Bortezomib zentiva: detailed information

Bortezomib Zentiva, 1 mg, powder for solution for intravenous injection
Bortezomib
Please read this leaflet carefully before using the medicine, as it contains
important information for the patient.

Keep this leaflet, so that you can read it again if necessary.
If you have any further questions, please consult your doctor or pharmacist.
If you experience any side effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of contents

What Bortezomib Zentiva is and what it is used for
Important information before using Bortezomib Zentiva
How to use Bortezomib Zentiva
Possible side effects
How to store Bortezomib Zentiva
Contents of the pack and other information

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

Bortezomib Zentiva contains the active substance called bortezomib, which is a so-called
"proteasome inhibitor". Proteasomes play an important role in regulating cell functions and their
development process. By interfering with their function, bortezomib may lead to the death of
cancer cells.
Bortezomib Zentiva is used in the treatment of multiple myeloma (a cancer of the bone marrow)
in patients aged at least 18 years:

as a single agent or in combination with other medicines: pegylated liposomal doxorubicin or dexamethasone, in patients whose disease has progressed (worsened) after at least one prior therapy and for whom autologous stem cell transplantation has failed or is not possible;
in combination with melphalan and prednisone, in patients who have not received prior treatment and who are not eligible for high-dose chemotherapy followed by autologous stem cell transplantation;
in combination with dexamethasone or with dexamethasone and thalidomide, in patients who have not received prior treatment and who are eligible for high-dose chemotherapy followed by autologous stem cell transplantation (induction treatment).

Bortezomib Zentiva is also used in the treatment of mantle cell lymphoma (a type of cancer
affecting the lymph nodes) in patients aged at least 18 years, in combination with the medicines:
rituximab, cyclophosphamide, doxorubicin, and prednisone, in those who have not received prior
treatment and who are not eligible for autologous stem cell transplantation.

2. Important information before using Bortezomib Zentiva

When not to use Bortezomib Zentiva

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 particularly severe lung or heart diseases.

Warnings and precautions
Before starting treatment with Bortezomib Zentiva, discuss with the doctor if the patient:

has low numbers of red or white blood cells;
has bleeding disorders and/or low platelet count;
has diarrhoea, constipation, nausea, or vomiting;
has previously experienced fainting, dizziness, or lightheadedness;
has kidney diseases;
has moderate to severe liver function impairment;
has previously experienced numbness, tingling, or pain in hands and feet (neuropathy symptoms);
has heart diseases or blood pressure problems;
has shortness of breath or cough;
has seizures;
has shingles (around the eyes or widespread over the body);
has symptoms of tumour lysis syndrome, such as muscle cramps, muscle weakness, confusion, vision loss or disturbances, and difficulty breathing;
experiences memory loss, thinking difficulties, difficulty walking, or vision loss. These may be signs of a serious brain infection, and the doctor may recommend further tests and monitoring.

Regular blood tests must be performed before and during treatment with Bortezomib Zentiva to monitor blood cell counts regularly.
If the patient has mantle cell lymphoma and is receiving a medicine containing rituximab together with Bortezomib Zentiva, inform the doctor:

if the patient suspects a hepatitis virus infection or has had it in the past. In some cases, patients with hepatitis B virus (HBV) infection have experienced reactivation of hepatitis, which could be fatal. If the patient has a history of HBV infection, they will be closely monitored by the doctor for signs of active HBV.

Before starting treatment with Bortezomib Zentiva, carefully read the package leaflets of all medicinal products the patient is taking during treatment to obtain information about them.
If thalidomide is being taken, pregnancy must be ruled out first, and effective contraception must be used (see section Pregnancy and breastfeeding).

Children and adolescents
Bortezomib Zentiva must not be used in children and adolescents, as the effect of the medicine in this group of patients is unknown.

Bortezomib Zentiva and other medicines
Tell the doctor about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take.
In particular, inform the treating doctor if the patient is taking medicines containing any of the following active substances:

ketoconazole, 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 medicines.

Pregnancy and breastfeeding
Do not use Bortezomib Zentiva during pregnancy unless absolutely necessary.
Both men and women receiving Bortezomib Zentiva must use effective contraception during treatment and for 3 months after treatment has ended. If a patient becomes pregnant despite these measures, inform the doctor immediately.
Patients must not breastfeed during treatment with Bortezomib Zentiva. The timing of safe return to breastfeeding after treatment should be discussed with the doctor.
Thalidomide causes birth defects and fetal death. When Bortezomib Zentiva is used in combination with thalidomide, patients must comply with the requirements of the "Thalidomide Pregnancy Prevention Programme" (see the thalidomide package leaflet).

Driving and operating machinery
Bortezomib Zentiva may cause fatigue, dizziness, fainting, and blurred vision. If these symptoms occur, the patient must not drive or operate tools or machines. Even if such symptoms do not occur, caution should still be exercised.

3. How to use Bortezomib Zentiva

Your doctor will adjust the appropriate dose of Bortezomib Zentiva based on the patient's height and body weight (body surface area). The most commonly used starting dose of Bortezomib Zentiva is 1.3 mg/m² of body surface area administered twice weekly. The doctor may modify the dose and the total number of treatment cycles depending on the patient's response to treatment, occurrence of adverse reactions, and additional medical conditions (e.g. liver disease).

Multiple myeloma
If Bortezomib Zentiva is administered as a single agent, the patient will receive 4 doses of Bortezomib Zentiva intravenously on days 1, 4, 8, and 11, followed by a 10-day treatment break. This 21-day period (3 weeks) is considered one treatment cycle. The patient may receive up to 8 cycles (24 weeks).

The patient may also receive Bortezomib Zentiva in combination with pegylated liposomal doxorubicin or dexamethasone.

When Bortezomib Zentiva is administered together with pegylated liposomal doxorubicin, the patient will receive Bortezomib Zentiva intravenously during the 21-day treatment cycle, and pegylated liposomal doxorubicin will be administered at a dose of 30 mg/m² as an intravenous infusion after injection of Bortezomib Zentiva on day 4 of the 21-day cycle. The patient may receive up to 8 cycles (24 weeks).

When Bortezomib Zentiva is administered together with dexamethasone, the patient will receive Bortezomib Zentiva intravenously during the 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 Zentiva treatment cycle. The patient may receive up to 8 cycles (24 weeks).

Previously untreated multiple myeloma
If the patient has not previously been treated for multiple myeloma and the patient is not eligible for hematopoietic stem cell transplantation, the patient will receive Bortezomib Zentiva in combination with other medications: melphalan and prednisone.

In this case, each treatment cycle lasts 42 days (6 weeks). The patient will receive 9 cycles (54 weeks).

During cycles 1–4, Bortezomib Zentiva is administered twice weekly on days: 1, 4, 8, 11, 22, 25, 29, and 32.
During cycles 5–9, Bortezomib Zentiva is administered once weekly 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 previously been treated for multiple myeloma and the patient is eligible for hematopoietic stem cell transplantation, the patient will receive Bortezomib Zentiva intravenously in combination with other medications: dexamethasone or dexamethasone with thalidomide during induction therapy.

When Bortezomib Zentiva is administered with dexamethasone, the patient will receive Bortezomib Zentiva intravenously in 21-day cycles, 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 Zentiva treatment cycle. The patient may receive up to 4 cycles (12 weeks).

When Bortezomib Zentiva is administered with dexamethasone and thalidomide, 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 Zentiva treatment cycle, and thalidomide is administered orally once daily at a dose of 50 mg up to day 14 of the first cycle; if this dose is tolerated, it is increased to 100 mg on days 15–28, and may subsequently be increased to 200 mg daily starting from the second cycle. The patient may receive up to 6 cycles (24 weeks).

Previously untreated mantle cell lymphoma
If the patient has not previously been treated for mantle cell lymphoma, the patient will receive Bortezomib Zentiva intravenously in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone.

Bortezomib Zentiva is administered intravenously on days 1, 4, 8, and 11, followed by a "rest period" without drug administration. Each treatment cycle lasts 21 days (3 weeks). The patient may receive up to 8 cycles (24 weeks).

The following medications are administered as intravenous infusions on day 1 of each 21-day Bortezomib Zentiva 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 Zentiva treatment cycle.

How Bortezomib Zentiva is administered
This medicine is administered intravenously only. Bortezomib Zentiva will be administered by medical personnel experienced in the use of cytotoxic drugs.

The Bortezomib Zentiva powder must be reconstituted before administration. The preparation is carried out by trained medical personnel. The resulting solution is then administered as a rapid intravenous injection over 3 to 5 seconds.

Accidental overdose of Bortezomib Zentiva
Since this medicine is administered by a doctor or nurse, it is highly unlikely that the patient will receive an excessive dose.
However, if this should exceptionally occur, the doctor will monitor the patient for any adverse reactions.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Some of these adverse reactions may be serious.
If the patient is receiving Bortezomib Zentiva for the treatment of multiple myeloma or mantle cell lymphoma, inform the doctor immediately if any of the following symptoms occur:

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

Treatment with Bortezomib Zentiva may very commonly lead to a reduction in the number of red blood cells, white blood cells, and platelets in the patient's blood. Therefore, blood tests must be performed frequently before and during treatment with Bortezomib Zentiva to regularly monitor blood cell counts. The patient may experience a reduction in:

platelets, which may result in a tendency to bruise or bleed without injury (e.g., bleeding from the intestines, stomach, mouth and gums, or haemorrhage in the brain or liver);
red blood cells, which may lead to anaemia, characterised by symptoms such as fatigue and pallor;
white blood cells, which may increase susceptibility to infections or cause flu-like symptoms.

If the patient is receiving Bortezomib Zentiva for the treatment of multiple myeloma, the following adverse reactions may occur:
Very common adverse reactions (may affect more than 1 in 10 people):

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

Common adverse reactions (may affect up to 1 in 10 people):

low blood pressure, sudden drop in blood pressure upon standing, which may 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, flu-like symptoms;
shingles (localized, e.g., around the eyes, or disseminated throughout the body);
chest pain, shortness of breath during physical exercise;
various types of skin rash;
itchy skin, skin nodules or dry skin;
facial flushing or capillary rupture;
skin redness;
dehydration;
heartburn, bloating, belching, flatulence, abdominal pain, bleeding from the intestine or stomach;
liver function abnormalities;
inflammation of the mouth or lips, dry mouth, mouth ulcers or sore throat;
weight loss, loss of taste;
muscle cramps, muscle weakness, limb pain;
blurred vision;
infection of the outer layer of the eye and inner surface of the eyelid (conjunctivitis);
nosebleeds;
difficulty sleeping, sweating, anxiety, mood swings, depressive mood, restlessness or agitation, changes in mental state, disorientation;
swelling, including around the eyes and other parts of the body.

Uncommon adverse reactions (may affect up to 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 coagulation disorders;
circulatory failure;
pericarditis (inflammation of the outer lining of the heart) or fluid in the pericardium;
infections including: urinary tract infections, influenza, herpes, ear infection, connective tissue infection;
blood in stool, bleeding from mucous membranes, e.g., from the mouth, vagina;
cerebral vascular disorders;
paralysis, seizures, falls, movement disorders, abnormal, altered or reduced sensation (touch, hearing, taste, smell), attention disorders, tremor, twitching;
joint inflammation, including inflammation of joints in fingers, toes and jaw;
lung disorders causing breathing difficulties. These include: difficulty breathing, dyspnoea, dyspnoea at rest, shallow breathing, or respiratory arrest, wheezing;
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 ears;
hormonal disorders affecting salt and water absorption;
hyperthyroidism;
insufficient insulin production or resistance to normal insulin levels;
eye irritation or inflammation, excessively watery eyes, eye pain, dry eyes, eye infections, eyelid nodule (sty), redness and swelling of the eyelid, eye discharge, vision disorders, eye bleeding;
enlarged lymph nodes;
joint 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;
infection or inflammation of the mouth, oesophagus, stomach and intestines, sometimes with associated pain and bleeding, weak intestinal peristalsis (including obstruction), abdominal and oesophageal discomfort, difficulty swallowing, vomiting blood;
skin infection;
bacterial and viral infections;
dental infections;
pancreatitis, biliary duct obstruction;
genital organ pain, erectile dysfunction;
weight gain;
thirst;
hepatitis;
injection site reactions or complications related to vascular catheter use;
skin reactions and disorders (which may be severe and life-threatening), skin ulceration;
bruising, falls and injuries;
inflammation or bleeding of blood vessels, manifesting as small red or purple spots (usually on legs) to large bruise-like subcutaneous patches;
benign cysts;
severe reversible encephalopathy syndrome, including seizures, high blood pressure, headache, fatigue, confusion, blindness or other visual disturbances.

Rare adverse reactions (may affect up to 1 in 1000 people):

heart diseases including heart attack, angina;
flushing attacks;
vein discoloration;
spinal cord inflammation;
ear diseases, ear bleeding;
hypothyroidism;
Budd-Chiari syndrome (clinical symptoms caused by blockage of hepatic veins);
altered or abnormal intestinal function;
brain haemorrhage;
yellowing of eyes or skin (jaundice);
severe allergic reaction (anaphylactic shock) with symptoms such as: difficulty breathing, chest pain or tightness, and/or dizziness/fainting, intense skin itching or raised skin rash, swelling of face, lips, tongue and/or throat, which may cause difficulty breathing and swallowing, collapse;
breast diseases;
vaginal ulceration;
genital swelling;
alcohol intolerance;
wasting or weight loss;
increased appetite;
fistula;
joint effusion;
cyst in joint lining (synovial cyst);
bone fractures;
rhabdomyolysis (muscle fibre breakdown) leading to further complications;
liver swelling, liver bleeding;
kidney cancer;
skin condition resembling psoriasis;
skin cancer;
skin pallor;
increased number of platelets or plasma cells (a type of white blood cell);
blood clot in small blood vessels (thrombotic microangiopathy);
abnormal reaction to blood transfusion;
partial or complete vision loss;
decreased libido;
drooling;
exophthalmos (protruding eyes);
photophobia (light sensitivity);
increased respiratory rate;
anal pain;
gallstones;
hernia;
cuts;
brittle or weak nails;
abnormal protein deposition in organs;
coma;
intestinal ulceration;
multi-organ failure;
death;
severe nerve inflammation which may cause paralysis and breathing difficulties (Guillain-Barré syndrome).

If the patient is receiving Bortezomib Zentiva in combination with other medicines for the treatment of mantle cell lymphoma, the following adverse reactions may occur:
Very common adverse reactions (may affect more than 1 in 10 people):

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

Common adverse reactions (may affect up to 1 in 10 people):

shingles (localized, e.g., around the eyes, or disseminated throughout the body);
herpes virus infection;
bacterial and viral infections;
respiratory tract infections, bronchitis, wet cough, flu-like symptoms;
fungal infections;
hypersensitivity (allergic reaction);
insufficient insulin production or resistance to normal insulin levels;
fluid retention;
sleep disturbances;
loss of consciousness;
altered level of consciousness, confusion;
dizziness;
rapid heartbeat, high blood pressure, sweating;
visual disturbances, blurred vision;
heart failure, heart attack, chest pain, discomfort in the chest, rapid or slow heart rate;
high or low blood pressure;
sudden drop in blood pressure upon changing position, which may lead to fainting;
shortness of breath during exertion;
cough;
hiccups;
ringing in ears, ear discomfort;
bleeding from intestine or stomach;
heartburn;
abdominal pain, belching;
difficulty swallowing;
infection or inflammation of stomach or intestines;
abdominal pain;
inflammation of mouth or lips, sore throat;
altered liver function;
skin itching;
skin redness;
rash;
muscle cramps;
urinary tract infection;
limb pain;
swelling affecting eyes and other body parts;
chills;
redness and pain at injection site;
general feeling of illness;
weight loss;
weight gain.

Uncommon adverse reactions (may affect up to 1 in 100 people):

hepatitis;
severe allergic reaction (anaphylactic reaction), symptoms of which may include: difficulty breathing, chest pain or tightness, dizziness or fainting, severe skin itching or blisters, swelling of face, lips, tongue, throat, which may cause difficulty swallowing, collapse;
movement disorders, paralysis, muscle twitching;
dizziness;
hearing loss, deafness;
lung disorders causing breathing difficulties. These include: difficulty breathing, dyspnoea, dyspnoea at rest, shallow breathing, or respiratory arrest, wheezing;
blood clots in the lungs;
jaundice (yellowing of skin and eyes);
eyelid nodule (sty), redness and swelling of the eyelid.

Rare adverse reactions (may affect up to 1 in 1000 people):

blood clot in small blood vessels (thrombotic microangiopathy).

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform the doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions of the Office for Registration 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
Adverse reactions can also be reported to the marketing authorisation holder or its representative in Poland.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Bortezomib Zentiva

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 vial label and outer packaging,
following "Expiry date (EXP)".
Store the vial in the outer packaging in order to protect it from light.
There are no special requirements for storage temperature.
Diluted solution
From a microbiological point of view, the diluted solution should be used immediately after preparation.
If not used immediately, the user is responsible for the storage duration and conditions.
The solution has been shown to be chemically and physically stable for 8 days at 25°C and 60% relative humidity,
or for 15 days at 5±3°C, protected from light, when stored in both the vial and in a polypropylene syringe.

6. Contents of the package and other information

What Bortezomib Zentiva contains

The active substance is bortezomib. Each vial contains 1 mg of bortezomib (as mannitol and boric acid ester).
Other ingredients: mannitol (E 421).

After reconstitution, 1 ml of injection solution contains 1 mg of bortezomib.
What Bortezomib Zentiva looks like and contents of the pack
Bortezomib Zentiva powder for solution for injection is a white or almost white solidified powder or powder.
Bortezomib Zentiva 1 mg is available in glass vials with a bromobutyl rubber stopper, aluminium seal, and plastic flip-off cap, packed in a cardboard box.
Each pack contains 1 single-use vial.
Marketing Authorisation Holder
Zentiva, k. s.
U Kabelovny 130
102 37 Prague 10
Czech Republic
Manufacturer
Synthon Hispania SL
Castelló 1101, Las Salinas
Barcelona, 08830, Spain
Synthon s.r.o. Blansko
Brnenska 32/c.p.597,
678 01 Blansko, Czech Republic
For more detailed information about the medicine and its names in the Member States of the
European Economic Area, please contact the representative of the Marketing Authorisation Holder in Poland:
Zentiva Polska Sp. z o.o.
ul. Bonifraterska 17
00-203 Warsaw
tel.: +48 22 375 92 00

The following information is intended for healthcare professionals only:
1. PREPARATION OF INTRAVENOUS INJECTION SOLUTION
Warning: Bortezomib Zentiva is a cytotoxic product. Exercise caution when handling and preparing the medicine. To protect against skin contact, the use of gloves and other protective clothing is recommended.
AS Bortezomib Zentiva DOES NOT CONTAIN PRESERVATIVES, ASEPTIC TECHNIQUES MUST BE STRICTLY FOLLOWED DURING HANDLING.
1.1. Reconstitution of the 1 mg vial: add 1 ml of sterile 9 mg/ml (0.9%) sodium chloride injection solution to the vial containing Bortezomib Zentiva powder. The lyophilized powder dissolves in less than 2 minutes.
The resulting solution will have a concentration of 1 mg/ml. After reconstitution, the solution is clear and colourless, with a pH between 4 and 7. There is no need to check the pH of the solution.
1.2. Visually inspect the solution for particulate matter and discoloration prior to administration. If particulates or discoloration are observed, the solution must be discarded. Check the concentration on the vial label to ensure the correct dose is administered intravenously (1 mg/ml).
1.3. The reconstituted solution contains no preservatives and should be used immediately. However, the chemical and physical stability of the prepared solution is maintained for 8 days at 25°C and 60% relative humidity, or for 15 days at 5±3°C, when stored protected from light, both in the vial and in a polypropylene syringe. If the diluted solution is not administered immediately after preparation, the person administering the medicine is responsible for the storage time and conditions prior to use.
2. ADMINISTRATION

After reconstitution, withdraw the appropriate volume of solution according to the dose calculated based on the patient's body surface area.
Before administration, confirm the dose and concentration of the medicine in the syringe (ensure the syringe is labelled for intravenous use).
Inject the solution as an intravenous bolus over 3 to 5 seconds through a centrally or peripherally inserted intravenous catheter.
The intravenous catheter used for administration should be flushed with a small amount of sterile 9 mg/ml (0.9%) sodium chloride injection solution.

Bortezomib Zentiva 1 mg powder for solution for injection MUST BE ADMINISTERED
INTRAVENOUSLY ONLY. Subcutaneous administration has resulted in death.
3. DISPOSAL OF THE MEDICINE
The vial is intended for single use only, and any unused solution must be discarded.
Any unused product or waste material must be disposed of in accordance with local requirements.