Bortezomib Fresenius Kabi: detailed information

Package leaflet: Information for the user

Bortezomib Fresenius Kabi 1 mg powder for solution for injection

Generic medicine
Please read this leaflet carefully before you use this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
If you get any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Bortezomib Fresenius Kabi is and what it is used for
What you need to know before using Bortezomib Fresenius Kabi
How to use Bortezomib Fresenius Kabi
Possible side effects
How to store Bortezomib Fresenius Kabi
Contents of the pack and other information

1. What Bortezomib Fresenius Kabi is and what it is used for

This medicinal product contains the active substance bortezomib, a so-called "proteasome inhibitor". Proteasomes play an important role in regulating cell functions and cell growth. By interfering with their function, bortezomib can kill tumour cells.

Bortezomib is used in the treatment of multiple myeloma (a type of malignant neoplasm of the bone marrow) in patients aged over 18 years:

alone or in combination with pegylated liposomal doxorubicin or dexamethasone, for patients with progressive disease after having received at least one prior therapy or in whom blood stem cell transplantation has failed or is not feasible;
in combination with melphalan and prednisone, for previously untreated patients who are not eligible for high-dose chemotherapy with blood stem cell transplantation;
in combination with dexamethasone or dexamethasone together with thalidomide, for previously untreated patients prior to receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment).

Bortezomib is also used for the treatment of mantle cell lymphoma (a type of malignant neoplasm affecting the lymph nodes) in patients aged 18 years or older, in combination with rituximab, cyclophosphamide, doxorubicin and prednisone, for previously untreated patients for whom blood stem cell transplantation is not feasible.

2. What you need to know before using Bortezomib Fresenius Kabi

Do not use bortezomib

if you are allergic to bortezomib, boron, or any of the excipients of this medicine (listed in section 6)
if you have severe lung or heart problems.

Warnings and precautions
Inform your doctor if you have:

low red blood cell or white blood cell counts
bleeding problems and/or low platelet count in the blood
diarrhoea, constipation, nausea, or vomiting
previous episodes of fainting, dizziness, or lightheadedness
kidney problems
moderate to severe liver problems
previous neurological conditions such as numbness, tingling, or pain in the hands or feet (neuropathy)
heart or blood pressure disorders
shortness of breath or cough
seizures
shingles (including around the eyes or spreading to other parts of the body)
symptoms of tumour lysis syndrome, such as muscle cramps, muscle weakness, confusion, visual disturbances, loss of vision, or shortness of breath
memory loss, difficulty thinking, difficulty walking, or loss of vision. These may be signs of a serious brain infection, and your doctor may recommend further tests and monitoring. You will need regular blood tests before and during treatment with bortezomib to monitor your blood cell counts continuously. If you have mantle cell lymphoma and are receiving rituximab together with bortezomib, inform your doctor:
if you think you have hepatitis or have had it in the past. In some cases, patients who have had hepatitis B may experience a reactivation of the disease, which can be fatal. If you have previously had hepatitis B infection, your doctor will need to monitor you closely for signs and symptoms of active hepatitis B. Read the package leaflets of all the medicines you are taking in combination with bortezomib for information about these medicines before starting bortezomib treatment. When bortezomib is administered together with the medicine thalidomide, pay special attention to the pregnancy testing and pregnancy prevention programme requirements (see “Pregnancy and breastfeeding” in this section). Children and adolescents This medicine must not be used in children and adolescents because its effects in this population are unknown. Other medicines and bortezomib Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. In particular, inform your doctor if you are 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 or other conditions
oral antidiabetic medicines Pregnancy and breastfeeding Do not use this medicine during pregnancy unless strictly necessary.

Women of childbearing potential must use effective contraception during treatment and for 8 months after the end of treatment. Consult your doctor if you wish to freeze your eggs before starting treatment. Men must not father a child during treatment with bortezomib and must use an effective contraceptive method during treatment and for 5 months after the end of treatment. Consult your doctor if you wish to preserve sperm before starting treatment.
You must not breastfeed during treatment with bortezomib. Discuss with your doctor the most appropriate time to resume breastfeeding after the end of therapy.
The medicine thalidomide causes congenital malformations and fetal death. When bortezomib is administered together with thalidomide, you must follow the thalidomide pregnancy prevention programme (see the thalidomide package leaflet).
Driving and use of machines
Bortezomib may cause fatigue, dizziness, fainting, or blurred vision.
Do not drive or operate machinery if you experience any of these symptoms. Exercise particular caution even if these effects are not present.

3. How to use Bortezomib Fresenius Kabi

Your doctor will calculate the dose of bortezomib based on your height and weight. The initial standard dose of bortezomib is 1.3 mg/m\textsuperscript{2} of body surface area, administered twice weekly. Your doctor may adjust the dose and the total number of treatment cycles depending on your response to treatment, the occurrence of certain side effects, and your overall health condition (e.g. liver problems).

Relapsed multiple myeloma
When bortezomib is given alone, you will receive 4 doses of bortezomib by intravenous or subcutaneous administration on days 1, 4, 8, and 11. This is followed by a 10-day "rest" period without treatment. This 21-day period (3 weeks) constitutes one treatment cycle. You may receive up to 8 cycles (24 weeks).

You may also receive bortezomib together with the medicines pegylated liposomal doxorubicin or dexamethasone. When bortezomib is administered together with pegylated liposomal doxorubicin, you will receive a 21-day treatment cycle with bortezomib given by intravenous or subcutaneous administration, and 30 mg/m\textsuperscript{2} of pegylated liposomal doxorubicin will be administered on day 4 of the 21-day bortezomib treatment cycle as an intravenous infusion after the bortezomib injection. You may receive up to 8 cycles (24 weeks of treatment).

When bortezomib is administered together with dexamethasone, you will receive a 21-day treatment cycle with bortezomib given by intravenous or subcutaneous administration and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day bortezomib treatment cycle. You may receive up to 8 cycles (24 weeks of treatment).

Previously untreated multiple myeloma
If you have never been treated before for multiple myeloma and are not eligible for blood stem cell transplantation, you will receive bortezomib together with two other medicines: melphalan and prednisone.
In this case, the duration of one treatment cycle is 42 days (6 weeks). You will receive 9 cycles (54 weeks).

In cycles 1–4, bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
In cycles 5–9, bortezomib is administered once weekly on days 1, 8, 22, and 29. Melphalan (9 mg/m\textsuperscript{2}) and prednisone (60 mg/m\textsuperscript{2}) are administered orally on days 1, 2, 3, and 4 of the first week of each cycle.

If you have never been treated before for multiple myeloma and are eligible for blood stem cell transplantation, you will receive bortezomib by intravenous or subcutaneous administration together with the medicines: dexamethasone, or dexamethasone and thalidomide, as induction treatment.

When bortezomib is administered together with dexamethasone, you will receive a 21-day treatment cycle with bortezomib given by intravenous or subcutaneous administration and dexamethasone 40 mg orally on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 21-day bortezomib treatment cycle. You will receive 4 cycles (12 weeks of treatment).

When bortezomib is administered together with thalidomide and dexamethasone, the treatment cycle duration is 28 days (4 weeks). Dexamethasone 40 mg is administered orally on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day bortezomib treatment cycle, and thalidomide is administered daily orally at a dose of 50 mg up to day 14 of the first cycle; if tolerated, the thalidomide dose is increased to 100 mg on days 15–28 and may subsequently be increased up to 200 mg daily starting from the second cycle onwards. You may receive up to 6 cycles (24 weeks of treatment).

Previously untreated mantle cell lymphoma
If you have never previously received specific treatment for mantle cell lymphoma, you will receive bortezomib by intravenous or subcutaneous administration together with the medicines rituximab, cyclophosphamide, doxorubicin, and prednisone. Bortezomib is administered by intravenous or subcutaneous injection on days 1, 4, 8, and 11, followed by a treatment-free "rest" period. The treatment cycle duration is 21 days (3 weeks). You may receive up to 8 treatment cycles (24 weeks).

The following medicines are administered on Day 1 of each 21-day bortezomib treatment cycle as intravenous infusions: rituximab at 375 mg/m\textsuperscript{2}, cyclophosphamide at 750 mg/m\textsuperscript{2}, and doxorubicin at 50 mg/m\textsuperscript{2}. Prednisone is administered orally at a dose of 100 mg/m\textsuperscript{2} on days 1, 2, 3, 4, and 5 of the bortezomib treatment cycle.

How bortezomib is administered
This medicine is for intravenous use only. Bortezomib will be administered by a healthcare professional experienced in the use of cytotoxic medicines. The bortezomib powder must be reconstituted before administration. This will be done by a healthcare professional. The resulting solution is then injected rapidly into a vein over a period of 3 to 5 seconds.

If you receive more bortezomib than you should
Since this medicine is administered by a doctor or nurse, it is unlikely that you will receive more than you should. In the unlikely event of an overdose, your doctor will monitor you for any side effects.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these side effects can be serious.
If you are being given bortezomib for multiple myeloma or mantle cell lymphoma, tell your doctor immediately if you notice any of the following symptoms:

Muscle cramps, muscle weakness
Confusion, vision disturbances or loss of vision, blindness, seizures, headache
Shortness of breath, swelling of the feet or changes in heartbeat, high blood pressure, fatigue, fainting
Cough and difficulty breathing or chest tightness

Treatment with bortezomib very commonly causes a decrease in the number of red blood cells, white blood cells, and platelets in the blood. Therefore, you will need regular blood tests before and during treatment with bortezomib to monitor your blood cell counts regularly. You may experience a reduction in the number of:

Platelets, which may make you more prone to bruising or bleeding without obvious injury (e.g. bleeding from the intestine, stomach, mouth and gums, or brain or liver haemorrhage)
Red blood cells, which can cause anaemia, with symptoms such as fatigue and paleness
White blood cells, which may increase your susceptibility to infections or flu-like symptoms

If you are being given bortezomib for the treatment of multiple myeloma, the side effects that may occur are listed below:

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

Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the 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 excess intestinal gas
Diarrhoea: if this occurs, it is important that you drink much more water than usual. Your doctor may prescribe medication to control diarrhoea
Tiredness (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 may lead to fainting
Increased blood pressure
Reduced kidney function
Headache
General feeling of discomfort, pain, dizziness, feeling of emptiness in the head, weakness or loss of consciousness
Chills
Infections, including pneumonia, respiratory infections, bronchitis, fungal infection, cough with phlegm, flu-like illness
Infection with Herpes zoster (localized, including around the eyes, or disseminated throughout the body)
Chest pain or shortness of breath during physical activity
Various types of skin rash
Itching of the skin, skin nodules or dry skin
Facial flushing or small capillary ruptures
Skin redness
Dehydration
Heartburn, bloating, belching, gas, stomach pain, intestinal or stomach bleeding
Altered liver function
Irritation of the mouth or lips, dry mouth, mouth ulcers or sore throat
Weight loss, loss of taste
Muscle cramps, muscle spasms, muscle weakness, pain in arms and legs
Blurred vision
Infection of the outer layer of the eye and inner surface of the eyelids (conjunctivitis)
Nosebleeds
Sleep disturbances or problems, sweating, anxiety, mood changes, depressed mood, restlessness or agitation, mental state changes, disorientation
Body swelling, including swelling around the eyes and in other parts of the body

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

Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate
Kidney failure
Vein inflammation, blood clots in veins and lungs
Blood clotting problems
Circulatory failure
Inflammation of the membrane surrounding the heart or fluid accumulation around the heart
Infections including urinary tract infections, influenza, herpes virus infections, ear infection and cellulitis
Blood in the stools, or mucosal bleeding, e.g. from mouth or vagina
Cerebrovascular disorders
Paralysis, seizures, falls, movement disorders, abnormal or reduced sensation (touch, hearing, taste, smell), attention disorders, tremor, spasms
Arthritis, including inflammation of the joints of the fingers, toes and jaw
Lung disorders preventing your body from receiving sufficient oxygen
Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, shallow or difficult breathing or need to stop breathing, wheezing
Hiccups, speech disorders
Increased or decreased urine production (kidney damage), painful urination or presence of blood/protein in the urine, fluid retention
Altered levels of consciousness, confusion, memory failure or loss
Hypersensitivity
Hearing loss, deafness or ringing in the ears, ear discomfort
Hormonal changes that may affect reabsorption of salts and water
Overactivity of the thyroid gland
Inability to produce enough insulin or resistance to normal insulin levels
Irritated or inflamed eyes, excessively watery eyes, eye pain, dry eyes, eye infections, eyelid swelling (chalazion), red and swollen eyelids, eye discharge, vision disturbances, eye bleeding
Enlargement of lymph nodes
Joint or muscle stiffness, feeling of heaviness, groin pain
Hair loss or abnormal hair texture
Allergic reactions
Redness or pain at the injection site
Mouth pain
Infection or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestine, sometimes associated with pain or bleeding, reduced intestinal motility (including intestinal blockage), abdominal or oesophageal discomfort, difficulty swallowing, vomiting with blood
Skin infections
Bacterial and viral infections
Dental infections
Pancreatitis, obstruction of bile ducts
Genital pain, erectile dysfunction
Weight gain
Thirst sensation
Hepatitis
Injection site or catheter site reactions
Skin reactions or disorders (which can be severe and life-threatening), skin ulcerations
Bruising, falls and injuries
Inflammation or bleeding of blood vessels, which may appear as small red or purple spots (usually on the legs) that may develop into large bruises on the skin or tissues
Benign cysts
A serious and reversible brain condition including seizures, high blood pressure, headache, fatigue, confusion, blindness or other vision problems

Rare side effects (may affect up to 1 in 1,000 people)

Heart problems including heart attack, angina
Severe nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome)
Hot flushes
Change in the colour of veins
Inflammation of the spinal nerve
Ear problems, ear bleeding
Reduced activity of the thyroid gland
Budd-Chiari syndrome (clinical signs caused by blockage of the liver veins)
Altered or abnormal intestinal function
Cerebral haemorrhage (brain bleeding)
Yellowing of the eyes and skin (jaundice)
Severe allergic reaction (anaphylactic shock), signs include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or appearance of swellings on the skin, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse
Breast disorders
Vaginal discharge
Genital swelling
Inability to tolerate alcohol consumption
Wasting or loss of body mass
Increased appetite
Fistulas
Joint effusion
Cysts in the membrane covering the joints (synovial cysts)
Fractures
Muscle fibre rupture leading to other complications
Enlarged liver, liver haemorrhage
Kidney tumour
Skin condition similar to psoriasis
Skin tumour
Skin pallor
Increased platelets or plasma cells (a type of white blood cell) in the blood
Blood clotting in small blood vessels (thrombotic microangiopathy)
Abnormal reaction to blood transfusion
Partial or total loss of vision
Decreased libido
Loss of saliva
Eye protrusion
Photophobia (excessive sensitivity of the eye to light)
Rapid breathing
Rectal pain
Gallstones
Hernia
Injuries
Brittle or weak nails
Abnormal deposition of proteins in vital organs
Coma
Intestinal ulcers
Damage to multiple organs
Death

If you are being given bortezomib in combination with other medicines for the treatment of mantle cell lymphoma, the side effects that may occur are listed below:

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

Pneumonia
Loss of appetite
Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet due to nerve damage
Nausea and vomiting
Diarrhoea
Mouth ulcers
Intestinal constipation
Muscle pain, bone pain
Hair loss or abnormal hair texture
Tiredness, feeling of weakness
Fever

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

Infection with Herpes zoster (localized, including around the eyes, or disseminated throughout the body)
Infection with herpes virus
Bacterial and viral infections
Respiratory infections, bronchitis, cough with phlegm, flu-like illness
Fungal infections
Hypersensitivity (allergic reaction)
Inability to produce enough insulin or resistance to normal insulin levels
Fluid retention
Difficulty or problems sleeping
Loss of consciousness
Altered levels of consciousness, confusion
Dizziness
Increased heart rate, high blood pressure, sweating
Vision disturbances, blurred vision
Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate
High or low blood pressure
Sudden drop in blood pressure when standing up, which may lead to fainting
Shortness of breath during physical activity
Cough
Hiccups
Ringing in the ears, ear discomfort
Intestinal or stomach bleeding
Heartburn
Stomach pain, bloating
Difficulty swallowing
Infection or inflammation of the stomach and intestine
Stomach pain
Irritation of the mouth or lips, sore throat
Altered liver function
Skin itching
Skin redness
Rash
Muscle spasms
Urinary tract infection
Limb pain
Body swelling, including swelling around the eyes and in other parts of the body
Chills
Redness and pain at the injection site
General feeling of malaise
Loss of body weight
Increase in body weight

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

Hepatitis
Severe allergic reaction (anaphylactic reaction), signs of which may include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or appearance of swellings on the skin, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse
Movement disorders, paralysis, contractions
Dizziness
Hearing loss, deafness
Lung disorders preventing your body from receiving sufficient oxygen
Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, shallow, difficult or interrupted breathing, wheezing
Blood clots in the lungs
Yellowing of the eyes and skin (jaundice)
Eyelid swelling (chalazion), red and swollen eyelids

Rare side effects (may affect up to 1 in 1,000 people)

Blood clotting in small blood vessels (thrombotic microangiopathy)
Severe nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Bortezomib Fresenius Kabi

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton after EXP.
This medicine does not require any special storage temperature conditions.
Keep the vial in its carton to protect it from light.
The chemical and physical in-use stability of the reconstituted solution at concentrations of 1 mg/mL is 96 hours at 25 °C and 8 days at 2–8 °C, when stored in the original vial and/or in a syringe.
From a microbiological point of view, the reconstituted solution should be used immediately after preparation. If not used immediately, the storage times and conditions during use are the responsibility of the user. The total storage time for the reconstituted medicinal product must not exceed 96 hours (if stored at 25 °C) and 8 days (if stored at 2–8 °C) prior to administration.
Bortezomib Fresenius Kabi is for single use only. Any unused product and waste materials must be disposed of in accordance with local regulations.

6. Package contents and other information

What Bortezomib Fresenius Kabi contains

The active substance is bortezomib. Each vial contains 1 mg of bortezomib (as mannitol boronic ester).
The other component is mannitol (E421).

Description of the appearance of Bortezomib Fresenius Kabi and contents of the pack
Bortezomib for injectable solution powder is a lyophilized or compacted powder, white to cream-white in colour. Each pack of Bortezomib Fresenius Kabi 1 mg powder for injectable solution contains one 5 ml clear glass vial with a grey rubber stopper and green aluminium seal with flip-off cap, containing 1 mg of bortezomib. The vial is wrapped in a heat-shrinkable film (without tray) or placed in a tray with a lid. Each pack contains one single-use vial.

Marketing Authorisation Holder
Fresenius Kabi Deutschland GmbH
Else-Kröner-Straße 1, 61352 Bad Homburg v.d. Höhe, Germany

Manufacturer
Fresenius Kabi Deutschland GmbH
Pfingstweide 53, 61169 Friedberg, Germany
or
Fresenius Kabi Polska Sp. z.o.o., ul. Sienkiewicza 25, Kutno, 99-300, Poland

For further information about this medicinal product, please contact the Marketing Authorisation Holder.
This patient information leaflet was last updated in

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.
The following information is intended for healthcare professionals only:

1. RECONSTITUTION FOR INTRAVENOUS INJECTION

Note: Bortezomib is a cytotoxic agent. Therefore, particular care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing to prevent skin contact.
DUE TO THE ABSENCE OF ANY KIND OF PRESERVATIVE, ASEPTIC TECHNIQUE MUST BE FOLLOWED DURING THE HANDLING OF BORTEZOMIB.
1.1 Preparation of the 1 mg vial: carefully add 1 ml of sterile 9 mg/ml (0.9%) sodium chloride injectable solution to the vial containing bortezomib powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
The concentration of the resulting solution is 1 mg/ml. The solution will be clear and colourless, with a final pH between 4 and 7. It is not necessary to check the pH of the solution.
1.2 The solution should be inspected visually before administration to check for the presence of particulate matter or discoloration. If particulate matter or discoloration is observed, the solution must not be used and should be discarded.
Confirm the concentration on the vial label to ensure that the correct dose is administered by intravenous route (1 mg/ml).
1.3 The chemical and physical in-use stability of the reconstituted solution at a concentration of 1 mg/ml is 96 hours at 25 °C and 8 days at 2–8 °C, when stored in the original vial and/or a syringe.
From a microbiological standpoint, the reconstituted solution should be used immediately after preparation. If not used immediately, the times and conditions of in-use storage are the responsibility of the user. The total storage time for the reconstituted medicinal product must not exceed 96 hours (if stored at 25 °C) and 8 days (if stored at 2–8 °C) before administration.
It is not necessary to protect the reconstituted medicinal product from light.

2. ADMINISTRATION

After reconstitution, withdraw the appropriate volume of the reconstituted solution according to the dose calculated based on the patient's body surface area.
Confirm the dose and concentration in the syringe before use (check that the syringe is labeled for intravenous administration).
Inject the solution intravenously as a bolus over 3–5 seconds through a peripheral or central venous catheter.
Flush the venous or peripheral catheter with sterile injectable sodium chloride solution 9 mg/ml (0.9%). Bortezomib Fresenius Kabi 1 mg IS FOR INTRAVENOUS USE ONLY. Do not administer by other routes. Intrathecal administration has resulted in deaths.

3. DISPOSAL

The vial is for single use and any remaining solution must be discarded.
Unused medicine and waste material derived from this medicine must be disposed of in
accordance with local applicable regulations.

Patient Information Leaflet: Information for the User

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection, 3.5 mg powder for solution for injection

Generic medicine
Please read 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 questions, ask your doctor or pharmacist.
If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4. Contents of this leaflet:
1. What Bortezomib Fresenius Kabi is and what it is used for
2. What you need to know before using Bortezomib Fresenius Kabi
3. How to use Bortezomib Fresenius Kabi
4. Possible side effects
5. How to store Bortezomib Fresenius Kabi
6. Contents of the pack and other information

1. What Bortezomib Fresenius Kabi is and what it is used for

Bortezomib is used in the treatment of multiple myeloma (a type of malignant neoplasm of the bone marrow) in patients aged over 18 years:

alone or in combination with pegylated liposomal doxorubicin or dexamethasone, for patients with progressive disease after having received at least one prior therapy, or in whom blood stem cell transplantation has failed or is not feasible
in combination with melphalan and prednisone, for patients with previously untreated disease who are not eligible for high-dose chemotherapy with blood stem cell transplantation
in combination with dexamethasone or dexamethasone together with thalidomide, for patients with previously untreated disease and prior to receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment)

Bortezomib is also used for the treatment of mantle cell lymphoma (a type of malignant neoplasm affecting the lymph nodes) in patients aged 18 years or older, in combination with rituximab, cyclophosphamide, doxorubicin and prednisone, for patients with previously untreated disease for whom blood stem cell transplantation is not feasible.

2. What you need to know before using Bortezomib Fresenius Kabi

Do not use bortezomib

if you are allergic to bortezomib, to boron, or to any of the excipients of this medicine (listed in section 6)
if you have severe problems with your lungs or heart.

Warnings and precautions
Tell your doctor if you have:

low red blood cell or white blood cell counts
bleeding problems and/or low platelet count in the blood
diarrhoea, constipation, nausea, or vomiting
a history of fainting, dizziness, or lightheadedness
kidney problems
moderate to severe liver problems
a history of numbness, tingling, or pain in the hands or feet (neuropathy)
heart or blood pressure problems
shortness of breath or cough
seizures
shingles (including around the eyes or spreading to other parts of the body)
symptoms of tumour lysis syndrome, such as muscle cramps, muscle weakness, confusion, vision disturbances, or loss of vision, and shortness of breath
memory loss, difficulty thinking, difficulty walking, or loss of vision. These may be signs of a serious brain infection, and your doctor may recommend further tests and monitoring. You will need to have regular blood tests before and during treatment with bortezomib to monitor your blood cell counts continuously. If you have mantle cell lymphoma and are receiving rituximab together with bortezomib, tell your doctor:
if you think you have hepatitis or have had it in the past. In some cases, patients who have had hepatitis B may experience a reactivation of the disease, which can be fatal. If you have had a previous hepatitis B infection, your doctor will need to monitor you closely for signs and symptoms of active hepatitis B. Read the package leaflets of all the medicines you are taking in combination with bortezomib for information about these medicines before starting treatment with bortezomib. When bortezomib is administered together with the medicine thalidomide, pay special attention to the instructions regarding pregnancy testing and the pregnancy prevention programme (see “Pregnancy and breastfeeding” in this section). Children and adolescents This medicine should not be used in children and adolescents because its effects in this population are unknown. Other medicines and bortezomib Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. In particular, tell your doctor if you are 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 or other conditions
oral antidiabetic medicines Pregnancy and breastfeeding You must not use this medicine during pregnancy unless strictly necessary.

Women of childbearing potential must use effective contraception during treatment and for 8 months after the end of treatment. Consult your doctor if you wish to freeze your eggs before starting treatment. Men must not father a child during treatment with bortezomib and must use an effective method of contraception during treatment and for 5 months after the end of treatment. Consult your doctor if you wish to preserve sperm before starting treatment. You must not breastfeed while taking bortezomib. Discuss with your doctor the most appropriate time to resume breastfeeding after the end of treatment. The medicine thalidomide causes birth defects and fetal death. When bortezomib is administered together with thalidomide, you must follow thalidomide’s pregnancy prevention programme (see the thalidomide package leaflet). Driving and using machines Bortezomib may cause fatigue, dizziness, fainting, or blurred vision. Do not drive or operate machinery if you experience any of these symptoms. Exercise particular caution even if these effects do not occur.

3. How to use Bortezomib Fresenius Kabi

Your doctor will calculate the dose of bortezomib based on your height and body weight. The standard starting dose of bortezomib is 1.3 mg/m\textsuperscript{2} of body surface area, administered twice weekly. Your doctor may adjust the dose and the total number of treatment cycles depending on your response to treatment, the occurrence of certain side effects, and your overall health condition (e.g. liver problems).

Relapsed multiple myeloma
When bortezomib is given alone, you will receive 4 doses of bortezomib by intravenous or subcutaneous injection on days 1, 4, 8, and 11. This is followed by a 10-day "rest" period without treatment. This 21-day period (3 weeks) constitutes one treatment cycle. You may receive up to 8 cycles (24 weeks).

You may also receive bortezomib together with the medicines pegylated liposomal doxorubicin or dexamethasone. When bortezomib is administered together with pegylated liposomal doxorubicin, you will receive a 21-day treatment cycle with bortezomib given by intravenous or subcutaneous injection, and 30 mg/m\textsuperscript{2} of pegylated liposomal doxorubicin will be administered on day 4 of the 21-day bortezomib treatment cycle as an intravenous infusion after the bortezomib injection. You may receive up to 8 cycles (24 weeks of treatment).

When bortezomib is administered together with dexamethasone, you will receive a 21-day treatment cycle with bortezomib given by intravenous or subcutaneous injection, and oral dexamethasone at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day bortezomib treatment cycle. You may receive up to 8 cycles (24 weeks of treatment).

Previously untreated multiple myeloma
If you have never been treated before for multiple myeloma and are not eligible for stem cell transplantation, you will receive bortezomib in combination with two other medicines: melphalan and prednisone.
In this case, the duration of one treatment cycle is 42 days (6 weeks). You will receive 9 cycles (54 weeks).

In cycles 1–4, bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
In cycles 5–9, bortezomib is administered once weekly on days 1, 8, 22, and 29.

Melphalan (9 mg/m\textsuperscript{2}) and prednisone (60 mg/m\textsuperscript{2}) are administered orally on days 1, 2, 3, and 4 of the first week of each cycle.

If you have never been treated before for multiple myeloma and are eligible for stem cell transplantation, you will receive bortezomib by intravenous or subcutaneous injection in combination with dexamethasone, or with dexamethasone and thalidomide, as induction therapy.

When bortezomib is administered together with dexamethasone, you will receive a 21-day treatment cycle with bortezomib given by intravenous or subcutaneous injection, and oral dexamethasone 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 21-day bortezomib treatment cycle. You will receive 4 cycles (12 weeks of treatment).

When bortezomib is administered together with thalidomide and dexamethasone, the treatment cycle duration is 28 days (4 weeks).
Oral dexamethasone 40 mg is administered on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day bortezomib treatment cycle, and thalidomide is administered daily by mouth at a dose of 50 mg up to day 14 of the first cycle; if tolerated, the thalidomide dose is increased to 100 mg on days 15–28, and may subsequently be increased up to 200 mg per day starting from the second cycle onwards. You may receive up to 6 cycles (24 weeks of treatment).

Previously untreated mantle cell lymphoma
If you have never previously received specific treatment for mantle cell lymphoma, you will receive bortezomib by intravenous or subcutaneous injection in combination with the medicines rituximab, cyclophosphamide, doxorubicin, and prednisone.
Bortezomib is administered by intravenous or subcutaneous injection on days 1, 4, 8, and 11, followed by a "rest" period without treatment. The treatment cycle duration is 21 days (3 weeks). You may receive up to 8 treatment cycles (24 weeks).

The following medicines are administered on day 1 of each 21-day bortezomib treatment cycle as intravenous infusions: rituximab at 375 mg/m\textsuperscript{2}, cyclophosphamide at 750 mg/m\textsuperscript{2}, and doxorubicin at 50 mg/m\textsuperscript{2}.

Prednisone is administered orally at a dose of 100 mg/m\textsuperscript{2} on days 1, 2, 3, 4, and 5 of the bortezomib treatment cycle.

How bortezomib is administered
This medicine is for intravenous or subcutaneous use. Bortezomib will be administered by a healthcare professional experienced in the use of cytotoxic medicines.
The bortezomib powder must be reconstituted before administration. This will be done by a healthcare professional. The resulting solution is then injected rapidly into a vein or under the skin. The intravenous injection is rapid, taking 3 to 5 seconds. The subcutaneous injection can be administered either in the thigh or the abdomen.

If you receive more bortezomib than you should
Since this medicine is administered by your doctor or nurse, it is unlikely that you will receive more than the prescribed amount. In the unlikely event of an overdose, your doctor will monitor you for any side effects.

4. Possible side effects

Muscle cramps, muscle weakness
Confusion, vision disturbances or loss of vision, blindness, seizures, headache
Shortness of breath, swelling of the feet or changes in heartbeat, high blood pressure, fatigue, fainting
Cough and difficulty breathing or chest tightness

Treatment with bortezomib very commonly causes a decrease in the number of red and white blood cells and platelets in the blood. Therefore, you will need regular blood tests before and during treatment with bortezomib to monitor your blood cell counts regularly. You may experience a reduction in the number of:

Platelets, which may make you more prone to bruising or bleeding without apparent injury (for example, bleeding from the intestine, stomach, mouth and gums, or brain or liver haemorrhage)
Red blood cells, which can cause anaemia, with symptoms such as fatigue and paleness
White blood cells, which may increase your susceptibility to infections or flu-like symptoms

If you are being given bortezomib for the treatment of multiple myeloma, the possible side effects are listed below:

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

Tingling, numbness, pins and needles, burning sensation of the skin, or pain in the 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 excess intestinal gas
Diarrhoea: if this occurs, it is important that you drink much more water than usual. Your doctor may prescribe medicines to control diarrhoea
Tiredness (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, which may lead to fainting
Increased blood pressure
Reduced kidney function
Headache
Feeling of general malaise, pain, dizziness, feeling of emptiness in the head, feeling of weakness or loss of consciousness
Chills
Infections, including pneumonia, respiratory infections, bronchitis, fungal infection, cough with phlegm, flu-like illness
Herpes zoster infection (localized, including around the eyes, or disseminated over the body)
Chest pain or difficulty breathing during physical activity
Various types of skin rash
Itching of the skin, skin nodules or dry skin
Facial flushing or small capillary ruptures
Skin redness
Dehydration
Heartburn, bloating, belching, gas, stomach pain, intestinal or stomach bleeding
Altered liver function
Irritation of the mouth or lips, dry mouth, oral ulcers or sore throat
Weight loss, loss of taste
Muscle cramps, muscle spasms, muscle weakness, pain in arms and legs
Blurred vision
Infection of the outer layer of the eye and inner surface of the eyelids (conjunctivitis)
Nosebleeds
Sleep disturbances or problems, sweating, anxiety, mood changes, depressed mood, restlessness or agitation, changes in mental status, disorientation
Swelling of the body, including swelling around the eyes and in other parts of the body

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

Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate
Kidney failure
Inflammation of a vein, blood clots in veins and lungs
Blood clotting problems
Circulatory failure
Inflammation of the membrane surrounding the heart or presence of fluid around the heart
Infections including urinary tract infections, influenza, herpes virus infections, ear infection and cellulitis
Blood in the stools, or bleeding from mucous membranes, for example mouth, vagina
Cerebrovascular disorders
Paralysis, seizures, falls, movement disorders, abnormal or reduced sensation (touch, hearing, taste, smell), attention disorders, tremor, spasms
Arthritis, including inflammation of the joints of the fingers, toes and jaw
Lung disorders, preventing your body from receiving sufficient oxygen
Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, shallow or difficult breathing or need to stop, wheezing
Hiccups, speech disorders
Increased or decreased urine production (kidney damage), painful urination or presence of blood/protein in the urine, fluid retention
Altered levels of consciousness, confusion, memory failure or loss
Hypersensitivity
Hearing loss, deafness or ringing in the ears, ear discomfort
Hormonal disturbances affecting the reabsorption of salts and water
Overactivity of the thyroid gland
Inability to produce enough insulin or resistance to normal insulin levels
Irritated or inflamed eyes, excessively watery eyes, eye pain, dry eyes, eye infections, eyelid swelling (chalazion), red and swollen eyelids, eye discharge, vision disturbances, eye bleeding
Enlarged lymph nodes
Joint or muscle stiffness, feeling of heaviness, groin pain
Hair loss or abnormal hair texture
Allergic reactions
Redness or pain at the injection site
Mouth pain
Infection or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestine, sometimes associated with pain or bleeding, reduced intestinal motility (including intestinal obstruction), abdominal or oesophageal discomfort, difficulty swallowing, vomiting with blood
Skin infections
Bacterial and viral infections
Dental infections
Pancreatitis, obstruction of bile ducts
Genital pain, erectile problems
Weight gain
Feeling of thirst
Hepatitis
Injection site or catheter site disorders
Skin reactions or disorders (which can be severe and life-threatening), skin ulceration
Bruising, falls and injuries
Inflammation or bleeding of blood vessels, which may appear as small red or purple spots (usually on the legs) that may develop into large bruises on the skin or tissues
Benign cysts
A serious but reversible brain condition including seizures, high blood pressure, headache, fatigue, confusion, blindness or other vision problems

Rare side effects (may affect up to 1 in 1,000 people)

Heart problems including heart attack, angina
Severe nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome)
Hot flushes
Change in the colour of veins
Inflammation of the spinal nerve
Ear problems, bleeding from the ear
Reduced activity of the thyroid gland
Budd-Chiari syndrome (clinical signs caused by blockage of the liver veins)
Change or abnormal intestinal function
Cerebral haemorrhage (bleeding in the brain)
Yellowing of the eyes and skin (jaundice)
Severe allergic reaction (anaphylactic shock), signs include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or skin swellings, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse
Breast disorders
Vaginal discharge
Swelling of the genitals
Inability to tolerate alcohol consumption
Wasting or loss of body mass
Increased appetite
Fistulas
Joint effusion
Cysts in the membrane covering the joints (synovial cysts)
Fractures
Rupture of muscle fibres leading to further complications
Enlarged liver, liver haemorrhage
Kidney tumour
Skin condition similar to psoriasis
Skin tumour
Pallor of the skin
Increased platelets or plasma cells (a type of white blood cell) in the blood
Blood clots in small blood vessels (thrombotic microangiopathy)
Abnormal reaction to blood transfusion
Partial or complete loss of vision
Decreased libido
Loss of saliva
Protruding eyes
Photophobia (excessive sensitivity of the eyes to light)
Rapid breathing
Rectal pain
Gallstones
Hernia
Injuries
Brittle or weak nails
Abnormal protein deposits in vital organs
Coma
Intestinal ulcers
Damage to multiple organs
Death

If you are being given bortezomib in combination with other medicines for the treatment of mantle cell lymphoma, the possible side effects are listed below:

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

Pneumonia
Loss of appetite
Tingling, numbness, pins and needles, burning sensation of the skin, or pain in the hands or feet due to nerve damage
Nausea and vomiting
Diarrhoea
Mouth ulcers
Intestinal constipation
Muscle pain, bone pain
Hair loss or abnormal hair texture
Tiredness, feeling of weakness
Fever

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

Herpes zoster infection (localized, including around the eyes, or disseminated over the body)
Herpes virus infection
Bacterial and viral infections
Respiratory infections, bronchitis, cough with phlegm, flu-like illness
Fungal infections
Hypersensitivity (allergic reaction)
Inability to produce enough insulin or resistance to normal insulin levels
Fluid retention
Difficulty or problems sleeping
Loss of consciousness
Altered levels of consciousness, confusion
Dizziness
Increased heart rate, high blood pressure, sweating
Vision disturbances, blurred vision
Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate
High or low blood pressure
Sudden drop in blood pressure when standing, which may lead to fainting
Shortness of breath during physical activity
Cough
Hiccups
Ringing in the ears, ear discomfort
Intestinal or stomach bleeding
Heartburn
Stomach pain, bloating
Difficulty swallowing
Infection or inflammation of the stomach and intestine
Stomach pain
Irritation of the mouth or lips, sore throat
Altered liver function
Skin itching
Skin redness
Rash
Muscle spasms
Urinary tract infection
Limb pain
Swelling of the body, including swelling around the eyes and in other parts of the body
Chills
Redness and pain at the injection site
Feeling of general malaise
Loss of body weight
Increase in body weight

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

Hepatitis
Severe allergic reaction (anaphylactic reaction), signs of which may include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or skin swellings, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse
Movement disorders, paralysis, contractions
Dizziness
Hearing loss, deafness
Lung disorders, preventing your body from receiving sufficient oxygen
Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, breathing becoming shallow, difficult or interrupted, wheezing
Blood clots in the lungs
Yellowing of the eyes and skin (jaundice)
Eyelid swelling (chalazion), red and swollen eyelids

Rare side effects (may affect up to 1 in 1,000 people)

Blood clotting in small blood vessels (thrombotic microangiopathy)
Severe nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome)

Reporting of side effects

If you get any side effects, including ones not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly via the national reporting system at the following website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Bortezomib Fresenius Kabi

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and the outer carton after EXP.
This medicine does not require any special temperature storage conditions.
Keep the vial in its original carton to protect it from light.
The chemical and physical in-use stability of the reconstituted solution is 96 hours at 25 °C and 8 days at 2-8 °C for concentrations of 1 mg/ml and 2.5 mg/ml, when stored in the original vial and/or in a syringe.
From a microbiological point of view, the reconstituted solution should be used immediately after preparation. If not used immediately, the duration and conditions of in-use storage are the responsibility of the user. The total storage time for the reconstituted medicinal product must not exceed 96 hours (if stored at 25 °C) and 8 days (if stored at 2-8 °C) prior to administration.
Bortezomib Fresenius Kabi is for single use only. Any unused product and waste material must be disposed of in accordance with local regulations.

6. Package contents and other information

What Bortezomib Fresenius Kabi contains

The active substance is bortezomib.
The other component is mannitol (E421).

Bortezomib Fresenius Kabi 2.5 mg powder for injectable solution
Each vial contains 2.5 mg of bortezomib (as mannitol boronic ester).

Bortezomib Fresenius Kabi 3.5 mg powder for injectable solution
Each vial contains 3.5 mg of bortezomib (as mannitol boronic ester).

Reconstitution for intravenous use: after reconstitution, 1 ml of intravenous injection solution contains 1 mg of bortezomib.
Reconstitution for subcutaneous use: after reconstitution, 1 ml of subcutaneous injection solution contains 2.5 mg of bortezomib.

Description of the appearance of Bortezomib Fresenius Kabi and contents of the pack
Bortezomib Fresenius Kabi powder for injectable solution is a lyophilized or compacted powder, white to cream-white in colour.

Bortezomib Fresenius Kabi 2.5 mg powder for injectable solution
Each pack of Bortezomib Fresenius Kabi 2.5 mg powder for injectable solution contains one 10 ml clear glass vial with grey rubber stopper and yellow aluminium seal with tamper-evident closure, containing 2.5 mg of bortezomib.

Bortezomib Fresenius Kabi 3.5 mg powder for injectable solution
Each pack of Bortezomib Fresenius Kabi 3.5 mg powder for injectable solution contains one 10 ml clear glass vial with grey rubber stopper and blue aluminium seal with tamper-evident closure, containing 3.5 mg of bortezomib.
The vial is wrapped in heat-shrinkable film (without tray) or placed in a tray with a lid. Each pack contains one single-use vial.

Marketing Authorization Holder
Fresenius Kabi Deutschland GmbH
Else-Kröner-Straße 1,
61352 Bad Homburg v.d. Höhe
Germany

Manufacturer
Fresenius Kabi Deutschland GmbH
Pfingstweide 53
61169 Friedberg,
Germany
or
Fresenius Kabi Polska Sp. z o.o.,
ul. Sienkiewicza 25, Kutno,
99-300, Poland

For further information about this medicinal product, please contact the Marketing Authorization Holder.
This patient information leaflet was last updated in

Other sources of information
More detailed information about this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu.
The following information is intended for healthcare professionals only:

1. RECONSTITUTION FOR INTRAVENOUS INJECTION

Note: Bortezomib is a cytotoxic agent. Therefore, particular care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing to prevent skin contact.
DUE TO THE ABSENCE OF ANY TYPE OF PRESERVATIVE, ASEPTIC TECHNIQUE MUST BE
OBSERVED DURING THE HANDLING OF BORTEZOMIB.
1.1 Reconstitution of the 2.5 mg vial: carefully add 2.5 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing bortezomib powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
Reconstitution of the 3.5 mg vial: carefully add 3.5 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing bortezomib powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
The concentration of the resulting solution is 1 mg/ml. The solution will be clear and colourless, with a final pH between 4 and 7. It is not necessary to check the pH of the solution.
1.2 The solution must be visually inspected prior to administration to check for the presence of particulate matter or discoloration. If particulate matter or discoloration is observed, the solution must not be used and should be discarded.
Confirm the concentration on the vial label to ensure that the correct dose is administered by intravenous route (1 mg/ml).
1.3 Chemical and physical in-use stability of the reconstituted solution has been demonstrated for concentrations of 1 mg/ml and 2.5 mg/ml for up to 96 hours at 25°C and 8 days at 2–8°C, when stored in the original vial and/or a syringe.
From a microbiological standpoint, the reconstituted solution should be used immediately after preparation. If not used immediately, the duration and conditions of storage during use are the responsibility of the user. The total storage time for the reconstituted medicinal product must not exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2–8°C) prior to administration.
It is not necessary to protect the reconstituted medicinal product from light.

2. ADMINISTRATION

After reconstitution, withdraw the appropriate volume of the reconstituted solution according to the dose calculated based on the patient's body surface area.
Confirm the dose and concentration in the syringe before use (check that the syringe is labeled for intravenous administration).
Inject the solution as an intravenous bolus over 3–5 seconds through a peripheral or central intravenous catheter.
Flush the intravenous or peripheral catheter with sterile injectable sodium chloride 9 mg/mL (0.9%) solution.

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg IS FOR SUBCUTANEOUS OR
INTRAVENOUS USE. Do not administer by other routes. Intrathecal administration has
resulted in deaths.

3. DISPOSAL

The vial is for single use only, and any remaining solution must be discarded.
Unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.
The following information is intended exclusively for healthcare professionals:
Only the 2.5 mg and 3.5 mg vials can be administered by subcutaneous route as described below.

1. RECONSTITUTION FOR SUBCUTANEOUS INJECTION

Note: Bortezomib is a cytotoxic agent. Therefore, particular care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing to prevent skin contact.
DUE TO THE ABSENCE OF ANY TYPE OF PRESERVATIVE, ASEPTIC TECHNIQUE MUST BE
OBSERVED DURING THE HANDLING OF BORTEZOMIB.
1.1 Preparation of the 2.5 mg vial: carefully add 1 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing bortezomib powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
Preparation of the 3.5 mg vial: carefully add 1.4 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing bortezomib powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
The concentration of the resulting solution is 2.5 mg/ml. The solution will be clear and colourless, with a final pH between 4 and 7. There is no need to check the pH of the solution.
1.2 The solution must be visually inspected before administration to check for the presence of particulate matter or any change in colour. If particulate matter or discoloration is observed, the solution must not be used and must be discarded.
Confirm the concentration on the vial label to ensure that the correct dose is administered subcutaneously (2.5 mg/ml).
1.3 Chemical and physical in-use stability of the reconstituted solution has been demonstrated for concentrations of 1 mg/ml and 2.5 mg/ml, up to 96 hours at 25 °C and 8 days at 2–8 °C, when stored in the original vial and/or a syringe.
From a microbiological standpoint, the reconstituted solution should be used immediately after preparation. If not used immediately, the user is responsible for the storage times and conditions prior to use. The total storage time for the reconstituted medicinal product must not exceed 96 hours (if stored at 25 °C) and 8 days (if stored at 2–8 °C) before administration.
It is not necessary to protect the reconstituted medicinal product from light.

2. ADMINISTRATION

After dissolution, withdraw the appropriate volume of the reconstituted solution according to the dose calculated based on the patient's body surface area.
Confirm the dose and concentration in the syringe before use (check that the syringe is labeled for subcutaneous administration).
Inject the solution subcutaneously at an angle of 45–90°.
The reconstituted solution is administered subcutaneously in the thighs (right or left) or in the abdomen (right or left).
For subsequent administrations, rotate the injection site.
If local reactions at the injection site occur after subcutaneous administration of bortezomib, a lower concentration of bortezomib solution may be administered (1 mg/ml instead of 2.5 mg/ml), or intravenous injection is recommended. Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg IS FOR SUBCUTANEOUS OR INTRAVENOUS USE. Do not administer by other routes. Intrathecal administration has resulted in deaths.

3. DISPOSAL

The vial is for single use and any remaining solution must be discarded.
Unused medicine and waste materials derived from this medicine must be disposed of in
accordance with local regulations.