Bortezomib Waverley 3.5 mg powder for injection solution EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Bortezomib Waverley 3.5 mg powder for solution for injection EFG

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, consult your doctor or pharmacist.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are adverse effects not listed in this leaflet. See section 4.

Leaflet contents

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

1. What Bortezomib Waverley 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 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 treatment, and for those patients for whom stem cell transplantation has not worked or is not suitable.
• in combination with melphalan and prednisone, for patients whose disease has not been previously treated and for whom high-dose chemotherapy followed by stem cell transplantation is not suitable.
• in combination with dexamethasone or dexamethasone plus thalidomide, for patients whose disease has not been previously treated and who are receiving high-dose chemotherapy followed by 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 stem cell transplantation is not considered appropriate.

2. What you need to know before using Bortezomib Waverley

Do not use Bortezomib Waverley

• 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

Consult your doctor or pharmacist 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,
• numbness, tingling, or pain in hands or feet (neuropathy) in the past,
• 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.

Inform your doctor if you have mantle cell lymphoma and are being treated with rituximab in combination with bortezomib:

• if you currently have or have had hepatitis infection in the past. In some cases, patients with previous hepatitis B infection may experience reactivation of 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.

Before starting treatment with bortezomib, you should read the package leaflets of all the medicines you will be taking 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 unknown how the medicine will affect them.

Other medicines and Bortezomib Waverley

Inform your doctor or pharmacist if you are using, have recently used, or might need to use 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 receiving bortezomib must use effective contraception during treatment and for at least 3 months after treatment ends. If you become pregnant despite these measures, 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 use of 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.

3. How to use Bortezomib Waverley

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 a week. 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 underlying 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) corresponds to 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 together 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 treatment cycle, by intravenous infusion after the bortezomib injection.

You may receive up to 8 cycles (24 weeks).

When bortezomib is administered together 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 eligible for stem cell transplantation, you will receive bortezomib intravenously 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 eligible for 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 together 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 together with thalidomide and dexamethasone, the duration of a 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 from days 15 to 28, and from the second cycle onwards, it may be further increased up 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 by 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 Waverley is administered

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

The bortezomib powder must be dissolved before administration. This will be done by a healthcare professional. The reconstituted solution is then injected into a vein or under the skin. The intravenous injection is rapid and lasts between 3 and 5 seconds. The subcutaneous injection is administered in the thighs or abdomen.

If you receive more Bortezomib Waverley 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 obvious injury (e.g., intestinal, stomach, mouth, and gum bleeding, 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 receiving bortezomib for the treatment of multiple myeloma, the adverse effects you may experience are listed below:

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 to drink more fluids than usual. Your doctor may prescribe another medicine to control diarrhea,
• exhaustion (fatigue), 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,
• reduced 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,
• shingles (localized, including around the eyes, or widespread),
• chest pain or difficulty breathing during exercise,
• various types of rashes,
• itchy skin, skin lumps, or dry skin,
• facial flushing or rupture of small capillaries,
• redness of the skin,
• dehydration,
• stomach burning, bloating, belching, flatulence, stomach pain, intestinal or stomach bleeding,
• altered 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 outer 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 body parts.

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,
• vein inflammation, 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, disturbances or changes in, or decreased sensitivity (touch, hearing, taste, smell), attention disorders, tremors, jerking,
• arthritis, including inflammation of the joints in the fingers, toes, and 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, labored breathing,
• hiccups, speech disorders,
• increased or decreased urine production (due to kidney injury), pain when urinating, or blood/protein 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), altered vision, eye bleeding,
• swollen 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 appearing 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 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,
• wasting or loss of body mass,
• increased appetite,
• fistula,
• joint effusion,
• cysts in the joint lining (synovial cysts),
• fracture,
• breakdown of muscle fibers causing other complications,
• liver swelling, liver bleeding,
• kidney cancer,
• skin disease resembling psoriasis,
• skin cancer,
• skin pallor,
• increased 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 receiving bortezomib in combination with other medicines for the treatment of mantle cell lymphoma, the adverse effects you may experience are listed below:

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)

• shingles (localized, including around the eyes, or widespread),
• 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,
• altered 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 the stomach and intestine,
• stomach pain,
• mouth or lip sores, sore throat,
• altered liver function,
• itchy skin,
• redness of the skin,
• rash,
• muscle spasms,
• urinary tract infection,
• limb pain,
• swelling of the body, including around the eyes and other body parts,
• 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 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, labored breathing,
• 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 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 Waverley

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

This medicine does not require any special temperature conditions for storage. Keep the vial in the outer packaging to protect it from light.

The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, the storage times after reconstitution and the conditions prior to use are the responsibility of the user. However, the reconstituted solution is stable for 8 hours at 25°C when stored in the original vial and for 3 hours in a syringe; therefore, the total storage time of the reconstituted medicine must not exceed 8 hours in the vial and 3 hours in the syringe before administration.

Bortezomib Waverley 3.5 mg powder for solution for injection is intended for single use only. Any unused medicine and all materials that have come into contact with it must be disposed of in accordance with local regulations.

6. Contents of the pack and other information

Composition of Bortezomib Waverley 3.5 mg powder for injectable solution

• The active substance is bortezomib.

Each vial contains 3.5 milligrams of bortezomib (as manitol boric ester).

• The other component is mannitol (E421).

Reconstitution for intravenous administration:

After reconstitution, 1 ml of the intravenous injection solution contains 1 mg of bortezomib.

Reconstitution for subcutaneous administration:

After reconstitution, 1 ml of the subcutaneous injection solution contains 2.5 mg of bortezomib.

What Bortezomib Waverley 3.5 mg powder for injection solution looks like and contents of the pack

Bortezomib Waverley 3.5 mg powder for injectable solution is a white or almost white paste or powder.

“Each pack of Bortezomib Waverley 3.5 mg powder for injection solution contains one 10 ml glass vial with a rubber stopper and an aluminium flip-off seal with a green plastic button.”

Marketing Authorization Holder

Waverley Pharma Europe Limited
Alexandra House, Office# 234, The Sweepstakes,
Ballsbridge, Dublin 4, D04 C7H2, Ireland

Manufacturer

United Kingdom: Mawdsley Brooks and Co. Ltd, Unit 22, Quest Park, Wheatley Hall Road, Doncaster DN2 4LT, United Kingdom
EU: Wessling KFT, Anonymus u. 6, Budapest 1045, Hungary
Wessling GmbH, Johann-Krane-Weg 42, 48149 Münster, Germany

For more information about this medicine, please contact the local representative of the Marketing Authorization Holder:

Viso Farmacéutica, S.L.U
C/ Retama 7, 7th Floor
28045 Madrid
Spain

This medicine is authorized in the Member States of the European Economic Area under the following names:

Member State	Medicinal Product Name
Netherlands	Bortezomib Waverley 1 mg powder for solution for injection Bortezomib Waverley 3.5 mg powder for solution for injection
United Kingdom	Bortezomib Waverley 1 mg powder for solution for injection Bortezomib Waverley 3.5 mg powder for solution for injection
Germany	Bortezomib Waverley 1 mg powder for solution for injection Bortezomib Waverley 3.5 mg powder for solution for injection
France	Bortezomib Waverley 1 mg, powder for injectable solution Bortezomib Waverley 3.5 mg, powder for injectable solution
Denmark	Bortezomib Waverley 1 mg powder for solution for injection Bortezomib Waverley 3.5 mg powder for solution for injection
Italy	Bortezomib Waverley
Norway	Bortezomib Waverley
Sweden	Bortezomib Waverley 1 mg powder for solution for injection Bortezomib Waverley 3.5 mg powder for solution for injection
Belgium	Bortezomib Waverley Pharma Europe 1 mg powder for solution for injection Bortezomib Waverley Pharma Europe 3.5 mg powder for solution for injection
Luxembourg	Bortezomib Waverley 1 mg powder for solution for injection Bortezomib Waverley 3.5 mg powder for solution for injection
Ireland	Bortezomib Waverley 1 mg powder for solution for injection Bortezomib Waverley 3.5 mg powder for solution for injection
Spain	Bortezomib Waverley 1 mg powder for injectable solution EFG Bortezomib Waverley 1 mg powder for injectable solution EFG

Date of the most recent review of this summary: September 2021

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

The following information is intended for healthcare professionals only:

1. RECONSTITUTION FOR INTRAVENOUS INJECTION

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

SINCE BORTEZOMIB DOES NOT CONTAIN PRESERVATIVES, STRICT ASEPTIC TECHNIQUE SHOULD BE FOLLOWED DURING HANDLING.

1. Preparation of a 3.5 milligram vial: Bortezomib must be reconstituted carefully by a healthcare professional with 3.5 milliliters of sterile sodium chloride 9 milligrams/milliliter (0.9%) injection solution into the vial containing the powder of Bortezomib Waverley 3.5 mg powder for injectable solution, using an appropriately sized syringe without removing the vial stopper. Dissolution of the lyophilized powder is complete within less than 2 minutes.

The resulting solution concentration will be 1 milligram/milliliter. The solution should be colourless and clear, 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 to exclude the presence of particles or 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).

2. The reconstituted solution contains no preservatives and should be used immediately after preparation. However, chemical and physical in-use stability has been demonstrated for 8 hours at 25°C when stored in the original vial and for 3 hours in a syringe. From a microbiological standpoint, unless the method of opening/reconstitution/dilution excludes the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. The total storage time of the reconstituted medicine must not exceed 8 hours in the vial and 3 hours in the syringe before administration. If not used immediately, the storage times and conditions prior to use are the responsibility of the user.

It is not necessary to protect the reconstituted product from light.

1. ADMINISTRATION
   • After dissolution, withdraw the appropriate amount of reconstituted 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 (check that 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 sterile sodium chloride 9 milligrams/milliliter (0.9%) solution.

Bortezomib Waverley 3.5 mg powder for injectable solution MUST BE ADMINISTERED ONLY BY INTRAVENOUS OR SUBCUTANEOUS ROUTE. Do not administer by other routes. Intrathecal administration has resulted in fatal cases.

1. DISPOSAL

Each 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.

The following information is intended for healthcare professionals only:

Only the 3.5 mg vial may be administered subcutaneously, as described below.

1. RECONSTITUTION FOR SUBCUTANEOUS INJECTION

SINCE BORTEZOMIB DOES NOT CONTAIN PRESERVATIVES, STRICT ASEPTIC TECHNIQUE SHOULD BE FOLLOWED DURING HANDLING.

1. Preparation of a 3.5 milligram vial: carefully add 1.4 milliliters of sterile sodium chloride 9 milligrams/milliliter (0.9%) injection solution to the vial containing the powder of Bortezomib Waverley 3.5 mg powder for injectable solution, using an appropriately sized syringe without removing the vial stopper.

The resulting solution concentration will be 2.5 milligrams/milliliter. The solution should be colourless and clear, 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 to exclude the presence of particles or 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).

2. The reconstituted solution contains no preservatives and should be used immediately after preparation. However, chemical and physical in-use stability has been demonstrated for 8 hours at 25°C when stored in the original vial and/or syringe. The total storage time of the reconstituted medicine must not exceed 8 hours in the vial and 3 hours in the syringe before administration. If the reconstituted solution is not used immediately, the storage times after reconstitution and conditions prior to use are the responsibility of the user.

It is not necessary to protect the reconstituted product from light.

1. ADMINISTRATION

• After dissolution, withdraw the appropriate amount of reconstituted 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 (check that the syringe is labelled for subcutaneous administration).
• Inject the solution subcutaneously at an angle of 45–90°.
• The reconstituted solution is administered subcutaneously in the thigh (right or left) or abdomen (right or left side).
• Injection sites should be rotated with each administration.
• If local reactions occur at the injection site following subcutaneous administration of Bortezomib Waverley 3.5 mg powder for injectable solution, either a less concentrated subcutaneous solution of Bortezomib Waverley 3.5 mg powder for injectable solution (1 mg/ml instead of 2.5 mg/ml) may be administered, or switching to intravenous injection is recommended.

Bortezomib Waverley 3.5 mg powder for injectable solution MUST BE ADMINISTERED ONLY BY INTRAVENOUS OR SUBCUTANEOUS ROUTE. Do not administer by other routes. Intrathecal administration has resulted in fatal cases.

1. DISPOSAL

Each 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.

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