Bortezomib krka

Package leaflet: Information for the user

Bortezomib Krka, 3.5 mg, powder for solution for injection
Bortezomibum
Please read all of this leaflet carefully before 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, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet:

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

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

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

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

Bortezomib Krka 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 rituximab, cyclophosphamide, doxorubicin, and prednisone, in those whose disease has not been previously treated and who are not eligible for haematopoietic stem cell transplantation.

2. Important information before using Bortezomib Krka

When not to use Bortezomib Krka

• 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
You should inform the doctor if the patient:

• has a low number of red or white blood cells;
• has bleeding disorders and/or a low platelet count;
• experiences diarrhea, constipation, nausea, or vomiting;
• has previously experienced fainting, dizziness, or lightheadedness;
• has kidney disease;
• has moderate to severe liver function impairment;
• has previously experienced numbness, tingling, or pain in the hands or feet (symptoms of neuropathy);
• has heart disease or blood pressure problems;
• experiences shortness of breath or cough;
• has seizures;
• has shingles (around the eye or widespread);
• has symptoms of tumor lysis syndrome, such as muscle cramps, muscle weakness, confusion, vision loss or disturbances, and difficulty breathing;
• experiences memory loss, thinking disorders, difficulty walking, or vision loss. These may be symptoms of a serious brain infection. The doctor may recommend further tests and monitoring. Regular blood tests must be performed before and during treatment with Bortezomib Krka to monitor blood cell counts regularly. If the patient has mantle cell lymphoma and is receiving rituximab together with Bortezomib Krka, inform the doctor:
• if the patient suspects a hepatitis virus infection or has had it in the past. In several cases, patients who previously had hepatitis B virus infection experienced reactivation of hepatitis, which could be fatal. In patients with a history of hepatitis B virus infection, the doctor will closely monitor for signs of active HBV. Before starting treatment with Bortezomib Krka, carefully read the package leaflets of all concomitantly used medicines to obtain information about them. If the patient is taking thalidomide, pregnancy must be ruled out and effective contraception must be used (see below "Pregnancy and breastfeeding"). Children and adolescents Bortezomib Krka should not be used in children and adolescents, as it is not known how the medicine works in this group. Bortezomib Krka and other medicines Inform the doctor about all medicines currently used, recently used, or planned for use. In particular, inform the 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 in the treatment of epilepsy;
• St. John's wort (Hypericum perforatum), used to treat depression and other conditions;
• oral antidiabetic medicines. Pregnancy and breastfeeding Bortezomib Krka should not be used during pregnancy unless absolutely necessary. Both men and women receiving Bortezomib Krka must use effective contraception during treatment and for 3 months after its completion. If pregnancy occurs despite using contraception, inform the doctor immediately. Breastfeeding must not be used during treatment with Bortezomib Krka. Discuss with the doctor the appropriate time to resume breastfeeding after treatment ends.

Thalidomide causes birth defects and fetal death. When Bortezomib Krka is used in combination with thalidomide, patients must comply with the requirements of the "Thalidomide Pregnancy Prevention Program" (see the thalidomide package leaflet).
Driving and using machines
Bortezomib Krka may cause fatigue, dizziness, fainting, and blurred vision. If such symptoms occur, the patient must not drive or operate tools or machinery. Even if no symptoms are present, caution should still be exercised.

3. How to use Bortezomib Krka

The treating physician will adjust the appropriate dose of Bortezomib Krka for the patient based on the patient's height and body weight (body surface area). The most commonly used starting dose of Bortezomib Krka is 1.3 mg/m² of body surface area administered twice weekly.
The physician 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 Krka is administered as a single agent, the patient will receive 4 doses of Bortezomib Krka 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 Krka in combination with the following medicines: pegylated liposomal doxorubicin or dexamethasone.

When Bortezomib Krka is administered together with pegylated liposomal doxorubicin, the patient will receive Bortezomib Krka 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 the injection of Bortezomib Krka on day 4 of the 21-day cycle.
The patient may receive up to 8 cycles (24 weeks).

When Bortezomib Krka is administered together with dexamethasone, the patient will receive Bortezomib Krka 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 treatment cycle with Bortezomib Krka.
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 does not qualify for hematopoietic stem cell transplantation, the patient will receive Bortezomib Krka in combination with other medicines: melphalan and prednisone.
In this case, the treatment cycle duration is 42 days (6 weeks). The patient will receive 9 cycles (54 weeks).

• During cycles 1–4, Bortezomib Krka is administered twice weekly on days: 1, 4, 8, 11, 22, 25, 29, and 32.
• During cycles 5–9, Bortezomib Krka 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 qualifies for hematopoietic stem cell transplantation, the patient will receive intravenous Bortezomib Krka in combination with other medicines: dexamethasone or dexamethasone with thalidomide as induction therapy.

When Bortezomib Krka is administered with dexamethasone, the patient will receive Bortezomib Krka 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 treatment cycle with Bortezomib Krka.
The patient will receive up to 4 cycles (12 weeks).

When Bortezomib Krka is administered with dexamethasone and thalidomide, the treatment cycle duration is 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 treatment cycle with Bortezomib Krka, and thalidomide is administered orally once daily at a dose of 50 mg until 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 Krka intravenously in combination with the following medicines: rituximab, cyclophosphamide, doxorubicin, and prednisone.
Bortezomib Krka is administered intravenously on days 1, 4, 8, and 11, followed by a "rest period" without administration of medicines. One treatment cycle lasts 21 days (3 weeks). The patient may receive up to 8 cycles (24 weeks).

The following medicines are administered as intravenous infusions on day 1 of each 21-day treatment cycle with Bortezomib Krka: 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 treatment cycle with Bortezomib Krka.

How Bortezomib Krka is administered
This medicine is administered intravenously or subcutaneously. Bortezomib Krka will be administered by trained medical personnel experienced in the use of cytotoxic medicines. The Bortezomib Krka powder must be reconstituted before administration. Preparation of the medicine is performed by trained medical personnel. The resulting solution is then administered as a rapid intravenous injection over 3 to 5 seconds, or subcutaneously. Subcutaneous injection is administered into the thigh or abdomen.

Use of a higher than recommended dose of Bortezomib Krka
Since this medicine is administered by a doctor or nurse, it is unlikely that the patient will receive too high a 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 Krka 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 of or changes in 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 chest tightness.

Treatment with Bortezomib Krka may very frequently cause 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 Krka to monitor blood cell counts regularly. The patient may experience a decrease in:

• platelets, which may lead to a tendency to bruise or bleed without injury (e.g., bleeding from the intestines, stomach, mouth, or gums, or hemorrhage in the brain or liver);

• red blood cells, which may lead to anemia, associated with symptoms such as fatigue and pallor;

• white blood cells, which may lead to increased susceptibility to infections or flu-like symptoms.

If the patient is receiving Bortezomib Krka 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;
• decreased number of red and/or white blood cells (see above);
• fever;
• nausea or vomiting, loss of appetite;
• constipation, with or without abdominal distension (symptoms may be severe);
• diarrhea: if diarrhea occurs, the patient must drink more fluids than usual. The doctor may recommend additional medications to control diarrhea;
• 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 production, flu-like symptoms;
• shingles (localized around the eyes or disseminated throughout the body);
• chest pain, shortness of breath during physical exercise;
• various types of rashes;
• 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;
• mouth or lip pain, dry mouth, mouth ulcers, or sore throat;
• weight loss, loss of taste;
• painful muscle cramps, muscle cramps, muscle weakness, limb pain;
• blurred vision;
• infection of the outer layer of the eyeball (cornea) and the mucous membrane lining the inner eyelid (conjunctivitis);
• nosebleeds;
• difficulty falling asleep, excessive 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;
• phlebitis, blood clots in veins and lungs;
• blood coagulation disorders;
• circulatory failure;
• pericarditis (inflammation of the outer sac surrounding the heart) or fluid in the pericardium;
• infections, including urinary tract infections, influenza, herpes virus infections, ear infection, and connective tissue inflammation;
• presence of blood in stool, bleeding from mucous membranes, e.g., from mouth, vagina;
• cerebral vascular disorders;
• paralysis, seizures, falls, movement disorders, abnormal, changed or reduced sensation (touch, hearing, taste, smell), attention disorders, tremor, muscle twitching;
• joint inflammation, including inflammation of joints in fingers, toes, and jaw;
• lung disorders making breathing difficult. These include: difficulty breathing, shortness of breath, dyspnea at rest, shallow breathing, or respiratory arrest, wheezing;
• hiccups, speech disorders;
• increased or decreased urine output (due to kidney damage), pain during urination, or presence of blood and/or protein in urine, fluid retention;
• disturbances 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, excessive tearing, eye pain, dry eyes, eye infections, eyelid nodule (sty), redness and swelling of eyelids, eye discharge, vision disturbances, bleeding in the eye;
• 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;
• infections or inflammation of the mouth, mouth ulcers, esophagus, stomach, and intestines, sometimes with associated pain or bleeding, weak intestinal peristalsis (including obstruction), abdominal or esophageal discomfort, difficulty swallowing, vomiting blood;
• skin infections;
• bacterial and viral infections;
• tooth infection;
• 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 appearing as small red or purple spots (usually on legs) to large, bruise-like subcutaneous patches;
• benign cysts;
• severe reversible brain disorders, including seizures, high blood pressure, headaches, fatigue, confusion, blindness, or other vision disturbances.

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

• heart diseases including heart attack, angina pectoris;
• severe nerve inflammation which may lead to paralysis and breathing difficulties (Guillain-Barré syndrome);
• 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 hemorrhage;
• 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 skin hives, swelling of face, lips, tongue and/or throat, which may cause difficulty breathing and swallowing, collapse;
• breast diseases;
• vaginal ulceration;
• genital organ swelling;
• alcohol intolerance;
• wasting or weight loss;
• increased appetite;
• fistula;
• joint effusion;
• cyst in joint lining (ganglion cyst);
• bone fractures;
• muscle fiber breakdown leading to further complications;
• liver swelling, liver bleeding;
• kidney cancer;
• skin changes resembling psoriasis;
• skin cancer;
• skin pallor;
• increased number of platelets or plasma cells (a type of white blood cell) in blood;
• blood clot in small blood vessels (thrombotic microangiopathy);
• abnormal reaction to blood transfusion;
• partial or complete vision loss;
• decreased libido;
• drooling;
• eye protrusion;
• light sensitivity;
• increased breathing rate;
• anal pain;
• gallstones;
• hernia;
• cuts;
• brittle or weak nails;
• abnormal protein deposition in organs;
• coma;
• intestinal ulceration;
• multi-organ failure;
• death.

If the patient is receiving Bortezomib Krka 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;
• diarrhea;
• 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 around the eyes or disseminated throughout the body);
• herpes virus infection;
• bacterial and viral infections;
• respiratory tract infections, bronchitis, cough with sputum production, flu-like symptoms;
• fungal infections;
• hypersensitivity (allergic reaction);
• insufficient insulin production or resistance to normal insulin levels;
• fluid retention;
• sleep disturbances;
• loss of consciousness;
• disturbances of consciousness, confusion;
• dizziness;
• rapid heartbeat, high blood pressure, sweating;
• abnormal vision, 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, bloating;
• difficulty swallowing;
• infection or inflammation of stomach or intestines;
• abdominal pain;
• mouth or lip pain, 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 malaise;
• 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, intense skin itching or skin blisters, swelling of face, lips, tongue and/or throat, which may cause difficulty swallowing, collapse;
• movement disorders, paralysis, muscle twitching;
• dizziness;
• hearing loss, deafness;
• lung disorders making breathing difficult. These include: difficulty breathing, shortness of breath, dyspnea at rest, shallow breathing, or respiratory arrest, wheezing.

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

• blood clot in small blood vessels (thrombotic microangiopathy);
• severe nerve inflammation which may lead to paralysis and breathing difficulties (Guillain-Barré syndrome).

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 Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 4921301, fax: +48 22 4921309, website: https://smz.ezdrowie.gov.pl. Adverse reactions can also be reported to the marketing authorization holder. Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Bortezomib Krka

Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging following the abbreviation EXP. The expiry date refers to the last day of the stated month.
Do not store above 30°C.
Keep the vial in the outer packaging to protect from light.
The prepared solution has been shown to remain chemically and physically stable for 8 hours when stored at 25°C in the original vial.
From a microbiological point of view, unless the method of opening/dissolving excludes the risk of microbiological contamination, the diluted solution should be used immediately after preparation.
If the solution is not used immediately, the person administering the medicine is responsible for the storage time and conditions prior to administration to the patient.
The total storage time of the diluted medicine before administration should not exceed 8 hours.
Do not use this medicine if the vial is damaged.
Medicines must not be disposed of via the sewage system or household waste. Ask a pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What Bortezomib Krka contains

• The active substance is bortezomib. Each vial contains 3.5 mg of bortezomib (in the form of a boronic acid ester with mannitol).
• Other ingredients are mannitol and nitrogen.

What Bortezomib Krka looks like and contents of the pack

Bortezomib Krka powder for solution for injection is a white or almost white lyophilised powder or powder.
A 10 ml vial made of colourless type I glass with a grey bromobutyl rubber stopper and a blue flip-off seal, containing 3.5 mg of bortezomib.
Bortezomib Krka is available in packs containing 1 vial.

Marketing authorisation holder and manufacturer / importer:
Krka, d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia

For further information about this medicinal product and its names in the European Economic Area member states, please contact the local representative of the marketing authorisation holder:
Krka-Polska Sp. z o.o.
Równoległa Street 5
02-235 Warsaw
Tel. 22 57 37 500

This medicinal product is authorised in the EEA member states under the following names:
Bortezomib Krka 1 mg Powder for solution for injection
DE:
Bortezomib Krka 3.5 mg Powder for solution for injection
Bortezomib Krka 1 mg powder for injection solution
SK: Bortezomib Krka 3.5 mg powder for injection solution
CZ: Bortezomib Krka
PL: Bortezomib Krka
Bortezomib Krka 1 mg powder for injection solution
HU:
Bortezomib Krka 3.5 mg powder for injection solution
Bortezomib Krka 1 mg powder for injection solution
BG:
Bortezomib Krka 3.5 mg powder for injection solution
Bortezomib Krka 1 mg powder for injectable solution
RO:
Bortezomib Krka 3.5 mg powder for injectable solution
Bortezomib Krka 1 mg powder for injection solution
LT:
Bortezomib Krka 3.5 mg powder for injection solution
Bortezomib Krka 1 mg powder for preparation of injection solution
LV:
Bortezomib Krka 3.5 mg powder for preparation of injection solution
EE: Bortezomib Krka
Bortezomib Krka 1 mg powder for injection solution
SI:
Bortezomib Krka 3.5 mg powder for injection solution
Bortezomib Krka 1 mg powder for injection solution
HR:
Bortezomib Krka 3.5 mg powder for injection solution
Bortezomib HCS 1 mg Powder for solution for injection
AT:
Bortezomib HCS 3.5 mg Powder for solution for injection
Bortezomib Krka 1 mg powder for solution for injection
BE:
Bortezomib Krka 3.5 mg powder for solution for injection
DK: Bortezomib Krka

Information intended exclusively for healthcare professionals:

Bortezomib Krka, 3.5 mg, powder for solution for injection

1. PREPARATION OF INTRAVENOUS INJECTION SOLUTION

Warning: Bortezomib Krka is a cytotoxic medicinal product. Great care must be taken when handling and preparing the medicinal product for use. To protect the skin from contact with the medicinal product, the use of gloves and other protective clothing is recommended.
SINCE BORTEZOMIB KRKA DOES NOT CONTAIN PRESERVATIVES, ASEPTIC TECHNIQUES MUST BE STRICTLY FOLLOWED WHEN HANDLING THE MEDICINAL PRODUCT.

1.1 Preparation of the 3.5 mg vial: Carefully add 3.5 ml of sterile 9 mg/ml (0.9%) sodium chloride injection solution to the vial containing Bortezomib Krka powder, using a 1 ml syringe, without removing the vial stopper. Dissolution of the lyophilized powder takes less than 2 minutes. The concentration of the resulting solution will be 1 mg/ml. After reconstitution, the solution will be clear and colourless, 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. If any discoloration or precipitation is observed, the solution must be discarded. Check the concentration on the vial label to ensure that the correct dose is administered intravenously (1 mg/ml).

1.3 The prepared solution does not contain preservatives and should be used immediately after preparation. However, the chemical and physical stability of the prepared solution is maintained for up to 8 hours prior to administration when stored at 25°C in the original vial and/or syringe. The total storage time of the solution in the syringe before administration must not exceed 8 hours. If the diluted solution is not administered immediately after preparation, the person administering the medicinal product to the patient is responsible for the time and conditions of storage prior to use.
There is no need to protect the prepared medicinal product solution from light.

2. ADMINISTRATION

• After reconstitution, withdraw the appropriate volume of the prepared solution according to the dose calculated based on the patient's body surface area.
• Before administration, confirm the dose and concentration of the medicinal product in the syringe (check that the syringe is labelled for intravenous administration).
• Inject the solution as an intravenous bolus over 3 to 5 seconds through a peripheral or central venous 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.
  BORTESOMIB KRKA POWDER FOR SOLUTION FOR INJECTION 3.5 MG IS ADMINISTERED INTRAVENOUSLY OR SUBCUTANEOUSLY. DO NOT ADMINISTER BY OTHER ROUTES. INTRATHECAL ADMINISTRATION HAS RESULTED IN DEATH.

3. DISPOSAL OF THE MEDICINAL PRODUCT

The vial is intended for single use only, and any unused portion of the solution must be discarded.
Any unused portions of the product or waste materials must be disposed of in accordance with local regulations.

The following information is intended exclusively for healthcare professionals:
Only the 3.5 mg vial may be used for subcutaneous administration, as described below.

1. PREPARATION OF SUBCUTANEOUS INJECTION SOLUTION

Warning: Bortezomib Krka is a cytotoxic medicinal product. Great care must be taken when handling and preparing the medicinal product for use. To protect against skin contact with the medicinal product, the use of gloves and other protective clothing is recommended.
SINCE BORTEZOMIB KRKA DOES NOT CONTAIN PRESERVATIVES, ASEPTIC TECHNIQUES MUST BE STRICTLY FOLLOWED WHEN HANDLING THE MEDICINAL PRODUCT.

1.4 Preparation of the 3.5 mg vial: Carefully add 1.4 ml of sterile 9 mg/ml (0.9%) sodium chloride injection solution to the vial containing Bortezomib Krka powder, using an appropriate syringe, without removing the vial stopper. Dissolution of the lyophilized powder takes less than 2 minutes.
The concentration of the resulting solution will be 2.5 mg/ml. After reconstitution, the solution will be clear and colourless, with a pH between 4 and 7. There is no need to check the pH of the solution.

1.5 Before administration, visually inspect the solution for particulate matter and discoloration. If any discoloration or precipitation is observed, the solution must be discarded. Ensure that the correct dose is administered subcutaneously (2.5 mg/ml).

1.6 The prepared solution does not contain preservatives and should be used immediately after preparation. However, the chemical and physical stability of the prepared solution is maintained for up to 8 hours prior to administration when stored at 25°C in the original vial and/or syringe. The total storage time of the solution in the syringe before administration must not exceed 8 hours. If the diluted solution is not administered immediately after preparation, the person administering the medicinal product to the patient is responsible for the time and conditions of storage prior to use.
There is no need to protect the prepared medicinal product solution from light.

2. ADMINISTRATION

• After reconstitution, withdraw the appropriate volume of the prepared solution according to the dose calculated based on the patient's body surface area.
• Before administration, confirm the dose and concentration of the medicinal product in the syringe (check that the syringe is labelled for subcutaneous administration).
• Inject the medicinal product solution subcutaneously at a 45–90° angle.
• The prepared solution is administered subcutaneously into the thigh (right or left) or abdomen (right or left side).
• The injection site should be rotated with each subsequent injection.
• In the event of local reactions following subcutaneous administration of Bortezomib Krka, it is recommended to administer a lower concentration subcutaneous solution of Bortezomib Krka (diluted to 1 mg/ml instead of 2.5 mg/ml) or switch to intravenous administration.
  BORTESOMIB KRKA POWDER FOR SOLUTION FOR INJECTION 3.5 MG IS ADMINISTERED INTRAVENOUSLY OR SUBCUTANEOUSLY. DO NOT ADMINISTER BY OTHER ROUTES. INTRATHECAL ADMINISTRATION HAS RESULTED IN DEATH.

3. DISPOSAL OF THE MEDICINAL PRODUCT

The vial is intended for single use only, and any unused portion of the solution must be discarded.
Any unused portions of the product or waste materials must be disposed of in accordance with local regulations.