Bendamustine Glenmark, before each subsequent treatment cycle, and during treatment breaks.
• if you have an infection. Contact your doctor if you develop signs of infection, including fever and respiratory symptoms.
• if you develop skin reactions during treatment with Bendamustine Glenmark. Skin reactions may worsen.
• if you develop a painful red or purplish rash that spreads, blisters, and/or other lesions starting on mucous membranes (e.g. in the mouth or lips), particularly if you previously had photosensitivity, respiratory tract infections (e.g. bronchitis), and/or fever.
• if you have pre-existing heart disease (e.g. heart attack, chest pain, severe cardiac arrhythmias).
• if you experience pain in your side, blood in your urine, or reduced urine output. If you have advanced disease, your body may be unable to eliminate substances produced by tumour cell breakdown. This is known as tumour lysis syndrome, which may cause kidney dysfunction and heart problems within 48 hours after the first dose of Bendamustine Glenmark. Your doctor may ensure you are adequately hydrated and may administer other medicines to prevent this.
• if you experience severe allergic reactions or hypersensitivity reactions. You should be aware of reactions occurring after the first treatment cycle.

Tell your doctor immediately if at any time during or after treatment you notice the following symptoms: memory loss, problems with thinking, difficulty walking, or loss of vision — these may be caused by a very rare but serious brain infection (progressive multifocal leukoencephalopathy, PML), which can be fatal.
If you notice any suspicious skin changes, contact your doctor due to an increased risk of certain types of skin cancer (non-melanoma skin cancer) associated with this medicine.

Children and adolescents
There is no clinical experience with the use of bendamustine hydrochloride in children and adolescents.

Bendamustine Glenmark and other medicines
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
If Bendamustine Glenmark is used together with medicines that suppress bone marrow function in blood cell production, the effect on bone marrow may be intensified.
If Bendamustine Glenmark is used together with medicines that affect the immune system, this effect may be enhanced.
Cytostatic medicines may reduce the effectiveness of vaccines containing live viruses. Cytostatic medicines also increase the risk of infections following vaccination with live vaccines (e.g. antiviral vaccines).

Pregnancy, breastfeeding and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, talk to your doctor or pharmacist before using this medicine.

Pregnancy
Bendamustine Glenmark may cause genetic damage and developmental abnormalities in animals. Bendamustine Glenmark must not be used during pregnancy unless considered absolutely necessary by your doctor. If treatment must be started, discuss with your doctor the possible adverse effects on the unborn child and consider genetic testing.
Women of childbearing potential should use effective contraception both before and during treatment with Bendamustine Glenmark. If you become pregnant while taking Bendamustine Glenmark, inform your doctor immediately and undergo genetic testing.

Breastfeeding
Bendamustine Glenmark must not be used during breastfeeding. If treatment with Bendamustine Glenmark is necessary, breastfeeding must be discontinued.

Talk to your doctor or pharmacist before taking any medicine.

Fertility
Men receiving Bendamustine Glenmark are advised not to plan fathering a child during treatment and for 6 months after its completion. Before starting treatment, men should seek advice regarding the possibility of sperm preservation due to the risk of permanent infertility.
Men should not plan to father a child while taking Bendamustine Glenmark or for 6 months after treatment ends. There is a risk that Bendamustine Glenmark may cause infertility; therefore, men should seek advice before treatment regarding the possibility of sperm preservation.

Driving and using machines
Bendamustine Glenmark has a marked influence on the ability to drive and use machines. Do not drive or operate machinery if you experience side effects such as dizziness or coordination problems.

3. How to use Bendamustine Glenmark

The medicine should always be used exactly as directed by the doctor or pharmacist. If in doubt, consult
the doctor or pharmacist.
Bendamustine Glenmark is administered intravenously at varying doses over 30–60 minutes, either as a
single agent (monotherapy) or in combination with other antineoplastic drugs.
Treatment should not be initiated if the white blood cell (leukocyte) count and/or platelet count fall
below the level determined by the physician.
The doctor will monitor these parameters at regular intervals.
Chronic lymphocytic leukemia

Repeat the cycle every 4 weeks, up to 6 times
Non-Hodgkin's lymphomas

Multiple myeloma

Treatment should be discontinued if the white blood cell (leukocyte) and/or platelet count decreases
below the level determined by the physician. Treatment may be continued if the white blood cell and
platelet counts increase.
Liver or kidney function disorders
Depending on the severity of liver function impairment, dose adjustment may be necessary (by 30% in cases
of moderate liver dysfunction). Dose adjustment is not required in patients with kidney function disorders.
The treating physician will decide whether dose adjustment is necessary.
Method of administration
Treatment with Bendamustine Glenmark should only be initiated by physicians experienced in cancer therapy.
The physician will administer the appropriate dose of Bendamustine Glenmark and apply necessary precautionary measures.
The treating physician will administer the infusion solution after it has been prepared according to the instructions.
The solution is administered intravenously as a short-term infusion over 30–60 minutes.
Treatment duration
There are no general guidelines regarding the duration of treatment with Bendamustine Glenmark. The length of
treatment depends on the disease and the patient's response to therapy.
If the patient has any doubts or questions about treatment with Bendamustine Glenmark, they should consult
their physician or nurse.
Missed dose of Bendamustine Glenmark
If a dose of Bendamustine Glenmark is missed, the physician will usually continue treatment according to
the established dosing schedule.
Discontinuation of Bendamustine Glenmark
The treating physician will decide whether to discontinue treatment or switch to another medication.
In case of any further doubts regarding the use of this medicine, consult your physician or pharmacist.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will experience them.
Some of the adverse reactions described below may only be identified after assessment
performed by a physician.
In evaluating adverse reactions, the following frequency definitions are used:
Very common: affects more than 1 in 10 people
Common: affects less than 1 in 10 people
Uncommon: affects less than 1 in 100 people
Rare: affects less than 1 in 1,000 people
Very rare: affects less than 1 in 10,000 people
Frequency not known: frequency cannot be determined from available data

Very rarely, tissue necrosis (tissue death) has been observed following accidental leakage of the drug into surrounding tissue outside the blood vessel (extravasation). A sign of such leakage may be a burning sensation at the site of needle insertion. Consequences of leakage may include pain and a slow-healing wound.

A side effect of Bendamustine Glenmark requiring dose reduction is bone marrow dysfunction, which usually returns to normal after treatment ends. Suppression of bone marrow function may lead to a reduced number of blood cells, which in turn may increase the risk of infection, anaemia, or bleeding.

Very common: may affect more than 1 in 10 patients

• Decrease in the number of white blood cells (cells involved in fighting disease),
• Decreased levels of red pigment (haemoglobin: a protein in red blood cells responsible for oxygen transport to cells) in the blood,
• Decrease in the number of platelets (blood cells responsible for blood clotting),
• Infections,
• Nausea,
• Vomiting,
• Mucositis (inflammation of the mucous membranes),
• Headache,
• Increased serum creatinine levels (a metabolic product formed in muscles),
• Increased serum urea levels (a metabolic product),
• Fever,
• Fatigue.

Common: may affect up to 1 in 10 patients

• Bleeding (haemorrhage),
• Metabolic disturbances related to the release of tumour cell contents into the bloodstream,
• Decreased number of red blood cells, which may cause paleness, weakness, or shortness of breath (anaemia),
• Decreased number of neutrophils (a type of white blood cell involved in fighting infections),
• Hypersensitivity reactions, such as allergic skin inflammation, urticaria,
• Increased activity of liver enzymes AspAT/AlAT (which may indicate inflammation or damage to liver cells),
• Increased activity of alkaline phosphatase enzyme (an enzyme produced mainly in the liver and bones),
• Increased levels of bile pigment (formed during the breakdown of red blood cells),
• Decreased potassium levels in the blood (potassium is necessary for proper functioning of nerve and muscle cells, including the heart muscle),
• Cardiac dysfunction,
• Heart rhythm disturbances (arrhythmia),
• Low or high blood pressure (hypotension or hypertension),
• Pulmonary dysfunction,
• Diarrhoea,
• Constipation,
• Mouth pain (oral mucositis),
• Loss of appetite,
• Hair loss,
• Skin changes,
• Absence of menstruation (amenorrhoea),
• Pain,
• Insomnia,
• Tremor,
• Dehydration,
• Dizziness,
• Itchy rash (urticaria).

Uncommon: may affect up to 1 in 100 patients

• Fluid accumulation in the pericardial sac surrounding the heart (pericardial effusion),
• Ineffective production of all blood cells in the bone marrow (the spongy structure inside bones responsible for blood cell production),
• Acute leukaemia,
• Myocardial infarction, chest pain,
• Heart failure.

Rare: may affect up to 1 in 1,000 patients

• Blood infection (sepsis),
• Severe hypersensitivity reactions (anaphylactic reactions),
• Impaired bone marrow function, leading to general malaise and evident in blood test results,
• Symptoms resembling anaphylactic reactions (anaphylactoid reactions),
• Drowsiness,
• Loss of voice (aphonia),
• Acute circulatory collapse (cessation of blood flow, primarily of cardiac origin, leading to cellular hypoxia, undernutrition, and inability to eliminate toxins),
• Skin redness (erythema),
• Dermatitis (skin inflammation),
• Itching (pruritus),
• Skin rash (maculopapular eruption),
• Excessive sweating.

Very rare: may affect up to 1 in 10,000 patients

• Primary atypical pneumonia,
• Haemolysis (breakdown of red blood cells),
• Sudden drop in blood pressure, sometimes with skin reactions or rash (anaphylactic shock),
• Disturbance of taste sensation,
• Sensory disturbances (paraesthesia),
• General malaise and limb pain (peripheral neuropathy),
• Severe condition resulting from blockade of certain receptors in the nervous system,
• Nervous system disorders,
• Lack of motor coordination (ataxia),
• Encephalitis (inflammation of the brain),
• Increased heart rate (tachycardia),
• Phlebitis (vein inflammation),
• Development of abnormal tissue in the lungs (pulmonary fibrosis),
• Bleeding and inflammation of the oesophagus (haemorrhagic oesophagitis),
• Bleeding from the stomach or intestines,
• Infertility,
• Multi-organ failure.

Frequency not known: frequency cannot be determined from available data

• Liver failure,
• Kidney failure,
• Irregular and often rapid heartbeat (atrial fibrillation),
• Painful red or purplish spreading rash with blisters and (or) other changes in mucous membranes (e.g. in the mouth and lips), particularly if the patient previously had photosensitivity, respiratory tract infection (e.g. bronchitis) and (or) fever,
• Drug rash with eosinophilia and systemic symptoms (DRESS syndrome or drug hypersensitivity syndrome) during combination therapy with rituximab,
• Pneumonitis (lung inflammation),
• Pulmonary haemorrhage (bleeding from the lungs),
• Excessive urination, including at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus).

There have been reports of secondary malignancies (myelodysplastic syndrome, acute myeloid leukaemia, lung cancer) in patients receiving Bendamustine Glenmark. However, a definitive causal relationship between the use of this medicine and the development of these conditions has not been established.

Seek immediate medical advice if any of the following adverse reactions occur (frequency not known):
Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These may present as red or round skin spots, often with central blisters on the trunk, skin peeling, mouth, throat, nose, genital, and eye ulcers, and may be preceded by fever and flu-like symptoms.
Widespread rash, high fever, swollen lymph nodes, and multi-organ involvement (drug reaction with eosinophilia and systemic symptoms, also known as DRESS syndrome or drug hypersensitivity syndrome).

If any adverse reaction worsens or if any adverse reactions not listed in this leaflet occur, inform your doctor.

Reporting of adverse reactions
If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, Tel: +48 22 49 21 301, Fax: +48 22 49 21 309,
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Bendamustine Glenmark

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer carton after: Expiry
(Exp) or on the label of the vial after the abbreviation EXP. The expiry date refers to the last day of the stated month.
The vial should be stored in the outer packaging to protect it from light.
Note on shelf life after opening and reconstitution
The solution prepared according to the instructions provided at the end of this leaflet is stable in polyethylene bags at room temperature and 60% relative humidity for 3.5 hours and for 2 days when stored in a refrigerator. Bendamustine Glenmark does not contain preservatives.
Therefore, the solution must not be used after the specified time has elapsed.
The user is responsible for maintaining aseptic conditions.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What Bendamustine Glenmark contains

• The active substance is bendamustine hydrochloride. One vial contains 25 mg or 100 mg of bendamustine hydrochloride. After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride.
• The other ingredient is mannitol.

What Bendamustine Glenmark looks like and contents of the pack
A white or almost white lyophilised powder in a 25 ml or 50 ml type I amber glass vial, with a bromobutyl rubber stopper and an aluminium flip-off seal.
The 25 ml amber glass vials contain 25 mg of bendamustine hydrochloride and are available in cardboard packs containing 5 vials.
The 50 ml amber glass vials contain 100 mg of bendamustine hydrochloride and are available in cardboard packs containing 5 vials.

Marketing Authorisation Holder
Glenmark Pharmaceuticals s.r.o.
Hvězdova 1716/2b
140 78 Prague 4
Czech Republic

Manufacturer
Synthon Hispania SL
C/ Castelló n 1, Pol. Las Salinas
Sant Boi de Llobregat
08830 Barcelona
Spain

Synthon, s.r.o.
Brněnská 32/čp. 597
678 01 Blansko
Czech Republic

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
Glenmark Pharmaceuticals Sp. z o.o.
Osmańska Street 14
02-823 Warsaw

Information intended exclusively for healthcare professionals:

As with all cytotoxic compounds, due to the potential of the drug to damage genetic material and induce neoplastic disease, nursing and medical personnel must observe more stringent than usual precautions during preparation.
When preparing bendamustine hydrochloride, inhalation (breathing in) of the drug and contact with skin and mucous membranes must be avoided (wear gloves, protective clothing, and, if possible, a face mask!).
Any body parts contaminated with the drug should be thoroughly washed with soap and water, and eyes should be rinsed with 0.9% (isotonic) sodium chloride solution. If possible, work should be performed on a specially protected surface (under a laminar flow hood) covered with a single-use, absorbent, fluid-impermeable drape. Contaminated materials constitute cytostatic waste. Please follow national guidelines for the disposal of materials with cytostatic properties!
Pregnant personnel must not be allowed to handle cytostatic products.
The ready-to-use solution should be prepared by dissolving the vial contents of bendamustine exclusively in water for injections, as follows:

1. Preparation of the concentrate
   • One vial containing 25 mg of bendamustine hydrochloride should first be dissolved in 10 ml by shaking
   • One vial containing 100 mg of bendamustine hydrochloride should first be dissolved in 40 ml by shaking
2. Preparation of the infusion solution Once a clear solution is obtained (usually within 5–10 minutes), the entire dose of bendamustine should be immediately further diluted in 0.9% (isotonic) sodium chloride solution to achieve a final volume of approximately 500 ml. Bendamustine must not be dissolved in other infusion or injection solutions. The infusion solution containing bendamustine must not be mixed with other substances.
3. Administration The solution should be administered as an intravenous infusion over 30–60 minutes. Vials are for single use only. Any unused portions of the medicinal product or waste materials should be disposed of in accordance with local regulations. In case of accidental extravasation (paravenous administration), the infusion must be immediately discontinued. After briefly aspirating the injected fluid, the needle should be removed. The extravasation site should be cooled and elevation of the affected limb should be recommended. It has not been established whether the administration of additional medications, such as corticosteroids, may yield definitively positive outcomes (see section 4).