BENDAMUSTINE HYDROCHLORIDE AQVIDA 100 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION - patient leaflet, side effects, dosage

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MACEUTICALS

Package leaflet: Information for the patient Bendamustine Hydrochloride AqVida 100 mg/ml concentrate for solution for infusion

bendamustine hydrochloride

Read all of this leaflet carefully before you start 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, hospital pharmacist or nurse.
• if you get any side effects talk to your doctor, hospital pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Bendamustine Hydrochloride AqVida is and what it is used for 2. What you need to know before you use Bendamustine Hydrochloride Aq­Vida

• 3. How to use Bendamustine Hydrochloride AqVida

• 4. Possible side effects

• 5. How to store Bendamustine Hydrochloride AqVida

• 6. Contents of the pack and other information

1. what bendamustine hydrochloride aqvida is and what it is used for

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

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

• chronic lymphocytic leukaemia in cases where fludarabine combination chemotherapy is not appropriate for you,
• non-hodgkin lymphomas, which had not, or only shortly, responded to prior rituximab treatment,
• multiple myeloma in cases where thalidomide or bortezomib containing therapy is not appropriate for you.

2. what you need to know before you use bendamustine hydrochloride aqvida

Do not use Bendamustine Hydrochloride AqVida:

• if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);
• while breast-feeding, if treatment with bendamustine hydrochloride AqVida is necessary during lactation you must discontinue breastfeeding (see section warning and precautions on breastfeeding);
• if you have severe liver dysfunction (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 your number of white blood cells and platelets in the blood;
• 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 (leucocytopenia);
• in combination with yellow fever vaccines.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Bendamustine Hydrochloride AqVida

• in case of reduced capability of the bone marrow to replace blood cells. You should have your number of white blood cells and platelets in the blood checked before starting treatment with Bendamustine Hydrochloride AqVida, before each subsequent course of treatment and in the intervals between courses of treatment.
• in case of infections. you should contact your doctor if you have signs of infection, including fever or lung symptoms.
• in case of reactions on your skin during treatment with Bendamustine Hydrochloride AqVida. The skin reactions may increase in severity.
• in case of painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membrane (e.g. mouth and lips), in particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) and/or fever.
• in cases of existing heart disease (e.g. heart attack, chest pain, severely disturbed heart rhythms).
• in case you notice any pain in your side, blood in your urine or 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 Bendamustine Hydrochloride AqVida. Your doctor may ensure you are adequately hydrated and give you other medicines to help prevent it.
• in case of severe allergic or hypersensitivity reactions. you should pay attention to infusion reactions after your first cycle of therapy.
• at any time during or after your treatment, tell your doctor immediately if you notice or someone notices in you: memory loss, trouble thinking, difficulty walking or sight loss -these may be due to a very rare but serious brain infection which can be fatal (progressive multifocal leukoencephalopathy or PML).
• contact your doctor if you notice any suspicious skin changes because there may be an increased risk of certain types of skin cancer (non-melanoma skin cancer) with the use of this medicine.

Children and adolescents

There is no experience in children and adolescents with Bendamustine Hydrochloride AqVida.

Other medicines and Bendamustine Hydrochloride AqVida

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

If Bendamustine Hydrochloride AqVida 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.

If Bendamustine Hydrochloride AqVida is used in combination with medicines which alter your immune response, this effect may be intensified.

Cytostatic medicines may diminish the effectiveness of live-virus vaccination. Additionally cytostatic medicines increase the risk of an infection after vaccination with live vaccines (e.g. viral vaccination).

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The following information is intended for medical or healthcare professionals only:

The concentration of Bendamustine Hydrochloride AqVida differs from other Bendamustine containing products. It must be diluted before use.

Handling:

The normal safety precautions for cytostatic agents must be observed when preparing and disposing of the infusion solution. Handling of the solution for infusion should be done in a safety box and protective coats and gloves should be used. If no safety box is available, the equipment should be supplemented with a mask and protective glasses.

When handling Bendamustine Hydrochloride AqVida, inhalation, skin contact or contact with mucous membranes should be avoided (wear gloves and protective clothes!). Contaminated body parts should be carefully rinsed with water and soap, the eye should be rinsed with physiological saline solution. If possible it is recommended to work on special safety workbenches (laminar flow) with liquid impermeable, absorbing disposable foil. Pregnant personnel should be excluded from handling cytostatics. If there is lasting irritation, a doctor should be consulted. If the solution is spilled on the skin, rinse thoroughly with water.

nstructions for dilution:

The only approved diluent for dilution of Bendamustine Hydrochloride AqVida is sodium chloride 9 mg/ml (0.9%) solution for injection (without preservative). The diluted bag is fabricated from a polyvinylchloride (PL 146 Plastic).

• 1. Use aseptic techniques preparation for Bendamustine Hydrochloride AqVida administration.

• 2. The total quantity of the Bendamustine Hydrochloride AqVida required for an individual patient should be diluted with sterile sodium chloride 9 mg/ml (0.9%) solution for injection, without preservative to produce a final volume of about 500 ml, yielding a concentration between 0.3 mg/ml and 0.6 mg/ml.The diluted solution is a clear colourless to yellow solution.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

Bendamustine Hydrochloride AqVida can cause genetic damage and has caused malformations in animal studies. You should not use Bendamustine Hydrochloride AqVida during pregnancy unless certainly indicated by your doctor. In case of treatment you should use medical consultation about the risk of potential adverse effects of your therapy for the unborn child and genetic consultation is recommended.

If you are a woman of childbearing potential you must use an effective method of contraception both before and during treatment with Bendamustine Hydrochloride AqVida. If pregnancy occurs during your treatment with Bendamustine Hydrochloride AqVida you must immediately inform your doctor and should use genetic consultation.

Breast-feeding

Bendamustine Hydrochloride AqVida must not be administered during breast feeding. If treatment with

Bendamustine Hydrochloride AqVida is necessary during lactation you must discontinue breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine.

Fertility

Men receiving treatment with Bendamustine Hydrochloride AqVida are advised not to father a child during treatment and for up to 6 months afterwards. Before starting treatment, you should seek advice on storing sperm because of the possibility of permanent infertility.

If you are a man, you should avoid fathering a child during treatment with Bendamustine Hydrochloride AqVida and for up to 6 months after treatment has stopped. There is a risk that treatment with

Bendamustine Hydrochloride AqVida will lead to infertility and you may wish to seek advice on conservation of sperm before treatment starts.

Driving and using machines

Bendamustine Hydrochloride AqVida has major influence on the ability to drive and use machines. Do not drive or operate machines if you experience side effects, such as dizziness or lack of coordination.

3. how to use bendamustine hydrochloride aqvida

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Bendamustine Hydrochloride AqVida 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) and/or your blood platelets have fallen to counts below determined levels.

Your doctor will determine these values at regular intervals.

Recommended dose

Chronic lymphocytic leukaemia

Bendamustine Hydrochloride AqVida 100 mg per square meter of your body surface area (based on your height and weight)	on Days 1+2
Repeat the cycle after 4 weeks up to 6 times

Non-Hodgkin lymphomas

Bendamustine Hydrochloride AqVida 120 mg per square meter of your body surface area (based on your height and weight)	on Days 1 + 2
Repeat the cycle after 3 weeks at least 6 times

Multiple myeloma

Bendamustine Hydrochloride AqVida 120 – 150 mg per square meter of your body surface area (based on your height and weight)	on Days 1 + 2
Prednisone 60 mg per square meter of your body surface area (based on your height and weight) by injection or orally.	on Days 1 – 4
Repeat the cycle after 4 weeks at least 3 times

Treatment should be terminated if white blood cell (leukocyte) and/or platelet values dropped to determined levels. Treatment can be continued after white blood cell values have increased.

Impaired liver or kidney function

Dependent on the degree of impairment of your liver function it may be necessary to adjust your dose (by 30% in case of moderate liver dysfunction). No dose adjustment is necessary in case of impairment of kidney function. Your attending doctor will decide whether a dosage adjustment is necessary.

How Bendamustine Hydrochloride AqVida is given

Treatment with Bendamustine Hydrochloride AqVida should be undertaken only by doctors experienced in tumour therapy. Your doctor will give you the exact dose of Bendamustine Hydrochloride AqVida and use the necessary precautions.

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

Duration of treatment

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

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

If you forget to use Bendamustine Hydrochloride AqVida

If a dose of Bendamustine Hydrochloride AqVida has been forgotten, your doctor will usually retain the normal dosage schedule.

If you stop using Bendamustine Hydrochloride AqVida

The doctor treating you will decide whether to interrupt the treatment or to change over to a different preparation.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. possible side effects

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

Tissue changes (necrosis) have been observed very rarely following leakage of Bendamustine Hydrochloride AqVida into the tissue outside

Preparation of the infusion solution:

If the vials are stored under refrigeration, allow the required number of boxes of Bendamustine Hydrochloride AqVida to stand below 25°C for 5 minutes before use. More than one vial of Bendamustine Hydrochloride AqVida may be necessary to obtain the required dose for the patient (see Table 1).

Aseptically withdraw the required amount of Bendamustine Hydrochloride AqVida using a calibrated syringe.

The required volume of Bendamustine Hydrochloride AqVida must be injected into an infusion bag containing 0.9% sodium chloride solution for infusion to produce final volume of 500 ml. Do not add other medicinal products to the prepared infusion solution or intravenous infusion set.

Mix the infusion bag manually using a rocking motion. Any portion left in the vial, after withdrawal of the volume to be diluted, must be disposed of in accordance with local requirements.

As with all parenteral medicinal products, Bendamustine Hydrochloride AqVida solution should be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.

The details are given in below table 1 for the total dose and volume required for the typical body surface area and no. of vials required.

Table 1: Sample calculations for patients receiving the recommended dose of 100 mg/m2 – 150 mg/m2 of bendamustine for body surface area ranging from 1.6 m2 to 2 m2 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 Hydrochloride AqVida is impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone marrow function may lead to an increased risk of infection, anemia 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 blood cells that carries oxygen throughout the body)
• low counts of platelets (colorless 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 your muscle)
• increased blood level of urea (a chemical waste product)
• fever
• fatigue
• 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)
• hypersensitivity reactions such as allergic inflammation of the skin (dermatitis), nettle rash (urticaria)
• 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 cell)
• 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 (urticaria)
• 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 leukemia
• heart attack, chest pain (myocardial infarction)
• heart failure
• infection of the blood (sepsis)
• severe allergic hypersensitivity reactions (anaphylactic reactions)
• reduction in your bone marrow function, which may make you feel unwell or show up in your blood tests
• signs similar to anaphylactic reactions (anaphylactoid reactions)
• drowsiness
• loss of voice (aphonia)
• 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)
• primary atypical inflammation of the lungs (pneumonia)
• break-down 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 condition resulting in the blockade of a specific receptor in the nervous systems
• 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
• liver failure
• renal 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 membrane (e.g. mouth and lips), in particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) and/or fever
• drug rash in combination therapy with rituximab
• pneumonitis
• bleeding from the lungs

There have been reports of tumours (myelodysplastic syndrome, acute myeloid leukemia (AML), bronchial carcinoma) following treatment

------------------- For chronic lymphocytic leukaemia:
Typical Body Surface Area (M2)	Total dose = patient BSA multiplied by recommended dose	Total volume to be diluted to 500 ml [100 mg/ml]	Number of vials needed
	Monotherapy for chronic lymphocytic leukaemia: 100 mg/m2
	mg	ml
1.6	160	1.6	1 vial of 200 mg
1.7	170	1.7	1 vial of 200 mg
1.8	180	1.8	1 vial of 200 mg
1.9	190	1.9	1 vial of 200 mg
2	200	2	1 vial of 200 mg

For indolent non-Hodgkin’s lymphomas refractory to rituximab:

Typical Body Surface Area (M2)	Total dose = patient BSA multiplied by recommended dose	Total volume to be diluted to 500 ml [100 mg/ ml])	Number of vials needed
	Monotherapy for indolent non-Hodgkin’s lymphomas refractory to rituximab: 120mg/m2
	mg	ml
1.6	192	1.9	1 vial of 200 mg
1.7	204	2.0	1 vial of 200 mg
1.8	216	2.2	1 vial of 200 mg + 1 vial of 50 mg
1.9	228	2.3	1 vial of 200 mg + 1 vial of 50 mg
2	240	2.4	1 vial of 200 mg + 1 vial of 50 mg

with Bendamustine Hydrochloride AqVida. No clear relationship with Bendamustine Hydrochloride AqVida 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 gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Reporting of side effects

If you get any side effects talk to your doctor, hospital pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the MHRA Yellow Card Scheme Website: or search for the MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. how to store bendamustine hydrochloride aqvida

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

Do not use Bendamustine Hydrochloride AqVida after the expiry date which is stated on the label and the carton. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C).

Note on shelf-life

After dilution

Physicochemical stability of the diluted solution has been demonstrated for 3.5 hours at 25 °C/ 60%RH and 2 days at 2°C to 8°C in polyvinylchlo­ride bags.

From a microbiological point of view, the solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C unless dilution has taken place in controlled and validated aseptic conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

6. contents of the pack and other informationwhat bendamustine hydrochloride aqvida contains the active substance is bendamustine hydrochloride.

One vial contains bendamustine hydrochloride monohydrate corresponding to 50 mg bendamustine Hydrochloride AqVida.

One vial contains bendamustine hydrochloride monohydrate corresponding to 100 mg bendamustine Hydrochloride AqVida.

One vial contains bendamustine hydrochloride monohydrate corresponding to 200 mg bendamustine Hydrochloride AqVida.

• the other ingredients are sucrose, n,n-dimethylacetamide, L-cysteine Hydrochloride monohydrate (E920) and water for injection.

What Bendamustine Hydrochloride AqVida looks like and contents of the pack

Amber glass vials with rubber stopper and an aluminium flip-off seal. Clear colorless to yellow solution.

Bendamustine Hydrochloride AqVida is supplied in packs of 1 and 5 vials. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer:

Marketing Authorisation Holder:

AqVida GmbH,

Kaiser-Wilhelm Strasse 89, 20355 Hamburg, Germany

Manufacturer:

Amneal Netherlands B.V.,

Emmaplein 4D, ‘s-Hertogenbosch, 5211 VW, The Netherlands

This leaflet was last revised in 02/2021

For Multiple myeloma:

Typical Body Surface Area (M2)	Total dose = patient BSA multiplied by recommended dose	Total volume to be diluted to 500 ml [100 mg/ml]	Number of vials needed
	Multiple myeloma: 120–150 mg/ m2
	mg	ml
1.6	192–240	1.9–2.4	1 vial of 200 mg – 1 vial of 200 mg + 1 vial of 50 mg
1.7	204–255	2.0–2.5	1 vial of 200 mg – 1 vial of 200 mg + 1 vial of 50 mg
1.8	216–270	2.2–2.7	1 vial of 200 mg + 1 vial of 50 mg – 1 vial of 200 mg + 1 vial of 100 mg
1.9	228–285	2.3–2.9	1 vial of 200 mg + 1 vial of 50 mg – 1 vial of 200 mg + 1 vial of 100 mg
2	240–300	2.4–3.0	1 vial of 200 mg + 1 vial of 50 mg – 1 vial of 200 mg + 1 vial of 100 mg

Administration:

The required solution is administered by intravenous infusion over 30–60 min period.

The vials are for single use only.

Since no antimicrobial preservative is included, dilution must be carried out under full aseptic conditions. Any unused 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 (see section 4).