Prospecto: information for the user

Bendamustine Hikma 2.5mg/ml powder for concentrate for solution for infusion EFG

Bendamustine hydrochloride

Read this prospect carefully before starting to use this medicine, because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed only to you, and you must not give it to other people
• even if they have the same symptoms as you, as it may harm them.
• If you experience adverse effects, consult your doctor or pharmacist, even if they do not appear in this prospect. See section4.

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

2.What you need to know before starting to use Bendamustine Hikma

3.How to use Bendamustine Hikma

4.Possible adverse effects

5.Storage of Bendamustine Hikma

6.Contents of the package and additional information

Bendamustina Hikma is a medication used for the treatment of certain types of cancer (it is a cytotoxic medication).

This medication is used alone (monotherapy) or in combination with other medications for the treatment of the following types of cancer:

• Chronic lymphocytic leukemia, if combination chemotherapy with fludarabine is not suitable for you,
• Non-Hodgkin lymphomas that have not responded, or have only responded for a short period of time, after previous treatment with rituximab,
• Multiple myeloma, if high-dose chemotherapy and an autotransplant of progenitor cells or treatments containing thalidomide or bortezomib are not suitable for you

No use Bendamustina Hikma

if you are allergic to hydrochloride bendamustine or to any of the other components of this medication (listed in section6).

• during breastfeeding; if treatment with this medication is necessary during breastfeedingbreastfeeding should be interrupted (see sectionpregnancy, breastfeeding and fertility).
• if you have severe liver dysfunction (liver cell functional damage).
• if you present a yellowish discoloration of the skin or the white of the eyes, caused by liver or blood problems (jaundice).
• if you present a severe disorder of the medullary function (bone marrow depression) and severe alterations of the number of white blood cells and platelets in the blood.
• if you have undergone a major surgical intervention in the 30days prior to the start of treatment.
• if you have had any infection, especially if it has been accompanied by a reduction in the number of white blood cells (leucocytopenia).
• in combination with yellow fever vaccines.

Warnings and precautions

Inform your doctor immediately if you notice or someone notices in you: memory loss, cognitive difficulties, difficulty walking or loss of vision. These symptoms may be due to a rare but severe brain infection that can be fatal (multifocal progressive leukoencephalopathy or LMP).

Contact your doctor if you detect any suspicious changes in the skin, as the use of this medication may increase the risk of developing certain types of skin cancer (non-melanoma skin cancer).

Consult your doctor or nurse before starting to use this medication

• in case your bone marrow has reduced its ability to replace blood cells. The number of white blood cells and platelets in the blood should be measured before starting treatment with this medication before each treatment cycle and between cycles.

• in case of infections. Ifyou present signs of infection, such as fever or respiratory symptoms, you should contact your doctor.
• if you presentskin reactionsduring treatment with bendamustine. The reactions may increase in intensity.
• in case of widespread painful red or purple rashes and blisters and/or other lesions that appear on the mucous membrane (p.eg. mouth and lips), particularly if you have had previous sensitivity to light, respiratory system infections (p.eg. bronchitis) and/or fever.
• if you have a heart disease (p.eg., heart attack, chest pain, severe heart rhythm disorders).
• if you experience pain in the side or if you observe blood in the urine or if you urinate less. If your disease is very severe, it is possible that your body may not be able to eliminate all the waste products of dying cancer cells. This is called tumor lysis syndrome and may cause kidney failure and heart problems within 48hours after the administration of the first dose ofthis medication. Your doctor will ensure that you are adequately hydrated and will give you other medications to prevent this from happening.
• in case of severe allergic reactions or hypersensitivity. You should pay attention to reactions to infusion after your first treatment cycle.

Use of Bendamustina Hikma with other medications

Inform your doctor or pharmacist if you areusing, haveusedrecentlyor may have to use any other medication.

If this medication is used in combination with medications that inhibit blood cell formation in the bone marrow, the effect on the bone marrow may be intensified.

If this medication is used in combination with medications that alter your immune response, this effect may be intensified.

Cytostatics may reduce the effectiveness of live virus vaccines. In addition, cytostatics increase the risk of infection after vaccination with live virus vaccines (p.eg., viral vaccination).

Pregnancy, breastfeeding and fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant, or if you plan to become pregnant, consult your doctor or pharmacist before using this medication.

Pregnancy

This medication may cause genetic damage and has caused malformations in studies conducted on animals. It should not be used during pregnancy unless the doctor considers it clearly necessary. If you receive this treatment, you should ask a doctor to explain the risk of possible adverse effects of the treatment for your child and genetic counseling is recommended.

If you are a fertile woman, you should use effective contraceptive measures before and during treatment with this medication. If you become pregnant during treatment with this medication, you should inform your doctor immediately and seek genetic counseling.

Breastfeeding

This medication should not be administered during breastfeeding. If you need treatment with bendamustina during breastfeeding, you should suspend breastfeeding.

Consult your doctor before starting to use any medication.

Fertility

It is recommended that men treated with this medication should not father children during treatment or for 6months after treatment. Before starting treatment, you should be advised on sperm conservation, as there is a possibility that it may cause permanent sterility.

If you are a man, you should not father children during treatment with this medication and for 6months after treatment. There is a risk that treatment with this medication may cause sterility; you may want to seek advice on sperm conservation before starting treatment.

Driving and operating machinery

The influence of this medication on your ability to drive and operate machinery is important. Do not drive or operate machinery if you experience adverse effects such as dizziness or lack of coordination.

Always use this medication exactly as your doctor or pharmacist explained. Check with your doctor or pharmacist if you are unsure.

This medication is administered through a vein for 30 to 60 minutes in various doses, either alone (monotherapy) or combined with other medications.

You will not be able to start treatment if your white blood cell count (leukocytes) and/or platelet count is below certain levels.

Your doctor will measure these values periodically.

Chronic Lymphocytic Leukemia

NHL (Non-Hodgkin Lymphoma)

Multiple Myeloma

Treatment will end if your white blood cell count (leukocytes) and/or platelet count is below certain levels. Treatment may be resumed when your leukocyte and platelet counts have increased.

Renal or Hepatic Insufficiency

Dose adjustment may be necessary based on the degree of liver function deterioration (by 30% in case of moderate liver deterioration). No dose adjustment is necessary in case of renal function alteration. Your doctor will decide if a dose adjustment is necessary.

How to Administer

This medication can only be administered by experienced oncologists. Your doctor will administer the exact dose of bendamustine and take necessary precautions.

Your doctor will administer the prepared solution for infusion. The solution is administered through a vein as a brief infusion for 30 to 60 minutes.

Treatment Duration

No specific treatment duration has been defined for this medication. Treatment duration depends on the disease and response to treatment.

If you have any concerns or doubts about treatment with this medication, speak with your doctor or nurse.

Missed Dose of Bendamustina Hikma

If you forget a dose of this medication, your doctor will usually proceed with the normal dosing schedule.

Discontinuing Treatment with Bendamustina Hikma

Your doctor will decide whether to discontinue treatment or use a different preparation.

If you have any other questions about using this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them. Some of the results listed below may be found after tests performed by your doctor:

The following frequencies are used to evaluate adverse reactions:

Very common: may affect more than 1 in 10 people

Common:may affect up to 1 in 10 people

Uncommon:may affect up to 1 in 100 people

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

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

Unknown: the frequency cannot be estimated from the available data

In rare cases, tissue alterations (necrosis) have been observed after unintentional injection into the tissue surrounding blood vessels (extravascular). A burning sensation at the site of needle insertion may be a sign of administration outside the vessel. The consequences of this type of administration may be pain and skin defects with poor healing.

The dose-limiting side effect of this medicine is a change in bone marrow function, which usually normalizes once treatment is completed. Suppression of bone marrow function may cause low blood cell counts, which in turn may increase the risk of infection, anemia, or a higher risk of bleeding.

Adverse effectsvery common

• Reduction in white blood cell count (defenses in the blood)
• Reduction in red blood cell pigment (hemoglobin: a protein in red blood cells that carries oxygen throughout the body)
• Reduction in platelet count (colorless blood cells that collaborate in blood coagulation)
• Infections
• Nausea
• Vomiting
• Mucous membrane inflammation
• Headache
• Increased blood creatinine concentration (a waste product produced by muscles)
• Increased blood urea concentration(a waste product)
• Fever
• Fatigue

Adverse effectscommon

• Bleeding (hemorrhage)
• Metabolic disorder caused by the release of cancer cell content into the circulatory system
• Decrease in red blood cells, which may cause pale skin and weakness or difficulty breathing (anemia)
• Reduction in neutrophil count (a type of white blood cell important for defending against infections)
• Hypersensitivity reactions, such as skin inflammation (dermatitis) or urticaria
• Elevation of liver enzymes AST/ALT (which may indicate inflammation or damage to liver cells)
• Increased alkaline phosphatase enzyme(an enzyme primarily produced in the liver and bones)
• Increased bilirubin pigment(a substance generated during normal red blood cell degradation)
• Low potassium blood level(a nutrient necessary for nerve and muscle cell function, including the heart)
• Cardiac function alteration (disfunction)
• Alteration of heart rhythm (arrhythmia)
• Elevation or decrease in blood pressure (hypotension or hypertension)
• Pulmonary function alteration
• Dyspepsia
• Constipation
• Mouth ulcers (stomatitis)
• Loss of appetite
• Hair loss
• Skin alterations
• Amenorrhea (absence of menstruation)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy skin rash (urticaria)

Adverse effectsuncommon

• Accumulation of fluid in the sac surrounding the heart (pericardial effusion)

• Ineffective production of all blood cells (myelodysplastic syndrome)
• Acute leukemia

• Myocardial infarction, chest pain (infarction of the heart muscle)
• Heart failure

Adverse effectsrare

• Blood infection (sepsis)
• Severe allergic and hypersensitivity reactions (anaphylactic reactions)
• Reactions similar to anaphylactic reactions (anaphylactoid reactions)
• Drowsiness
• Loss of voice (aphonia)
• Acute circulatory failure(failure in blood circulation primarily of cardiac origin with failure to maintain oxygen and nutrient supply to tissues and elimination of toxins)
• Redness of the skin (erythema)
• Skin inflammation (dermatitis)
• Itching (pruritus)
• Itchy skin rash (exanthema maculosa)
• Excessive sweating (hyperhidrosis)

Adverse effectsvery rare

• Atypical primary inflammation of the lungs (pneumonia)
• Destruction of red blood cells
• Rapid decrease in blood pressure, sometimes with skin reactions or rashes (anaphylactic shock)
• Alteration of taste
• Alteration of sensitivity (paresthesias)
• Discomfort (weakness) and pain in the limbs (peripheral neuropathy)
• Inhibition of the physiological action of acetylcholine, especially as a neurotransmitter (cholinergic syndrome)
• Nervous system diseases
• Neurological disorders
• Lack of coordination (ataxia)
• Brain inflammation (encephalitis)
• Increased heart rate (tachycardia)
• Vein inflammation (phlebitis)
• Pulmonary tissue formation (pulmonary fibrosis)
• Haemorrhagic esophageal inflammation (oesophagitis haemorrhagica)
• Gastric or intestinal hemorrhage
• Infertility
• Multi-organ failure

Adverse effectsunknown frequency

• Liver insufficiency

• Renal failure
• Irregular and often rapid heartbeats (atrial fibrillation)

• Widespread painful red or purple rashes and blisters and/or other lesions that begin to appear on mucous membranes (p.e.g. mouth and lips), particularly if you have had previous sensitivity to light, respiratory system infections (p.e.g. bronchitis) and/or fever
• Medication exanthema in combination therapy with rituximab
• Pneumonitis
• Bleeding from the lungs

There have been reports of secondary tumors (myelodysplastic syndromes, LMA, bronchial carcinoma) after treatment with this medicine. A clear relationship with this medicine could not be determined.

Contact your doctor or seek immediate medical attention if you experience any of the following adverse effects (unknown frequency):

Severe skin eruptions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These may appear as circular, red spots with central blisters on the trunk, peeling, mouth ulcers, throat, nose, genitals, and eyes, which may be preceded by fever and flu-like symptoms.

Widespread rash, high body temperature, swollen lymph nodes, and other organ alterations (Drug Reaction with Eosinophilia and Systemic Symptoms, also known as DRESS or drug hypersensitivity syndrome).

If any of the adverse effects worsen, or if you notice any adverse effect not included in this prospectus, please inform your doctor.

Reporting adverse effects

If you experience any other type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect not appearing in this prospectus. You can also report them directly to www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the label and on the box after CAD. The expiration date is the last day of the month indicated.

Store below 25 °C. Store the vial in the outer packaging to protect the contents from light.

Note on the validity period after opening or preparation of the solution

Infusion solution

After reconstitution and dilution, the chemical and physical stability has been demonstrated for 3.5 hours at 25°/ 60% HR and 2 days at 2ºC to 8ºC in polyethylene bags.

From a microbiological standpoint, the solution must be used immediately. Otherwise, the storage times and conditions prior to use are the responsibility of the user and will not normally exceed 24 hours at 2ºC–8ºC unless reconstitution/dilution takes place in validated and controlled aseptic conditions.

The user is responsible for maintaining aseptic conditions.

Bendamustine Hikma Composition

The active ingredient is bendamustine hydrochloride.

1 vial contains 25 mg or 100 mg of bendamustine hydrochloride (as bendamustine hydrochloride monohydrate).

After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride.

The other component is mannitol.

Product Appearance and Packaging Contents

Amber glass vials with rubber stopper and aluminum flip-off cap.

White and crystalline powder.

This medication is available in packaging containing 1 or 5 vials.

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó, 8 - Terrugem

2705-906 Sintra

Portugal

Manufacturer

Thymoorgan GmbH Pharmazie

Schiffgraben, 23

38690 Goslar

Germany

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Hikma España, S.L.U.

Calle Anabel Segura nº11, Edificio A, planta 1ª, oficina 2

28108 - Alcobendas, Madrid

Spain

Last review date of this leaflet: December 2020.

Further information on this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) www.aemps.gob.es

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This information is intended solely for healthcare professionals:

As with all similar cytotoxics, healthcare personnel and doctors must exercise extreme caution due to the potential genotoxicity and carcinogenicity of the preparation. Avoid inhalation (inspiration) and contact with the skin and mucous membranes while handling this medication (wear gloves, protective clothing, and, if possible, a mask!). If any part of the body becomes contaminated, clean it carefully with water and soap, and rinse the eyes with isotonic saline solution (0.9%). If possible, work on a special safety workbench (laminar flow) with a disposable impermeable absorbent sheet. Contaminated items are cytostatic waste. Please follow national guidelines for the disposal of cytostatic material! Pregnant women working in healthcare should not work with cytotoxics.

This ready-to-use solution must be prepared by dissolving the contents of one vial of this medicinal product exclusively in water for injection, as indicated below:

1. Concentrate preparation

• First, dissolve one vial of this medicinal product containing 25 mg of bendamustine hydrochloride in 10 ml, agitating it.
• First, dissolve one vial of this medicinal product containing 100 mg of bendamustine hydrochloride in 40 ml, agitating it.

2. Preparation of the perfusion solution

Once a clear solution is obtained, dissolve the total recommended dose of this medicinal product in isotonic saline solution (0.9%) to achieve a final volume of approximately 500 ml. This medicinal product should not be dissolved with other perfusion or injection solutions. This medicinal product should not be mixed with other substances in perfusion.

3. Administration

The solution will be administered by intravenous perfusion over 30-60 minutes.

The vials are for single use.

Any remaining product in the vial or material should be discarded according to local regulations.

If extravasation occurs, the injection should be stopped immediately. The needle will be removed after brief aspiration. The affected tissue area will then be cooled. The arm will be elevated. It is unclear whether additional treatment, such as the use of corticosteroids, is beneficial (see section 4).