Bortezomib Ever Pharma 2.5 mg/ml solution for injection

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Bortezomib EVER Pharma 2.5 mg/ml solution for injection

Read the entire leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

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

This medicine contains the active substance bortezomib, a "proteasome inhibitor". Proteasomes play an important role in regulating cell function and growth. Bortezomib can destroy cancer cells by interfering with their normal function.

Bortezomib is used in the treatment of multiple myeloma (a cancer of the bone marrow) in patients over 18 years of age:

• alone or in combination with pegylated liposomal doxorubicin or dexamethasone, for patients whose disease is progressing after having received at least one prior therapy, and for those patients for whom blood stem cell transplantation has failed or is not suitable.
• in combination with melphalan and prednisone, for patients who have not previously been treated and for whom high-dose chemotherapy followed by blood stem cell transplantation is not suitable.
• in combination with dexamethasone or with dexamethasone and thalidomide, for patients who have not previously been treated and who are undergoing high-dose chemotherapy followed by blood stem cell transplantation (induction treatment).

Bortezomib is used in the treatment of mantle cell lymphoma (a type of cancer affecting the lymph nodes) in patients aged 18 years or older, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, for patients whose disease has not been previously treated and for whom blood stem cell transplantation is not considered appropriate.

2. What you need to know before using Bortezomib EVER Pharma

Do not use Bortezomib EVER Pharma

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

Warnings and precautions

Tell your doctor if you have any of the following:

• low red or white blood cell counts
• bleeding problems and/or low platelet count in the blood
• diarrhoea, constipation, nausea, or vomiting
• history of fainting, dizziness, or lightheadedness
• kidney problems
• moderate to severe liver problems
• past history of numbness, tingling, or pain in hands or feet (neuropathy)
• heart problems or blood pressure issues
• difficulty breathing or cough
• seizures
• shingles (localized including around the eyes or widespread throughout the body)
• symptoms of tumour lysis syndrome, such as muscle cramps, muscle weakness, confusion, vision loss or changes, and difficulty breathing
• memory loss, thinking changes, difficulty walking, or vision loss. 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 regularly.

You must inform your doctor if you have mantle cell lymphoma and are receiving rituximab together with bortezomib:

• if you currently have or have previously had hepatitis infection. In a few cases, patients who have had hepatitis B may experience recurrent hepatitis, which can be fatal. If you have a history of hepatitis B infection, your doctor will closely monitor you for signs of active hepatitis B.

Before starting treatment with bortezomib, you should read the package leaflets of all the medicines you are due to take in combination with bortezomib to review information related to these medicines.

When using thalidomide, special attention must be paid to pregnancy testing and preventive measures (see Pregnancy and Breastfeeding in this section).

Children and adolescents

Bortezomib must not be used in children and adolescents because it is not known how the medicine will affect them.

Use of Bortezomib EVER Pharma with other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might need to 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 for depression or other conditions
• oral antidiabetic medicines

Pregnancy and breastfeeding

You must not use bortezomib if you are pregnant unless clearly necessary.

Both men and women using bortezomib must use effective contraception during treatment and for at least 3 months after treatment ends. If you become pregnant despite these precautions, inform your doctor immediately.

You must not breastfeed while receiving bortezomib. Consult your doctor about when it is safe to restart breastfeeding after completing your treatment.

Thalidomide causes birth defects and fetal death. When bortezomib is administered in combination with thalidomide, the thalidomide pregnancy prevention programme must be followed (refer to the thalidomide package leaflet).

Driving and using machines

Bortezomib may cause fatigue, dizziness, fainting, or blurred vision. Do not drive or operate tools or machinery if you experience these side effects. Even if you do not experience them, you should still exercise caution.

Bortezomib EVER Pharma contains sodium

This medicine contains less than 23 mg (1 mmol) of sodium per vial; therefore, it is essentially “sodium-free”.

3. How to use Bortezomib EVER Pharma

Your doctor will determine the dose of bortezomib based on your height and weight (body surface area). The usual starting dose of bortezomib is 1.3 mg/m² 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 adverse effects, and your baseline condition (e.g., liver problems).

Relapsed multiple myeloma

When bortezomib is given alone, you will receive 4 doses of bortezomib intravenously or subcutaneously on days 1, 4, 8, and 11, 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 in combination with pegylated liposomal doxorubicin or dexamethasone.

When bortezomib is administered in combination with pegylated liposomal doxorubicin, you will receive bortezomib intravenously or subcutaneously in a 21-day treatment cycle, and pegylated liposomal doxorubicin 30 mg/m² is administered on day 4 of the 21-day bortezomib cycle via intravenous infusion after the bortezomib injection. You may receive up to 8 cycles (24 weeks).

When bortezomib is administered in combination with dexamethasone, you will receive bortezomib intravenously or subcutaneously in a 21-day treatment cycle, and dexamethasone 20 mg is administered 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).

Previously untreated multiple myeloma

If you have not previously been treated for multiple myeloma and are not a candidate for blood 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 to 4, bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5 to 9, bortezomib is administered once weekly on days 1, 8, 22, and 29.

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 you have not previously received treatment for multiple myeloma and are a candidate for blood stem cell transplantation, you will receive bortezomib intravenously or subcutaneously in combination with dexamethasone, or with dexamethasone and thalidomide, as induction therapy.

When bortezomib is administered in combination with dexamethasone, you will receive bortezomib intravenously or subcutaneously in a 21-day treatment cycle, and dexamethasone is administered orally at a dose of 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).

When bortezomib is administered in combination with thalidomide and dexamethasone, the duration of one treatment cycle 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 orally once daily 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 from the second cycle onwards may be further increased to 200 mg daily. You may receive up to 6 cycles (24 weeks).

Previously untreated mantle cell lymphoma

If you have not previously been treated for mantle cell lymphoma, you will receive bortezomib intravenously or subcutaneously in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone.

Bortezomib is administered intravenously or subcutaneously on days 1, 4, 8, and 11, followed by a "rest period" without treatment. The duration of one treatment cycle is 21 days (3 weeks). You may receive up to 8 cycles (24 weeks).

The following medicines are administered via intravenous infusion on day 1 of the 21-day bortezomib treatment cycle:

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

How Bortezomib EVER Pharma is administered

This medicine is administered subcutaneously or, after dilution, intravenously. Bortezomib will be administered by a healthcare professional experienced in the use of cytotoxic agents.

The solution is injected into a vein or under the skin. The intravenous injection is rapid, lasting between 3 and 5 seconds. The subcutaneous injection is administered in the thighs or abdomen.

If you receive more Bortezomib EVER Pharma than you should

This medicine will be administered by your doctor or nurse, so it is unlikely that you will receive too much. In the unlikely event of an overdose, your doctor will monitor you for any adverse effects.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them. Some of these effects may be serious.

If you are being administered bortezomib for multiple myeloma or mantle cell lymphoma, inform your doctor immediately if you notice any of the following symptoms:

• Muscle cramps, muscle weakness
• Confusion, loss or changes in vision, blindness, seizures, headaches
• Difficulty breathing, swelling of the feet, or changes in heart rhythm, high blood pressure, fatigue, fainting
• Cough and difficulty breathing or chest tightness.

Treatment with bortezomib may very commonly cause a decrease in the number of red blood cells, white blood cells, and platelets in the blood. Therefore, you will need to have 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 (contusions) or bleeding without evident injury (for example, bleeding in the intestine, stomach, mouth and gums, or bleeding in the brain or liver)
• Red blood cells, which may cause anemia, with symptoms such as fatigue and paleness
• White blood cells, which may make you more susceptible to infections or flu-like symptoms.

If you are being administered bortezomib for the treatment of multiple myeloma, the adverse effects you may experience include the following:

Very common adverse effects (may affect more than 1 in 10 patients)

• Tenderness, numbness, tingling, or burning sensation in the skin or pain in hands or feet due to nerve damage
• Reduction in the number of red blood cells and/or white blood cells (see above)
• Fever
• Feeling unwell (nausea) or vomiting, loss of appetite
• Constipation with or without bloating (may be severe)
• Diarrhea: if this occurs, it is important that you drink more water than usual. Your doctor may give you another medicine to control the diarrhea
• Exhaustion (tiredness), feeling of weakness
• Muscle pain, bone pain

Common adverse effects (may affect up to 1 in 10 patients)

• Low blood pressure, sudden drop in blood pressure when standing, which could lead to fainting
• High blood pressure
• Decreased kidney function
• Headache
• General feeling of discomfort, pain, dizziness, lightheadedness, feeling of weakness or loss of consciousness
• Chills
• Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, cough with phlegm, flu-like illness
• Herpes zoster (localized including around the eyes or spread throughout the body)
• Chest pain or difficulty breathing during exercise
• Various types of rashes
• Itching of the skin, skin lumps or dry skin
• Facial flushing or rupture of small capillaries
• Redness of the skin
• Dehydration
• Heartburn, bloating, belching, flatulence, stomach pain, intestinal or stomach bleeding
• Impaired liver function
• Mouth or lip sores, dry mouth, mouth ulcers or sore throat
• Weight loss, loss of taste
• Muscle cramps, muscle spasms, muscle weakness, limb pain
• Blurred vision
• Infection of the outermost layer of the eye and inner surface of the eyelids (conjunctivitis)
• Nosebleeds
• Difficulty or problems sleeping, sweating, anxiety, mood changes, depressed mood, restlessness or agitation, changes in mental state, disorientation
• Swelling of the body, including around the eyes and other parts of the body

Uncommon adverse effects (may affect up to 1 in 100 patients)

• 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
• Poor circulation
• Inflammation of the lining of the heart or fluid around the heart
• Infections, including urinary tract infections, flu, herpes virus infection, ear infection, and cellulitis
• Bloody stools or bleeding from mucous membranes, for example, from the mouth or vagina
• Cerebrovascular disorders
• Paralysis, seizures, falls, movement disorders, alterations or changes in, or decreased sensitivity (touch, hearing, taste, smell), attention disorders, tremors, jerking
• Arthritis, including inflammation of the joints of the fingers of the hands and feet and of the jaw
• Disorders affecting the lungs, preventing the body from receiving enough oxygen. Some of these include difficulty breathing, shortness of breath, breathlessness without exertion, breathing that may become shallow, difficult or stop, wheezing
• Hiccups, speech disorders
• Increased or decreased urine production (due to kidney injury), pain when urinating or blood/proteins in the urine, fluid retention
• Altered level of consciousness, confusion, memory impairment or loss
• Hypersensitivity
• Hearing loss, deafness or ringing in the ears (tinnitus), ear discomfort
• Hormonal disorders that may affect salt and water absorption
• Overactivity of the thyroid gland
• Inability to produce enough insulin or resistance to normal insulin levels
• Eye irritation or inflammation, excessively watery eyes, eye pain, dry eyes, eye infections, eyelid cyst (chalazion), red and swollen eyelids, watery eyes (lacrimation), abnormal vision, eye hemorrhage
• Swelling of lymph nodes
• Stiffness of joints or muscles, feeling of heaviness, groin pain
• Hair loss and abnormal hair texture
• Allergic reactions
• Redness or pain at the injection site
• Mouth pain
• Infections or inflammation of the mouth, ulcers in the mouth, esophagus, stomach and intestine, sometimes associated with pain or bleeding, reduced intestinal movement (including obstruction), abdominal or esophageal discomfort, difficulty swallowing, vomiting blood
• Skin infections
• Bacterial and viral infections
• Dental infection
• Pancreatitis, obstruction of bile ducts
• Genital pain, difficulty achieving an erection
• Weight gain
• Thirst
• Hepatitis
• Injection site reactions or device-related disorders
• Skin reactions and disorders (which may be severe and life-threatening), skin ulcers
• Bruising, falls and injuries
• Inflammation or bleeding of blood vessels, which may appear as small red or purple spots (usually on the legs) up to large bruise-like patches under the skin or tissue
• Benign cysts
• A serious and reversible brain disorder including seizures, high blood pressure, headaches, fatigue, confusion, blindness or other vision problems.

Rare adverse effects (may affect up to 1 in 1,000 patients)

• Heart problems, including heart attack, angina
• Severe nerve inflammation, which may cause paralysis and difficulty breathing (Guillain-Barré syndrome)
• Flushing
• Discoloration of veins
• Inflammation of spinal nerves
• Ear problems, ear bleeding
• Underactivity of the thyroid gland
• Budd–Chiari syndrome (clinical symptoms caused by obstruction of the hepatic veins)
• Changes or abnormalities in intestinal function
• Cerebral hemorrhage
• Yellowing of the eyes and skin (jaundice)
• Severe allergic reaction (anaphylactic shock), whose signs may include difficulty breathing, chest pain or tightness and/or dizziness/fainting, intense itching of the skin or skin lumps, swelling of the face, lips, tongue and/or throat, which may cause difficulty swallowing, collapse
• Breast disorders
• Vaginal tear
• Genital inflammation
• Inability to tolerate alcohol consumption
• Emaciation or loss of body mass
• Increased appetite
• Fistula
• Joint effusion
• Cysts in the lining of joints (synovial cysts)
• Fracture
• Breakdown of muscle fibers causing other complications
• Liver swelling, liver hemorrhage
• Kidney cancer
• Skin disease resembling psoriasis
• Skin cancer
• Paleness of the skin
• Increase in platelets or plasma cells (a type of white blood cell) in the blood
• Blood clot in small blood vessels (thrombotic microangiopathy)
• Abnormal reaction to blood transfusions
• Partial or complete loss of vision
• Loss of libido
• Drooling
• Bulging eyes
• Light sensitivity
• Rapid breathing
• Rectal pain
• Gallstones
• Hernia
• Wounds
• Weak or brittle nails
• Abnormal protein deposits in vital organs
• Coma
• Intestinal ulcers
• Multi-organ failure
• Death

If you are being administered bortezomib in combination with other medicines for the treatment of mantle cell lymphoma, the adverse effects you may experience include the following:

Very common adverse effects (may affect more than 1 in 10 patients)

• Pneumonia
• Loss of appetite
• Tenderness, numbness, tingling, or burning sensation in the skin or 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 texture
• Exhaustion, feeling of weakness
• Fever

Common adverse effects (may affect up to 1 in 10 patients)

• Herpes zoster (localized including around the eyes or spread throughout 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 level of consciousness, confusion
• Dizziness
• Increased heart rate, high blood pressure, sweating
• Abnormal vision, 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 could lead to fainting
• Difficulty breathing during exercise
• Cough
• Hiccups
• Ringing in the ears (tinnitus), ear discomfort
• Intestinal or stomach bleeding
• Heartburn
• Stomach pain, bloating
• Difficulty swallowing
• Infection or inflammation of stomach and intestine
• Stomach pain
• Mouth or lip sores, sore throat
• Impaired liver function
• Itching of the skin
• Redness of the skin
• Rash
• Muscle spasms
• Urinary tract infection
• Limb pain
• Swelling of the body, including around the eyes and other parts of the body
• Chills
• Redness and pain at the injection site
• General feeling of discomfort
• Weight loss
• Weight gain

Uncommon adverse effects (may affect up to 1 in 100 patients)

• Hepatitis
• Severe allergic reaction (anaphylactic reaction), whose signs may include difficulty breathing, chest pain or tightness and/or dizziness/fainting, intense itching of the skin or skin lumps, swelling of the face, lips, tongue and/or throat, which may cause difficulty swallowing, collapse
• Movement disorders, paralysis, jerking
• Dizziness
• Hearing loss, deafness
• Disorders affecting the lungs, preventing the body from receiving enough oxygen. Some of these include difficulty breathing, shortness of breath, breathlessness without exertion, breathing that may become shallow, difficult or stop, wheezing
• Blood clots in the lungs
• Yellowing of the eyes and skin (jaundice)
• Eyelid cyst (chalazion), red and swollen eyelids

Rare adverse effects (may affect up to 1 in 1,000 patients)

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

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Bortezomib EVER Pharma

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 outer packaging following EXP. The expiry date refers to the last day of the month indicated.

Store in a refrigerator (2 °C – 8 °C).

Keep the vial in the outer packaging to protect it from light.

The solution should be used immediately after first opening/dilution. If the solution (diluted) is not used immediately, the storage times and conditions prior to use are the responsibility of the user. However, when the solution is stored in the original vial and/or in a polypropylene syringe, the solution (diluted) is stable for 28 days at 2 °C - 8 °C and up to 25 °C protected from light, and for 24 hours up to 25 °C under normal indoor lighting conditions.

Regarding stability within the syringe, the same storage period applies to both diluted and undiluted solution.

Bortezomib is for single use only. Any unused medicine and all materials that have been in contact with it must be disposed of in accordance with local regulations.

6. Contents of the container and other information

Composition of Bortezomib EVER Pharma

The active substance is bortezomib. 1 millilitre of injectable solution contains 2.5 milligrams of bortezomib (as boric acid ester of mannitol). Each vial containing 1 millilitre of injectable solution contains 2.5 milligrams of bortezomib (as boric acid ester of mannitol). Each vial containing 1.4 millilitres of injectable solution contains 3.5 milligrams of bortezomib (as boric acid ester of mannitol).

Each vial contains an additional overage of 0.2 ml.

The other components are mannitol (E421), sodium chloride, sodium hydroxide (to adjust pH), hydrochloric acid (to adjust pH) and water for injections.

1 ml vial

Subcutaneous route: The product is ready to use at a concentration of 2.5 mg/ml.

Intravenous route: Add 1.8 ml of 0.9% sodium chloride solution to obtain a final concentration of 1 mg/ml.

1.4 ml vial

Subcutaneous route: The product is ready to use at a concentration of 2.5 mg/ml.

Intravenous route: Add 2.4 ml of 0.9% sodium chloride solution to obtain a final concentration of 1 mg/ml.

Appearance of Bortezomib EVER Pharma and contents of the container

Bortezomib EVER Pharma 2.5 mg/ml solution for injection is a clear, colourless to pale yellow solution.

Bortezomib EVER Pharma is supplied in a colourless glass vial with a rubber stopper, and an aluminium cap with a plastic flip-off seal.

Pack sizes

1 vial of 1 ml (2.5 mg/1 ml)

5 vials of 1 ml (2.5 mg/1 ml)

1 vial of 1.4 ml (3.5 mg/1.4 ml)

5 vials of 1.4 ml (3.5 mg/1.4 ml)

Only some pack sizes may be marketed.

Marketing Authorization Holder

EVER Valinject GmbH

Oberburgau 3

4866 Unterach am Attersee

Austria

Manufacturer

EVER Pharma Jena GmbH

Otto Schott Str. 15

07745 Jena

Germany

EVER Pharma Jena GmbH

Brüsseler Str. 18

07747 Jena

Germany

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:

EVER Pharma Therapeutics Spain, S.L.

C/Toledo 170

28005 Madrid

Spain

This medicinal product is authorized in the EEA Member States under the following names:

Belgium	Bortezomib EVER Pharma 2.5 mg/ml solution for injection/oplossing voor injectie/solution injectable
Denmark	Bortezomib EVER Pharma 2.5 mg/ml concentrate for solution for injection
Finland	Bortezomib EVER Pharma 2.5 mg/ml solution for injection
France	Bortezomib EVER Pharma 2.5 mg/ml solution injectable
Hungary	Bortezomib EVER Pharma 2.5 mg/ml oldatos injekció
Ireland	Bortezomib 2.5 mg/ml solution for injection
Italy	Bortezomib EVER Pharma 2.5 mg/ml soluzione iniettabile
Netherlands	Bortezomib EVER Pharma 2.5 mg/ml oplossing voor injectie
Norway	Bortezomib EVER Pharma 2.5 mg/ml injeksjonsvæske, oppløsning
Portugal	Bortezomib EVER Pharma 2.5 mg/ml solução injetável
Spain	Bortezomib EVER Pharma 2.5 mg/ml solución inyectable
Sweden	Bortezomib EVER Pharma 2.5 mg/ml injektionsvätska, lösning

Date of the most recent review of this summary: 09/2021

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency of Medicines and Medical Devices (Agencia Española del Medicamento y Productos Sanitarios, AEMPS) (http://www.aemps.gob.es)

---

This information is intended for healthcare professionals only:

1. PREPARATION FOR INTRAVENOUS INJECTION

Note: Bortezomib is a cytotoxic agent. Therefore, caution should be exercised during handling and preparation. The use of gloves and other protective clothing is recommended to prevent skin contact. Pregnant individuals must not handle this medicine.

SINCE BORTEZOMIB DOES NOT CONTAIN PRESERVATIVES, STRICT ADHERENCE TO ASEPTIC TECHNIQUE IS ADVISED DURING HANDLING.

1. Preparation of a 1 ml vial: add 1.8 millilitres of sterile sodium chloride injection solution 9 mg/ml (0.9%) to the vial containing bortezomib.

Or

Preparation of a 1.4 ml vial: add 2.4 millilitres of sterile sodium chloride injection solution 9 mg/ml (0.9%) to the vial containing bortezomib.

The resulting solution concentration will be 1 mg/ml. The solution should be clear, colourless to pale yellow, with a final pH of 4 to 7. It is not necessary to check the pH of the solution.

1. Before administration, visually inspect the solution for the presence of particles and discoloration. If discoloration or particles are observed, the solution must be discarded. Confirm that the correct dose is being used for intravenous administration (1 mg/ml).

1.3 The solution contains no preservatives and should be used immediately after preparation. However, chemical and physical in-use stability of the diluted solution has been demonstrated for:

• 28 days at 2 °C - 8 °C and protected from light
• 28 days at 25 °C and protected from light
• 24 hours when stored at 25 °C and under normal indoor lighting conditions in the original vial and/or in a polypropylene syringe.

If the diluted solution is not used immediately, the storage times and conditions prior to use are the responsibility of the user.

1. ADMINISTRATION

• After dilution, withdraw the appropriate amount of the diluted solution according to the dose calculated based on the patient's Body Surface Area.
• Confirm the dose and concentration contained in the syringe before use (ensure the syringe is labelled for intravenous administration).
• Inject the solution as an intravenous bolus over 3-5 seconds through a peripheral or central intravenous catheter into a vein.
• Flush the peripheral or intravenous catheter with sodium chloride solution, 9 milligrams/millilitre (0.9%) sterile.

Bortezomib EVER Pharma 2.5 mg/ml solution for injection MUST BE ADMINISTERED ONLY BY INTRAVENOUS OR SUBCUTANEOUS ROUTE. Do not administer by other routes. Intrathecal administration has resulted in fatal cases.

3. DISPOSAL

A vial is for single use only, and any remaining solution must be discarded.

Disposal of unused medicine and all materials that have come into contact with it must be carried out in accordance with local regulations for cytotoxic agents.

This information is intended for healthcare professionals only:

1. PREPARATION FOR SUBCUTANEOUS INJECTION

Note: Bortezomib is a cytotoxic agent. Therefore, caution should be exercised during handling and preparation. The use of gloves and other protective clothing is recommended to prevent skin contact. Pregnant individuals must not handle this medicine.

SINCE BORTEZOMIB DOES NOT CONTAIN PRESERVATIVES, STRICT ADHERENCE TO ASEPTIC TECHNIQUE IS ADVISED DURING HANDLING.

1.1 Bortezomib is ready for use. The solution concentration will be 2.5 mg/ml. The solution is clear, colourless to pale yellow, with a pH of 4.0 to 5.5. It is not necessary to check the pH of the solution.

1.2 Before administration, visually inspect the solution for the presence of particles and discoloration. If discoloration or particles are observed, the solution must be discarded. Confirm that the correct dose is being used for subcutaneous administration (2.5 mg/ml).

1.3 The solution contains no preservatives and should be used immediately after withdrawing the appropriate amount. However, chemical and physical stability of the solution has been demonstrated for:

o 28 days at 2 °C - 8 °C and protected from light
o 28 days at 25 °C and protected from light
o 24 hours when stored at 25 °C and under normal indoor lighting conditions in the original vial and/or in a polypropylene syringe.

If the solution is not used immediately, the storage times and conditions prior to use are the responsibility of the user.

During preparation for administration and during administration itself, it is not necessary to protect the medicine from light.

2. ADMINISTRATION

• Withdraw the appropriate amount of solution according to the dose calculated based on the patient's Body Surface Area.
• Confirm the dose and concentration contained in the syringe before use (ensure the syringe is labelled for subcutaneous administration).
• Inject the solution subcutaneously at an angle of 45-90°.
• The solution is administered subcutaneously in the thigh (right or left) or in the abdomen (right or left side).
• Injection sites should be rotated with each injection.
• If local reactions occur at the injection site following subcutaneous administration of bortezomib, either a less concentrated solution (1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously, or switching to intravenous injection is recommended.

Bortezomib EVER Pharma 2.5 mg/ml solution for injection MUST BE ADMINISTERED ONLY BY INTRAVENOUS OR SUBCUTANEOUS ROUTE. Do not administer by other routes. Intrathecal administration has resulted in fatal cases.

3. DISPOSAL

A vial is for single use only, and any remaining solution must be discarded.

Disposal of unused medicine and all materials that have come into contact with it must be carried out in accordance with local regulations for cytotoxic agents.