Bortezomib Adamed

Patient Information Leaflet: User Information

Bortezomib Adamed 1 mg, powder for solution for intravenous injection

Bortezomib

Read the package leaflet carefully before using the medicine, as it contains important information for you.

• You should keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor or pharmacist. See section 4.

Table of Contents of the Leaflet:

• 1. What is Bortezomib Adamed and what is it used for
• 2. Important information before using Bortezomib Adamed
• 3. How to use Bortezomib Adamed
• 4. Possible side effects
• 5. How to store Bortezomib Adamed
• 6. Contents of the pack and other information

1. What is Bortezomib Adamed and what is it used for

Bortezomib Adamed contains the active substance bortezomib, which is a so-called "proteasome inhibitor". Proteasomes play a crucial role in controlling cell functions and their development process. By disrupting their function, bortezomib can lead to the death of cancer cells.
Bortezomib Adamed is used to treat multiple myeloma (a type of bone marrow cancer) in patients over 18 years of age:

• as a single drug or in combination with other drugs: pegylated liposomal doxorubicin or dexamethasone in patients whose disease has progressed after receiving at least one previous treatment and in whom hematopoietic stem cell transplantation was not successful or not possible;
• in combination with the drugs: melphalan and prednisone, in patients who have not been previously treated and do not qualify for high-dose chemotherapy with hematopoietic stem cell transplantation.
• in combination with the drugs dexamethasone or dexamethasone with thalidomide in patients who have not been previously treated and qualify for high-dose chemotherapy with hematopoietic stem cell transplantation (induction treatment).

Bortezomib Adamed is used to treat mantle cell lymphoma (a type of cancer that affects the lymph nodes) in patients over 18 years of age in combination with the drugs: rituximab, cyclophosphamide, doxorubicin, and prednisone, in patients who have not been previously treated and do not qualify for hematopoietic stem cell transplantation.

2. Important information before using Bortezomib Adamed

When not to use Bortezomib Adamed

• -if the patient is allergic to bortezomib, boron, or any of the other ingredients of this medicine (listed in section 6);
• -if the patient has severe lung or heart disease.

Warnings and precautions

Tell your doctor if you have:

• a low number of red or white blood cells;
• bleeding disorders and (or) a low platelet count;
• diarrhea, constipation, nausea, or vomiting;
• a history of fainting, dizziness, and lightheadedness;
• kidney disease;
• moderate to severe liver function disorders;
• a history of numbness, tingling, and pain in the hands and feet (symptoms of neuropathy);
• heart disease or blood pressure problems;
• shortness of breath or cough;
• seizures;
• shingles (around the eyes or widespread on the body);
• symptoms of tumor lysis syndrome, such as muscle cramps, muscle weakness, confusion, loss of vision, and shortness of breath;
• memory loss, thinking disorders, difficulty walking, or vision loss. These may be symptoms of a serious brain infection, and your doctor may recommend further tests and monitoring.

The patient must have regular blood tests before and during treatment with Bortezomib Adamed to regularly check the blood cell count.
If the patient has mantle cell lymphoma and is receiving Bortezomib Adamed with a drug containing rituximab, tell your doctor:

• if you suspect you have a hepatitis B virus infection or have had it in the past. In a few cases, patients who had hepatitis B infection may have had recurring episodes of hepatitis, which could be fatal. If you have a history of hepatitis B, your doctor will closely monitor you for signs of active hepatitis B.

Before starting treatment with Bortezomib Adamed, read the package leaflets of all medicinal products you are taking during treatment to get information about them. When taking thalidomide, you must exclude pregnancy and then use effective contraception (see section Pregnancy and breastfeeding).

Children and adolescents

Bortezomib Adamed should not be used in children and adolescents, as it is not known how the medicine works in this age group.

Other medicines and Bortezomib Adamed

Tell your doctor about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take.
In particular, inform your doctor if you are taking medicines containing any of the following active substances:

• ketokonazole, used to treat fungal infections;
• ritonavir, used to treat HIV infection;
• rifampicin, an antibiotic used to treat bacterial infections;
• carbamazepine, phenytoin, or phenobarbital for the treatment of epilepsy;
• St. John's Wort (Hypericum perforatum) for the treatment of depression and other conditions;
• oral antidiabetic drugs.

Pregnancy and breastfeeding

Bortezomib Adamed should not be used during pregnancy, unless it is absolutely necessary.
Both men and women receiving Bortezomib Adamed must use effective contraceptive methods during and for 3 months after the end of treatment. If, despite the use of these methods, the patient becomes pregnant, the doctor should be informed immediately.
Women should not breastfeed during treatment with Bortezomib Adamed.
It is necessary to discuss with the doctor the issue of safe return to breastfeeding after the end of treatment in the patient.
Thalidomide causes birth defects and fetal death. When Bortezomib Adamed is used in combination with thalidomide, patients must follow the "Thalidomide Pregnancy Prevention Program" (see thalidomide package leaflet).

Driving and using machines

Bortezomib Adamed may cause fatigue, dizziness, fainting, and blurred vision. If these symptoms occur, do not drive or operate tools or machinery; even if symptoms do not occur, caution should still be exercised.

3. How to use Bortezomib Adamed

The doctor will adjust the appropriate dose of Bortezomib Adamed for the patient based on the patient's growth and body weight (body surface area). The most commonly used initial dose of Bortezomib Adamed is 1.3 mg/m2 of body surface area, administered twice a week.
The doctor may change the dose and total number of treatment cycles depending on the patient's response to treatment, the occurrence of side effects, and additional diseases (e.g., liver disease).
Relapsed multiple myeloma
If the product Bortezomib Adamed is administered as a single drug, the patient will receive 4 doses of Bortezomib Adamed intravenously on days: 1, 4, 8, and 11, followed by a 10-day break in treatment.
The described 21-day period (3 weeks) is considered one treatment cycle. The patient will receive up to 8 cycles (24 weeks).
The patient may also receive Bortezomib Adamed in combination with the drugs: pegylated liposomal doxorubicin or dexamethasone.
When Bortezomib Adamed is administered in combination with pegylated liposomal doxorubicin, the patient will receive Bortezomib Adamed intravenously during a 21-day treatment cycle, and pegylated liposomal doxorubicin will be administered at a dose of 30 mg/m2 in an intravenous infusion on day 4 of the 21-day cycle.
The patient may receive up to 8 cycles (24 weeks).
When Bortezomib Adamed is administered in combination with dexamethasone, the patient will receive Bortezomib Adamed intravenously during a 21-day treatment cycle, and dexamethasone will be administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortezomib Adamed 21-day cycle. The patient may receive up to 8 cycles (24 weeks).
Previously untreated multiple myeloma
If the patient has not been previously treated for multiple myeloma and the patientdoes not qualify for hematopoietic stem cell transplantation, they will receive Bortezomib Adamed in combination with the drugs: melphalan and prednisone.
In this case, the duration of the treatment cycle is 42 days (6 weeks). The patient will receive 9 cycles (54 weeks).

• During cycles 1-4, Bortezomib Adamed is administered twice a week, on days: 1, 4, 8,
• 11, 22, 25, 29, and 32.
• During cycles 5-9, Bortezomib Adamed is administered once a week, on days: 1, 8, 22, and
• 29. Both melphalan (9 mg/m2) and prednisone (60 mg/m2) are administered orally on days
• 1, 2, 3, and 4 of the first week of each cycle.

If the patient has not been previously treated for multiple myeloma and the patientqualifies for hematopoietic stem cell transplantation, they will receive Bortezomib Adamed intravenously in combination with the drugs: dexamethasone or dexamethasone with thalidomide in induction treatment.
When Bortezomib Adamed is administered with dexamethasone, the patient will receive Bortezomib Adamed intravenously during a 21-day cycle, and dexamethasone will be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 21-day Bortezomib Adamed cycle. The patient may receive up to 4 cycles (12 weeks).
When Bortezomib Adamed is administered with dexamethasone and thalidomide, the duration of the treatment cycle is 28 days (4 weeks). Dexamethasone will be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day Bortezomib Adamed cycle, and thalidomide will be administered orally once a day at a dose of 50 mg up to day 14 of the first cycle, and if the dose is tolerated, it will be increased to 100 mg on days 15-28 and may be further increased to 200 mg per day from the second cycle.
The patient may receive up to 6 cycles (24 weeks).
Previously untreated mantle cell lymphoma
If the patient has not been previously treated for mantle cell lymphoma, they will receive Bortezomib Adamed intravenously in combination with the drugs: rituximab, cyclophosphamide, doxorubicin, and prednisone.
Bortezomib Adamed is administered intravenously on days 1, 4, 8, and 11, followed by a "rest period" without administration of the drug. One treatment cycle lasts 21 days (3 weeks). The patient may receive up to 8 cycles (24 weeks).
The following drugs are administered as intravenous infusions on day 1 of each 21-day Bortezomib Adamed cycle: rituximab at a dose of 375 mg/m2, cyclophosphamide at a dose of 750 mg/m2, and doxorubicin at a dose of 50 mg/m2.
Prednisone is administered orally at a dose of 100 mg/m2 on days 1, 2, 3, 4, and 5 of the Bortezomib Adamed cycle.

How Bortezomib Adamed is administered

This medicine is for intravenous use only. Bortezomib Adamed will be administered by a healthcare professional with experience in the use of cytotoxic drugs.
The powder of Bortezomib Adamed must be dissolved before administration. The preparation of the medicine is carried out by a healthcare professional. Then, the prepared solution is injected quickly intravenously, over 3 to 5 seconds.

Overdose of Bortezomib Adamed

Since this medicine is administered by a doctor or nurse, it is unlikely that the patient will receive too much of the medicine.
If this happens, the doctor will monitor the patient for side effects.

4. Possible side effects

Like all medicines, Bortezomib Adamed can cause side effects, although not everybody gets them.
Some of these side effects may be serious.
If you are receiving Bortezomib Adamed for multiple myeloma or mantle cell lymphoma, you should tell your doctor immediately if you experience any of the following symptoms:

• muscle cramps, muscle weakness;
• confusion, loss of vision, blindness, seizures, headaches;
• shortness of breath, swelling of the feet or changes in heart rhythm, high blood pressure, fatigue, fainting;
• cough and difficulty breathing or pressure in the chest.

Treatment with Bortezomib Adamed can very often cause a decrease in the number of red and white blood cells and platelets in the patient's blood. Therefore, the patient must have regular blood tests before and during treatment with Bortezomib Adamed to regularly check the blood cell count. The patient may experience a decrease in the number of:
platelets, which can lead to a tendency to bruise or bleed without injury (e.g., bleeding from the gut, stomach, mouth, and gums, or bleeding in the brain or liver);
red blood cells, which can lead to anemia, which is accompanied by symptoms such as fatigue and paleness;

• white blood cells, which can lead to a greater susceptibility to infections or the occurrence of flu-like symptoms.

If you are receiving Bortezomib Adamed for multiple myeloma, you may experience the following side effects:

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

• hypersensitivity, numbness, tingling, or burning sensation of the skin, pain in the hands or feet
• caused by nerve damage;
• decrease in the number of red and (or) white blood cells (see above);
• fever;
• nausea or vomiting, loss of appetite;
• constipation occurring with or without bloating (the severity of symptoms may be significant);
• diarrhea: if it occurs, the patient should drink more water than usual, the doctor may recommend taking additional medicines to control diarrhea;
• fatigue, feeling of weakness;
• muscle pain, bone pain.

Common side effects (may affect up to 1 in 10 people):

• low blood pressure, sudden drop in blood pressure when standing up, which can lead to fainting;
• high blood pressure;
• decreased kidney function;
• headache;
• general feeling of being unwell, pain, dizziness, lightheadedness, feeling of weakness or loss of consciousness;
• chills;
• infections, including: pneumonia, respiratory tract infections, bronchitis, fungal infections, cough with expectoration, flu-like symptoms;
• shingles (localized, e.g., around the eyes or widespread on the body);
• chest pain, shortness of breath during exercise;
• various types of rash;
• itching of the skin, skin nodules or dry skin;
• flushing of the face or breaking of blood vessels;
• redness of the skin;
• dehydration;
• heartburn, bloating, belching, gas, abdominal pain, bleeding from the gut or stomach;
• liver function disorders;
• mouth or lip inflammation, dry mouth, mouth ulcers;
• weight loss, loss of taste;
• muscle cramps, muscle weakness, bone pain;
• blurred vision;
• conjunctivitis;
• nosebleeds;
• difficulty sleeping, sweating, anxiety, mood swings, depressive mood, restlessness or

excitement, changes in mental state, disorientation;

• swelling, including around the eyes and other parts of the body.

Uncommon side effects (may affect up to 1 in 100 people):

• heart failure, heart attack, chest pain, feeling of discomfort in the chest, rapid or slow heart rate;
• kidney failure;
• vein inflammation, blood clots in veins and lungs;
• blood clotting disorders;
• circulatory failure;
• inflammation of the sac surrounding the heart (pericarditis) or fluid in the pericardium;
• infections, including: urinary tract infections, flu, herpes, ear and soft tissue infections;
• bleeding from the gut or stomach, bleeding from mucous membranes, e.g., from the mouth, vagina;
• nerve damage. Porphyria cutanea tarda has been reported in patients treated with bortezomib, with some reports being serious. If you experience blistering of the skin or other skin abnormalities, discuss them with your doctor;
• joint inflammation, including inflammation of the joints of the fingers, toes, and jaw;
• lung disorders that make breathing difficult. Some of these include: difficulty breathing, shortness of breath, shortness of breath at rest, shallow breathing, or cessation of breathing,
• wheezing;
• hiccups, speech disorders;
• increased or decreased urine production (due to kidney damage), painful urination, or blood/protein in the urine, fluid retention;
• altered state of consciousness, confusion, worsening or loss of memory;
• hypersensitivity;
• hearing loss, deafness, ringing or discomfort in the ears;
• hormonal disorders that can affect salt and water absorption;
• hyperthyroidism;
• insulin deficiency or resistance to normal insulin levels;
• eye irritation or inflammation, excessive tearing, eye pain, dry eyes, eye infections, stye (hordeolum), eyelid redness and swelling, eye discharge, vision disturbances, eye bleeding;
• lymph node enlargement;
• joint stiffness or muscle stiffness, feeling of heaviness;
• hair loss and abnormal hair structure;
• allergic reactions;
• redness or pain at the injection site;
• mouth pain;
• mouth or throat infection, mouth ulcers, esophagus, stomach, and intestine ulcers, sometimes with accompanying pain and bleeding, poor intestinal motility (including obstruction),
• abdominal discomfort and esophagus, difficulty swallowing, vomiting blood;
• skin infection;
• bacterial and viral infections;
• tooth infection;
• pancreatitis, bile duct obstruction;
• genital pain, erectile dysfunction;
• weight gain;
• thirst;
• hepatitis;
• injection site reactions or complications related to the use of a venous catheter;
• skin reactions (which can be severe and life-threatening), skin ulcers;
• bruises, falls, and injuries;
• vascular inflammation or bleeding, manifested by small red or purple spots (usually on the legs) to large spots similar to bruises under the skin;

Blood clots in small blood vessels (microangiopathic thrombosis) have been reported in patients treated with bortezomib.

• mild cysts;
• severe reversible brain disorders, which include seizures, high blood pressure, headache, fatigue, confusion, blindness, or other vision disturbances.

Rare side effects (may affect up to 1 in 1000 people):

• heart disease, including heart attack, angina pectoris;
• flushing;
• vein discoloration;
• spinal cord inflammation;
• ear disorders, ear bleeding;
• hypothyroidism;
• Budd-Chiari syndrome (clinical symptoms caused by blockage of liver veins);
• abnormal bowel function;
• brain bleeding;
• jaundice (yellowing of the skin and eyes);
• stye (hordeolum), eyelid redness and swelling.

If you are receiving Bortezomib Adamed in combination with other medicines for the treatment of mantle cell lymphoma, you may experience the following side effects:

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

• pneumonia;
• loss of appetite;
• hypersensitivity, numbness, tingling, or burning sensation of the skin, pain in the hands or feet
• caused by nerve damage;
• nausea or vomiting;
• diarrhea;
• mouth ulcers;
• constipation;
• muscle pain, bone pain;
• hair loss and abnormal hair structure;
• fatigue, feeling of weakness;
• fever.

Common side effects (may affect up to 1 in 10 people):

• shingles (localized, e.g., around the eyes or widespread on the body);
• herpes virus infection;
• bacterial and viral infections;
• respiratory tract infections, bronchitis, wet cough, flu-like symptoms;
• fungal infections;
• hypersensitivity (allergic reaction);
• insulin deficiency or resistance to normal insulin levels;
• fluid retention;
• sleep disorders;
• loss of consciousness;
• altered state of consciousness, confusion;
• dizziness;
• rapid heartbeat, high blood pressure, sweating;
• abnormal vision, blurred vision;
• heart failure, heart attack, chest pain, feeling of discomfort in the chest, rapid or slow heart rate;
• high or low blood pressure;
• sudden drop in blood pressure when changing body position, which can lead to fainting;
• shortness of breath during exercise;
• cough;
• hiccups;
• ringing or discomfort in the ears;
• gastrointestinal bleeding;
• heartburn;
• mouth or throat pain;
• abdominal pain;
• difficulty swallowing;
• infection or inflammation of the stomach or intestines;
• abdominal pain;
• mouth or lip inflammation, throat pain, mouth ulcers;
• liver function changes;
• itching of the skin;
• skin redness;
• rash;
• muscle cramps;
• muscle pain, bone pain;
• urinary tract infections;
• limb pain;
• swelling, including around the eyes and other parts of the body;
• chills;
• redness and pain at the injection site;
• general feeling of illness;
• weight loss;
• weight gain.

Uncommon side effects (may affect up to 1 in 100 people)

• hepatitis;
• severe allergic reaction (anaphylactic reaction), which can include: difficulty breathing, pain or pressure in the chest, dizziness or fainting, severe itching of the skin or blisters on the skin, swelling of the face, lips, tongue, and throat, which can cause difficulty breathing and swallowing, collapse;
• movement disorders, paralysis, muscle cramps, muscle tremors;
• dizziness;
• hearing loss, deafness;
• lung disorders that make breathing difficult. Some of these include: difficulty breathing, shortness of breath, shortness of breath at rest, shallow breathing, or cessation of breathing,
• blood clots in the lungs;
• jaundice (yellowing of the skin and eyes);
• stye (hordeolum), eyelid redness and swelling.

Rare side effects (may affect up to 1 in 1000 people)

• blood clots in small blood vessels (microangiopathic thrombosis).

Reporting side effects

If you experience any side effects, talk to your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety Monitoring of the 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
Side effects can also be reported to the marketing authorization holder.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Bortezomib Adamed

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label of the vial and the outer packaging, after "EXP".
Store the vial in the outer packaging to protect from light.
There are no special precautions for storage temperature of the medicinal product.
Reconstituted solution
Chemical and physical stability of the medicinal product has been demonstrated for 8 hours at 25°C and 60% RH, in the original vial and in a polypropylene syringe.
From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, the in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.
Bortezomib Adamed is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6. Contents of the pack and other information

What Bortezomib Adamed contains

• The active substance is bortezomib. Each vial contains 1 mg of bortezomib (as a mannitol boron ester). After reconstitution, 1 ml of the solution for injection contains 1 mg of bortezomib.
• The other ingredients are: mannitol (E 421).

What Bortezomib Adamed looks like and contents of the pack

Bortezomib Adamed powder for solution for injection is a white or off-white lyophilized powder or powder.
Bortezomib Adamed is packaged in a 6 ml clear glass vial with a bromobutyl rubber stopper and an aluminum seal with a plastic flip-off cap, in a cardboard box.
The pack contains 1 vial for single use.

Marketing authorization holder:

Adamed Pharma S.A.
Pieńków, ul. M. Adamkiewicza 6A
05-152 Czosnów

Manufacturer:

Synthon Hispania S.L.
Castello, 1
Poligono Las Salinas
08830 Sant Boi de Llobregat
Spain
Synthon s.r.o. Blansko
Brnenska 32/c.p.597, 678 01 Blansko,
Czech Republic
Adamed Pharma S.A.
Pieńków, ul. M. Adamkiewicza 6A
05-152 Czosnów

Date of last revision of the leaflet:

• 04.2021

The following information is intended for healthcare professionals only:

1. PREPARATION OF THE SOLUTION FOR INTRAVENOUS INJECTION

Caution: Bortezomib Adamed is a cytotoxic product. When handling the product and preparing it for use, caution should be exercised. To protect against skin contact with the product, gloves and other protective clothing should be worn.
AS Bortezomib Adamed CONTAINS NO PRESERVATIVES, ASEPTIC TECHNIQUES MUST BE STRICTLY FOLLOWED WHEN HANDLING THE PRODUCT.

• 1.1. Preparation of the 1 mg vial: add 1 mlof sterile, 9 mg/ml (0.9%) sodium chloride injection to the vial containing the Bortezomib Adamed powder. Dissolution of the lyophilized powder takes less than 2 minutes.

The concentration of the resulting solution will be 1 mg/ml. After dissolution, the solution will be clear and colorless, with a pH between 4 and 7. There is no need to check the pH of the solution.

• 1.2. Before administration, visually inspect the solution for particulate matter and discoloration. In case of particulate matter or discoloration, the solution should be discarded. Check the concentration on the vial to ensure that the correct dose is administered intravenously (1 mg/ml).
• 1.3. The reconstituted solution is preservative-free and should be used immediately after preparation. However, the chemical and physical stability of the reconstituted solution has been demonstrated for 8 hours at 25°C, in the original vial and in a polypropylene syringe. The total storage time of the reconstituted solution in the syringe should not exceed 8 hours. If the reconstituted solution is not administered immediately, the storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.

There is no need to protect the reconstituted solution from light.

2. ADMINISTRATION

• After reconstitution, withdraw the required dose from the vial and administer as a bolus intravenous injection through a peripheral or central intravenous catheter.
• Confirm the dose and concentration of the solution in the syringe (ensure that the syringe is labeled as for intravenous use).
• Administer the solution as an intravenous bolus injection over 3 to 5 seconds.
• Flush the intravenous catheter with a small volume of sterile sodium chloride 9 mg/ml (0.9%) injection after administration of Bortezomib Adamed.

Bortezomib Adamed (1 mg powder for solution for injection) SHOULD BE ADMINISTERED

INTRAVENOUSLY ONLY. Intrathecal administration has resulted in death.

3. DISPOSAL

The vial is for single use only and any unused solution should be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.