Bortezomib Ever Pharma

Leaflet accompanying the packaging: Information for the user

Bortezomib EVER Pharma, 2.5 mg/mL, solution for injection

bortezomib

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

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor or pharmacist.
• If the patient experiences any side effects, including any not listed in this leaflet, they should inform their doctor or pharmacist. See section 4.

Table of contents of the leaflet

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

1. What is Bortezomib EVER Pharma and what is it used for

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

• as a single drug or in combination with other drugs: pegylated liposomal doxorubicin or dexamethasone in patients whose disease has progressed after at least one previous treatment and for whom hematopoietic stem cell transplantation has failed or is not possible.
• In combination with 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 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 EVER Pharma is used to treat mantle cell lymphoma (a type of cancer that affects the lymph nodes) in patients aged 18 and over in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, who have not been previously treated and do not qualify for hematopoietic stem cell transplantation.

2. Important information before using Bortezomib EVER Pharma

When not to use Bortezomib EVER Pharma

• 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 certain severe lung or heart diseases.

Warnings and precautions

The patient should inform their doctor if they have any of the following:

• low red or white blood cell count
• bleeding disorders and/or low platelet count
• diarrhea, constipation, nausea, or vomiting
• history of fainting, dizziness, and lightheadedness
• kidney disease
• moderate to severe liver function disorders
• history of numbness, tingling, and pain in hands and feet (symptoms of neuropathy)
• heart disease or blood pressure disorders
• 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 loss of vision. These may be symptoms of a severe brain infection, and the doctor may recommend further tests and observation.

The patient must have regular blood tests before and during treatment with Bortezomib EVER Pharma to regularly check their blood cell count.
If the patient has mantle cell lymphoma and is also receiving rituximab with Bortezomib EVER Pharma, they should tell their doctor:

• if they suspect or have had hepatitis B virus infection 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 the patient has a history of hepatitis B, they will be closely monitored by their doctor for symptoms of active hepatitis B.

Before starting treatment with Bortezomib EVER Pharma, the patient should carefully read the leaflets of all medicinal products they are taking during treatment to obtain information about them. If they are taking thalidomide, they should ensure that the female patient is not pregnant and then use effective contraception (see "Pregnancy and breastfeeding").

Children and adolescents

Bortezomib EVER Pharma should not be used in children and adolescents, as its effect in this patient group is unknown.

Bortezomib EVER Pharma and other medicines

The patient should tell their doctor about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take.
In particular, the patient should inform their doctor if they 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, used to treat epilepsy
• St. John's Wort (Hypericum perforatum), used to treat depression and other conditions
• oral antidiabetic drugs

Pregnancy and breastfeeding

Bortezomib EVER Pharma should not be used during pregnancy unless absolutely necessary.
Both men and women receiving Bortezomib EVER Pharma must use effective contraception during and for 3 months after completing treatment. If, despite using these methods, the patient becomes pregnant, they should immediately inform their doctor.
Patients should not breastfeed during treatment with Bortezomib EVER Pharma.
It is necessary to discuss with the doctor the safe timing of returning to breastfeeding after completing treatment in the patient.
Thalidomide causes birth defects and fetal death. When Bortezomib EVER Pharma is used in combination with thalidomide, patients must follow the "Thalidomide Pregnancy Prevention Program" (see thalidomide leaflet).

Driving and using machines

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

Bortezomib EVER Pharma contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per vial, which means the medicine is considered "sodium-free".

3. How to use Bortezomib EVER Pharma

The doctor will determine the appropriate dose of Bortezomib EVER Pharma for the patient based on their height and weight (body surface area). The most commonly used initial dose of Bortezomib EVER Pharma is 1.3 mg/m2 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).
Progressive multiple myeloma
If Bortezomib EVER Pharma is administered as a single drug, the patient will receive 4 doses of Bortezomib EVER Pharma intravenously or subcutaneously 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 EVER Pharma in combination with pegylated liposomal doxorubicin or dexamethasone.
When Bortezomib EVER Pharma is administered in combination with pegylated liposomal doxorubicin, the patient will receive Bortezomib EVER Pharma intravenously or subcutaneously during a 21-day treatment cycle, and pegylated liposomal doxorubicin will be administered at a dose of 30 mg/m2 body surface area by intravenous infusion after Bortezomib EVER Pharma injection on day 4 of the 21-day Bortezomib EVER Pharma treatment cycle. The patient may receive up to 8 cycles (24 weeks).
When Bortezomib EVER Pharma is administered in combination with dexamethasone, the patient will receive Bortezomib EVER Pharma intravenously or subcutaneously 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 21-day Bortezomib EVER Pharma treatment 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 patient does notqualify for hematopoietic stem cell transplantation, they will receive Bortezomib EVER Pharma in combination with other drugs: melphalan and prednisone. In this case, the treatment cycle lasts 42 days (6 weeks). The patient will receive 9 cycles (54 weeks).

• During cycles 1-4, Bortezomib EVER Pharma is administered twice a week, on days: 1, 4, 8, 11, 22, 25, 29, and 32.
• During cycles 5-9, Bortezomib EVER Pharma is administered once a week, on days: 1, 8, 22, and 29. Both melphalan (at a dose of 9 mg/m2 body surface area) and prednisone (at a dose of 60 mg/m2 body surface area) 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 EVER Pharma intravenously or subcutaneously in combination with other drugs: dexamethasone or dexamethasone with thalidomide in induction treatment.
When Bortezomib EVER Pharma is administered with dexamethasone, the patient will receive Bortezomib EVER Pharma intravenously or subcutaneously during a 21-day cycle, and dexamethasone at a dose of 40 mg will be administered orally on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 21-day Bortezomib EVER Pharma treatment cycle. The patient may receive up to 4 cycles (12 weeks).
When Bortezomib EVER Pharma is administered with thalidomide and dexamethasone, the treatment cycle lasts 28 days (4 weeks).
Dexamethasone at a dose of 40 mg will be administered orally on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day Bortezomib EVER Pharma treatment 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 EVER Pharma intravenously in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone.
Bortezomib EVER Pharma is administered intravenously on days 1, 4, 8, and 11, followed by a "rest period" without medication administration. 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 EVER Pharma treatment cycle:

• Rituximab at a dose of 375 mg/m2 body surface area, cyclophosphamide at a dose of 750 mg/m2 body surface area, and doxorubicin at a dose of 50 mg/m2 body surface area.
• Prednisone is administered orally at a dose of 100 mg/m2 body surface area on days 1, 2, 3, 4, and 5 of the Bortezomib EVER Pharma treatment cycle.

How Bortezomib EVER Pharma is administered

This medicine is administered subcutaneously or, after dilution, intravenously. Bortezomib EVER Pharma will be administered by medical personnel experienced in the use of cytotoxic drugs.
The solution for injection is administered intravenously or subcutaneously. The intravenous injection is performed very quickly and lasts from 3 to 5 seconds. The subcutaneous injection is administered into the thigh or abdomen.

Use of a higher than recommended dose of Bortezomib EVER Pharma

This medicine is administered by a doctor or nurse, so 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 EVER Pharma can cause side effects, although not everybody gets them.
Some of these side effects can be serious.
If the patient is receiving Bortezomib EVER Pharma for multiple myeloma or mantle cell lymphoma, they should immediately tell their doctor if they 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 EVER Pharma 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 EVER Pharma to regularly check their blood cell count. The patient may experience a decrease in:

• platelet count, which can lead to bruising or bleeding that is not caused by injury (e.g., gastrointestinal bleeding, bleeding from the mouth, vagina, or gums, or cerebral hemorrhage)
• red blood cell count, which can lead to anemia, characterized by symptoms such as fatigue and pallor
• white blood cell count, which can lead to increased susceptibility to infections or flu-like symptoms

If the patient is receiving Bortezomib EVER Pharma for multiple myelomatreatment, they may experience the following side effects:
Very common side effects (may occur in more than 1 in 10 people)

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

Common side effects (may occur in less than 1 in 10 people)

• low blood pressure, sudden drop in blood pressure, which can lead to fainting
• high blood pressure
• reduced 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 sputum production, flu-like symptoms
• shingles (localized around the eyes or widespread on the body)
• chest pain, shortness of breath during exercise
• various types of rash
• itching, skin rash, or dry skin
• flushing of the face or broken blood vessels
• redness of the skin
• dehydration
• heartburn, bloating, belching, gas, abdominal pain, gastrointestinal bleeding
• liver function disorders
• mouth or lip inflammation, dry mouth, mouth ulcers, or sore throat
• weight loss, loss of taste
• muscle cramps, muscle weakness, limb pain
• blurred vision
• conjunctivitis
• nosebleeds
• difficulty sleeping, sweating, anxiety, mood swings, depression, restlessness, or agitation, changes in mental state, disorientation
• swelling, including around the eyes and other parts of the body

Uncommon side effects (may occur in less than 1 in 100 people)

• heart failure, heart attack, chest pain, discomfort in the chest, rapid or slow heart rate
• kidney failure
• vein inflammation, blood clots in veins and lungs
• blood clotting disorders
• circulatory failure
• pericarditis (inflammation of the outer layer of the heart) or fluid in the pericardium;
• infections, including urinary tract infections, flu, herpes, ear and connective tissue infections
• blood in stool, bleeding from mucous membranes, e.g., mouth, vagina
• cerebrovascular disorders
• paralysis, seizures, falls, movement disorders, abnormal or changed sensation (touch, hearing, taste, smell), attention disorders, tremors, sudden movements (jerking)
• arthritis, including joint pain in fingers, toes, and jaw
• respiratory disorders that make breathing difficult. Some of these include: difficulty breathing, shortness of breath, shortness of breath at rest, shallow breathing, or breathing cessation
• hiccups, speech disorders
• increased or decreased urine production (due to kidney damage), painful urination, or blood/protein in urine, fluid retention
• altered level 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 disorders, eye bleeding

oczu, guzek w powiece (gradówka), zaczerwienienie i obrzęk powieki, wydzielina z oczu,
zaburzenia widzenia, krwawienia z oczu

• lymph node enlargement
• joint stiffness or muscle stiffness, feeling of heaviness, groin pain
• hair loss and abnormal hair structure
• allergic reactions
• redness or pain at the injection site
• mouth pain
• infections or inflammation of the mouth, esophagus, stomach, and intestines, sometimes with accompanying pain and bleeding, poor intestinal motility (including obstruction), abdominal discomfort, and difficulty swallowing, vomiting blood
• skin infection
• bacterial and viral infections
• tooth infection
• pancreatitis, bile duct obstruction
• genital pain, erectile dysfunction
• weight gain
• thirst
• hepatitis
• disorders related to the injection site or use of a vascular catheter
• skin reactions and disorders (which can be severe and life-threatening), skin ulcers
• bruises, falls, and injuries
• vessel inflammation or bleeding, manifested by small red or purple spots (usually on the legs) to large, bruise-like spots under the skin
• benign cysts
• severe reversible brain disorders, including seizures, high blood pressure, headache, fatigue, confusion, blindness, or other vision disorders

Rare side effects (may occur in less than 1 in 1000 people)

• heart disease, including heart attack, angina pectoris
• severe nerve inflammation, which can cause paralysis and difficulty breathing (Guillain-Barré syndrome)
• flushing
• vein discoloration
• spinal cord inflammation
• ear disorders, ear bleeding
• hypothyroidism
• Budd-Chiari syndrome (clinical symptoms caused by blockage of liver veins)
• altered or abnormal bowel function
• brain bleeding
• jaundice (yellowing of the skin and eyes)
• stye (hordeolum), eyelid redness and swelling

Very rare side effects (may occur in less than 1 in 10,000 people)

• blood clots in small blood vessels (thrombotic microangiopathy);
• severe nerve inflammation, which can cause paralysis and difficulty breathing (Guillain-Barré syndrome).

Reporting side effects

If side effects occur, including any not listed in this leaflet, the patient should inform their doctor or pharmacist. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181 C, 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.
Reporting side effects will help gather more information on the safety of the medicine.

5. How to store Bortezomib EVER Pharma

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and outer packaging after "Expiry Date (EXP)". The expiry date refers to the last day of the month.
Store in a refrigerator (2°C - 8°C).
Store the vial in the outer packaging to protect from light.
The solution should be used immediately after opening/dilution. If the diluted solution is not administered immediately after preparation, the user is responsible for the storage time and conditions of the medicine before administration. However, the (diluted) solution, stored in the original vial and/or polypropylene syringe, remains stable for 28 days when stored in a refrigerator (2°C - 8°C) and up to 25°C and protected from light, and for 24 hours at up to 25°C in normal indoor lighting conditions.
Regarding the stability of the solution in the syringe, the same storage conditions apply to the diluted solution as to the undiluted solution.
Bortezomib EVER Pharma is for single use only. Any unused medicine or waste material should be disposed of in accordance with local regulations.

6. Contents of the packaging and other information

What Bortezomib EVER Pharma contains

• The active substance of the medicine is bortezomib. 1 mL of the solution contains 2.5 mg of bortezomib (as a mannitol and boric acid ester). Each vial with 1 mL of solution for injection contains 2.5 mg of bortezomib (as a mannitol and boric acid ester). Each vial with 1.4 mL of solution for injection contains 3.5 mg of bortezomib (as a mannitol and boric acid ester). Each vial contains an additional excess of solution, amounting to 0.2 mL.
• The other ingredients are: mannitol (E 421), sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment), and water for injections.

Vial with a volume of 1 mL:
Solution for subcutaneous injection: The product is ready for use at a concentration of 2.5 mg/mL.
Intravenous administration: Add 1.8 mL of sterile, 9 mg/mL (0.9%) sodium chloride solution for injection to the vial containing Bortezomib EVER Pharma.
OR
Vial with a volume of 1.4 mL:
Solution for subcutaneous injection: The product is ready for use at a concentration of 2.5 mg/mL.
Intravenous administration: Add 2.4 mL of sterile, 9 mg/mL (0.9%) sodium chloride solution for injection to the vial containing Bortezomib EVER Pharma.
The concentration of the resulting solution will be 1 mg/mL. After dilution, the solution will be clear and colorless to light yellow, with a pH between 4 and 7. It is not necessary to check the pH of the solution.

What Bortezomib EVER Pharma looks like and contents of the pack

Bortezomib EVER Pharma is a clear, colorless to light yellow solution.
Bortezomib EVER Pharma is supplied in a vial made of type 1 colorless glass, closed with a rubber stopper and an aluminum seal, with a plastic flip-off cap, in a cardboard box.
Pack sizes
1 x 1 mL vial (2.5 mg/1 mL)
5 x 1 mL vial (2.5 mg/1 mL)
1 x 1.4 mL vial (3.5 mg/1.4 mL)
5 x 1.4 mL vial (3.5 mg/1.4 mL)
Not all pack sizes may be marketed.

Marketing authorization holder

EVER Valinject GmbH
Oberburgau 3
4866 Unterach am Attersee
Austria

Manufacturer

EVER Pharma Jena GmbH
Otto-Schott-Strasse 15
07745 Jena
Germany
EVER Pharma Jena GmbH
Brüsseler Str. 18
07747 Jena
Germany