Vortemiel

Package Leaflet: Information for the User

Vortemyel, 1 mg, Powder for Solution for Injection

(Bortezomib)

Read all of this leaflet carefully before taking this medicine.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the Pack

• 1. What Vortemyel is and what it is used for
• 2. Important information before taking Vortemyel
• 3. How to take Vortemyel
• 4. Possible side effects
• 5. How to store Vortemyel
• 6. Contents of the pack and other information

1. What Vortemyel is and what it is used for

Vortemyel contains the active substance bortezomib, which is a so-called "proteasome inhibitor". Proteasomes play a crucial role in controlling cell functions and their development process. By disrupting their function, bortezomib can lead to the death of cancer cells.

Vortemyel is used to treat multiple myeloma (a type of bone marrow cancer) in patients over 18 years of age:

• as a single medicine or in combination with other medicines: pegylated liposomal doxorubicin or dexamethasone in patients:
• whose disease has worsened (progressed) after previous treatment with at least one other type of treatment or whose hematopoietic stem cell transplantation was unsuccessful or not possible;
• in combination with melphalan and prednisone in patients who have not been previously treated and do not qualify for high-dose chemotherapy with hematopoietic stem cell transplantation;
• in combination with dexamethasone or dexamethasone with thalidomide in patients who have not been previously treated and qualify for high-dose chemotherapy with hematopoietic stem cell transplantation (induction treatment).

Vortemyel is used to treat mantle cell lymphoma (a type of lymph node cancer) in patients over 18 years of age in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, in patients who have not been previously treated and do not qualify for hematopoietic stem cell transplantation.

2. Important information before taking Vortemyel

When not to take Vortemyel

• If you are allergic to bortezomib or any of the other ingredients of this medicine (listed in section 6).
• If you have severe lung or heart disease.

Warnings and precautions

Tell your doctor if you:

• have a low number of red or white blood cells;
• have bleeding disorders and (or) a low number of platelets;
• experience diarrhea, constipation, nausea, or vomiting;
• have a history of fainting, dizziness, and lightheadedness;
• have kidney disease;
• have moderate to severe liver function disorders;
• have a history of numbness, tingling, and pain in hands and feet (symptoms of neuropathy);
• have heart disease or blood pressure problems;
• have shortness of breath or cough;
• have seizures;
• have shingles (around the eyes or widespread on the body);
• experience symptoms of tumor lysis syndrome, such as muscle cramps, muscle weakness, confusion, loss of vision, and shortness of breath;
• experience memory loss, thinking disorders, difficulty walking, or vision loss. These may be symptoms of a serious brain infection, and your doctor may recommend further tests and monitoring.

Regular blood tests must be performed before and during treatment with Vortemyel to regularly check the number of blood cells.

If you are taking Vortemyel for mantle cell lymphoma and are also taking a medicine containing rituximab, tell your doctor:

• if you suspect you have a hepatitis B virus infection or have had it in the past. In a few cases, patients who had a hepatitis B infection may have had recurring episodes of hepatitis, which could be fatal. If you have a history of hepatitis B, your doctor will closely monitor you for symptoms of active hepatitis B.

Before starting treatment with Vortemyel, read the package leaflets of all medicines you are taking during treatment to get information about them. If you are taking thalidomide, you must exclude pregnancy and then use effective contraception (see section "Pregnancy and breastfeeding").

Children and adolescents

Vortemyel should not be used in children and adolescents because it is not known how the medicine works in this age group.

Vortemyel and other medicines

Tell your doctor or pharmacist about all medicines you are taking, have recently taken, or might take, including those obtained without a prescription.

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 for the treatment of epilepsy;
• St. John's Wort (Hypericum perforatum) for the treatment of depression and other conditions;
• oral antidiabetic medicines.

Pregnancy and breastfeeding

Do not take Vortemyel during pregnancy unless it is absolutely necessary.

Both men and women taking Vortemyel must use effective contraception during and for 3 months after treatment. If you become pregnant despite using these methods, tell your doctor immediately.

Women should not breastfeed during treatment with Vortemyel. It is necessary to discuss with your doctor the safe timing of returning to breastfeeding after treatment.

Thalidomide causes birth defects and fetal death. When Vortemyel is used in combination with thalidomide, patients must follow the "Thalidomide Pregnancy Prevention Program" (see thalidomide package leaflet).

Driving and using machines

Vortemyel may cause fatigue, dizziness, fainting, and blurred vision. If you experience these symptoms, do not drive or operate machinery. If the symptoms do not occur, be cautious.

3. How to take Vortemyel

Your doctor will adjust the appropriate dose of Vortemyel based on your height and weight (body surface area). The most commonly used initial dose of Vortemyel is 1.3 mg/m² administered twice a week.

The doctor may change the dose and total number of treatment cycles based on your response to treatment, the occurrence of side effects, and additional diseases (e.g., liver problems).

Relapsed multiple myeloma

If Vortemyel is administered as a single medicine, you will receive 4 doses of Vortemyel intravenously on days 1, 4, 8, and 11, followed by a 10-day rest period. One treatment cycle lasts 21 days (3 weeks). You may receive up to 8 cycles (24 weeks).

You may also receive Vortemyel in combination with other medicines: pegylated liposomal doxorubicin or dexamethasone.

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

When Vortemyel is administered with dexamethasone, you will receive Vortemyel intravenously during a 21-day treatment cycle, and dexamethasone will be administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day Vortemyel treatment cycle. You may receive up to 8 cycles (24 weeks).

Previously untreated multiple myeloma

If you have not been previously treated for multiple myeloma and do not qualifyfor hematopoietic stem cell transplantation, you will receive Vortemyel intravenously in combination with melphalan and prednisone.

In this case, the treatment cycle lasts 42 days (6 weeks). You will receive 9 cycles (54 weeks).

• During cycles 1-4, Vortemyel is administered twice a week on days 1, 4, 8, 11, 22, 25, 29, and 32.
• 29 and 32.
• During cycles 5-9, Vortemyel is administered once a week on days 1, 8, 22, and 29.

Both melphalan (9 mg/m²) and prednisone (60 mg/m²) are administered orally on days 1, 2, 3, and 4 of the first week of each cycle.

If you have not been previously treated for multiple myeloma and qualifyfor hematopoietic stem cell transplantation, you will receive Vortemyel intravenously in combination with dexamethasone or dexamethasone with thalidomide for induction treatment.

When Vortemyel is administered with dexamethasone, you will receive Vortemyel intravenously during a 21-day cycle, and dexamethasone will be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 21-day Vortemyel treatment cycle. You may receive up to 4 cycles (12 weeks).

When Vortemyel is administered with dexamethasone and thalidomide, the treatment cycle lasts 28 days (4 weeks). Dexamethasone will be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day Vortemyel treatment cycle, and thalidomide will be administered orally once daily at a dose of 50 mg up to day 14 of the first cycle, and if the dose is tolerated, it will be increased to 100 mg on days 15-28 and may be further increased to 200 mg/day from the second cycle. You may receive up to 6 cycles (24 weeks).

Previously untreated mantle cell lymphoma

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

Vortemyel is administered intravenously on days 1, 4, 8, and 11, followed by a rest period without medication administration. One treatment cycle lasts 21 days (3 weeks). You may receive up to 8 cycles (24 weeks).

The following medicines are administered as intravenous infusions on day 1 of each 21-day Vortemyel 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 Vortemyel treatment cycle.

Administration of Vortemyel

This medicine is administered intravenously. Vortemyel will be administered by a healthcare professional with experience in the use of cytotoxic medicines.

The powder of Vortemyel must be dissolved before administration. The preparation of the medicine is performed by a healthcare professional. The prepared solution is administered intravenously.

The intravenous injection is rapid, lasting more than 3 to 5 seconds.

Overdose of Vortemyel

Since this medicine is administered by a doctor or nurse, it is unlikely that you will receive too much medicine. If this happens, your doctor will monitor you for side effects.

4. Possible side effects

Like all medicines, Vortemyel can cause side effects, although not everybody gets them.

Some side effects can be serious.

If you are taking Vortemyel for multiple myeloma or mantle cell lymphoma, tell your doctor immediately if you experience any of the following symptoms:

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

Treatment with bortezomib can very often cause a decrease in the number of red and white blood cells and platelets in the blood. Therefore, regular blood tests must be performed before and during treatment with Vortemyel to regularly check the number of blood cells.

You may experience a decrease in:

• platelets, which can lead to bruising or bleeding that is not caused by injury (e.g., gastrointestinal bleeding, bleeding from the mouth, or bleeding in the brain or liver);
• red blood cells, which can lead to anemia, characterized by symptoms such as fatigue and pallor;
• white blood cells, which can lead to increased susceptibility to infections or flu-like symptoms.

If you are taking Vortemyel for multiple myeloma, you may experience the following side effects:

Very common side effects(occurring in more than 1 in 10 people):

• allergic reactions, numbness, tingling, or burning sensation of the skin, pain in the hands or feet caused by nerve damage;
• decrease in the number of red and (or) white blood cells (see above);
• fever;
• nausea or vomiting, loss of appetite;
• constipation, which may be severe;
• diarrhea: if you experience diarrhea, you should drink more water than usual, and your doctor may recommend taking additional medicines to treat diarrhea;
• fatigue, feeling of weakness;
• muscle pain, bone pain.

Common side effects(occurring in less than 1 in 10 people):

• decreased blood pressure, sudden decrease in blood pressure when standing up, which can lead to fainting;
• increased blood pressure;
• decreased kidney function;
• headache;
• general malaise, pain, dizziness, lightheadedness, feeling of weakness or loss of consciousness;
• chills;
• infections, including pneumonia, respiratory tract infections, bronchitis, fungal infections, cough with expectoration, flu-like symptoms;
• shingles (localized, e.g., around the eyes or widespread on the body);
• chest pain, shortness of breath during exercise;
• rash of various types;
• itching, skin rash, or dry skin;
• flushing of the face or broken blood vessels;
• redness of the skin;
• dehydration;
• heartburn, bloating, belching, gas, stomach pain, gastrointestinal bleeding;
• liver function disorders;
• mouth ulcers or mouth pain, dry mouth, oral thrush;
• weight loss, loss of taste;
• muscle cramps, muscle weakness, bone pain;
• blurred vision;
• eye infection or conjunctivitis;
• nasal bleeding;
• difficulty sleeping, sweating, anxiety, mood swings, depression, restlessness, or agitation, changes in mental status, disorientation;
• swelling, including around the eyes and other parts of the body.

Uncommon side effects(occurring in less than 1 in 100 people):

• heart failure, heart attack, chest pain, discomfort in the chest, rapid or slow heart rate;
• kidney failure;
• vein inflammation, blood clots in veins and lungs;
• blood clotting disorders;
• circulatory failure;
• pericarditis or fluid in the pericardium;
• infections, including urinary tract infections, flu, herpes, ear and soft tissue infections;
• bleeding from the gastrointestinal tract or other mucous membranes;
• cerebrovascular disorders;
• paralysis, seizures, falls, movement disorders, abnormal or changed sensation (touch, hearing, taste, smell), attention disorders, tremors;
• arthritis, including finger, toe, or jaw joint inflammation;
• respiratory disorders that make breathing difficult. Some of these include difficulty breathing, shortness of breath, shortness of breath at rest, shallow breathing, or cessation of breathing, wheezing;
• hiccups, speech disorders;
• increased or decreased urine production (due to kidney damage), painful urination, or blood/protein in the urine, fluid retention;
• altered level of consciousness, confusion, worsening or loss of memory;
• allergic reactions;
• hearing loss, deafness, ringing, or discomfort in the ears;
• hormonal disorders that can affect salt and water absorption;
• hyperthyroidism;
• insulin deficiency or insulin resistance;
• eye irritation or inflammation, excessive tearing, eye pain, dry eyes, eye infections, stye, eyelid redness and swelling, eye discharge, vision disorders, eye bleeding;
• lymph node enlargement;
• joint stiffness, muscle cramps or spasms, groin pain;
• hair loss and abnormal hair structure;
• allergic reactions;
• redness or pain at the injection site;
• mouth pain;
• mouth or throat infections, mouth ulcers, esophagus, stomach, or intestine ulcers, sometimes with accompanying pain and bleeding, slowed intestinal motility (including obstruction), abdominal discomfort, and difficulty swallowing, vomiting blood;
• skin infection;
• bacterial and viral infections;
• tooth infection;
• pancreatitis, bile duct obstruction;
• genital pain, erectile dysfunction;
• weight gain;
• thirst;
• hepatitis;
• injection site reactions or complications related to the use of a venous catheter;
• skin reactions (which can be severe and life-threatening), skin ulcers;
• bruises, falls, and injuries;
• inflammation or bleeding of blood vessels, manifested by small red or purple spots (usually on the legs) to large bruise-like spots under the skin;
• mild cysts;
• severe reversible brain disorders, including seizures, high blood pressure, headache, fatigue, confusion, blindness, or other vision disorders.

Rare side effects(occurring in less than 1 in 1,000 people)

• heart disease, including heart attack, angina;
• skin redness;
• vein discoloration;
• microangiopathic thrombocytopenia (blood clots in small blood vessels);
• spinal cord inflammation;
• ear disorders, ear bleeding;
• hypothyroidism;
• Budd-Chiari syndrome (clinical symptoms caused by blockage of liver veins);
• abnormal or changed intestinal function;
• brain bleeding;
• jaundice (yellowing of the skin and eyes);
• severe allergic reaction (anaphylactic shock) with symptoms such as difficulty breathing, chest pain, or discomfort, and (or) dizziness or fainting, severe itching of the skin or hives, facial, lip, tongue, and (or) throat swelling, which can cause difficulty breathing and swallowing, collapse;
• breast disorders;
• vaginal ulcers;
• genital swelling;
• alcohol intolerance;
• weight loss, wasting;
• increased appetite;
• fistula;
• joint effusion;
• ganglion cyst;
• bone fractures;
• muscle fiber breakdown leading to further complications;
• liver swelling, liver bleeding;
• kidney cancer;
• skin condition similar to psoriasis;
• skin cancer;
• skin pallor;
• increased platelet count or plasma cells (a type of white blood cell);
• abnormal reaction to blood transfusion;
• partial or complete loss of vision;
• decreased libido;
• excessive salivation;
• exophthalmos;
• photophobia;
• increased respiratory rate;
• rectal pain;
• gallstones;
• hernia;
• injuries;
• brittle or weak nails;
• abnormal protein deposition in organs;
• coma;
• intestinal ulcers;
• multi-organ failure;
• death;
• severe nerve inflammation, which can cause paralysis and breathing difficulties (Guillain-Barré syndrome).

If you are taking Vortemyel in combination with other medicines for mantle cell lymphoma, you may experience the following side effects:

Very common side effects (occurring in more than 1 in 10 people):

• pneumonia;
• loss of appetite;
• allergic reactions, numbness, tingling, or burning sensation of the skin, pain in the hands or feet caused by nerve damage;
• nausea or vomiting;
• diarrhea;
• mouth ulcers;
• constipation;
• muscle pain, bone pain;
• hair loss and abnormal hair structure;
• fatigue, feeling of weakness;
• fever.

Common side effects (occurring in less than 1 in 10 people):

• shingles (localized, e.g., around the eyes or widespread on the body);
• herpes virus infection;
• bacterial and viral infections;
• respiratory tract infections, bronchitis, wet cough, flu-like symptoms;
• fungal infections;
• allergic reactions;
• insulin deficiency or insulin resistance;
• fluid retention;
• difficulty sleeping and sleep disorders;
• loss of consciousness;
• altered level of consciousness, confusion;
• dizziness;
• rapid heartbeat, high blood pressure, sweating;
• abnormal vision, blurred vision;
• heart failure, heart attack, chest pain, discomfort in the chest, rapid or slow heart rate;
• high or low blood pressure;
• sudden drop in blood pressure when changing body position, which can lead to fainting;
• shortness of breath during exercise;
• cough;
• hiccups;
• ringing or discomfort in the ears;
• bleeding from the gastrointestinal tract or stomach;
• heartburn;
• abdominal pain, bloating;
• difficulty swallowing;
• infection or inflammation of the stomach or intestines;
• abdominal pain;
• mouth or throat infection, throat pain;
• liver function changes;
• itching;
• skin redness;
• rash;
• muscle cramps;
• urinary tract infections;
• limb pain;
• swelling, including around the eyes and other parts of the body;
• chills;
• redness and pain at the injection site;
• general malaise;
• weight loss;
• weight gain.

Uncommon side effects (occurring in less than 1 in 100 people):

• hepatitis;
• severe allergic reaction (anaphylactic reaction), which can cause symptoms such as difficulty breathing, chest pain, or discomfort, and (or) dizziness or fainting, severe itching of the skin or hives, facial, lip, tongue, and (or) throat swelling, which can cause difficulty breathing and swallowing, collapse;
• movement disorders, paralysis, muscle tremors;
• dizziness;
• hearing loss, deafness;
• respiratory disorders that make breathing difficult. Some of these include difficulty breathing, shortness of breath, shortness of breath at rest, shallow breathing, or cessation of breathing, wheezing;
• blood clots in the lungs;
• jaundice (yellowing of the skin and eyes), stye, eyelid redness and swelling.

Rare side effects (occurring in less than 1 in 1,000 people):

• blood clots in small blood vessels (microangiopathic thrombocytopenia).

Reporting side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet.

Side effects can be reported directly to the Department of Drug Safety Monitoring, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl. Side effects can also be reported to the marketing authorization holder.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Vortemyel

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after "EXP".

Store the vial in the outer carton in order to protect from light.

No special storage instructions are required.

Reconstituted solution

The physical and chemical stability of the prepared solution has been demonstrated for 8 hours at 25°C/60%RH in the dark for both vials and polypropylene syringes.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Normally, the product should be used within 24 hours of reconstitution/dilution, provided that it has been stored in a refrigerator at 2-8°C and handled in accordance with good aseptic practices.

Vortemyel is for single use only. Any unused solution or waste material should be disposed of in accordance with local requirements.

6. Contents of the pack and other information

What Vortemyel contains

The active substance is bortezomib. One vial contains 1 mg of bortezomib (as a mannitol boronate ester). After reconstitution: 1 ml of the solution for infusion contains 1 mg of bortezomib.

The other excipient is mannitol (E 421).

Solution for infusion:

After reconstitution: 1 ml of the solution for infusion contains 1 mg of bortezomib.

What Vortemyel looks like and contents of the pack

Vortemyel powder for solution for injection is a white or off-white lyophilized powder or powder.

Vortemyel is packed in a 6 ml glass vial, type I, with a bromobutyl rubber stopper and an aluminum flip-off cap with a plastic flip-off cap, in a cardboard carton.

One pack contains one vial.

Marketing authorization holder

Alvogen Pharma Trading Europe EOOD, 86, Bulgaria blvd., 1680 Sofia, Bulgaria

Manufacturer

Synthon Hispania SL, C/Castelló n°1, Pol Las Salinas, Sant Boi de Llobregat, 08830 Barcelona, Spain

For further information on this medicine, please contact:

Alvogen Poland Sp. z o.o., ul. Kniaźnina 4a, 01-607 Warsaw, tel. 22 460 92 00

Date of revision of the text:May 2021

Alvogen (logo)

Information intended for healthcare professionals only

1. Preparation of the Solution for Injection

Caution: Vortemyel is a cytotoxic product. Handle and prepare the product with care. To minimize the risk of skin exposure, wear protective clothing, including gloves.

AS VORTEMYEL DOES NOT CONTAIN PRESERVATIVES, ASEPTIC TECHNIQUES MUST BE STRICTLY FOLLOWED DURING HANDLING AND PREPARATION.

• 1.1. Preparation of the 1 mg vial: carefully add 1.0 mlof sterile, 9 mg/ml (0.9%) sodium chloride injection to the vial containing the Vortemyel powder using a 1 ml syringe without removing the vial stopper. Reconstitution of the lyophilized powder takes less than 2 minutes.

The resulting solution will contain 1 mg/ml of bortezomib. After reconstitution, the solution is clear and colorless with a pH of 4 to 7. There is no need to check the pH of the solution.

• 1.2.Before administration, inspect the solution for any visible signs of precipitation or particulate matter. If any are present, discard the solution. Ensure that the dose to be administered is accurately calculated for intravenous use(1 mg/ml).
• 1.3.The reconstituted solution is preservative-free and should be used immediately. However, the chemical and physical stability of the reconstituted solution has been demonstrated for 8 hours at 25°C in the original vial and/or a polypropylene syringe. The total storage time of the reconstituted solution before administration should not exceed 8 hours. If the reconstituted solution is not used immediately, the storage times and conditions are the responsibility of the user. Normally, the product should be used within 24 hours of reconstitution, provided that it has been stored in a refrigerator at 2-8°C and handled in accordance with good aseptic practices.

There is no need to protect the reconstituted solution from light.

• 2. Administration
• Withdraw the calculated dose of Vortemyel from the vial into a syringe.
• Confirm the dose and concentration of the solution before administration (check that the syringe is labeled as for intravenous use).
• Administer the solution as an intravenous bolus injection over 3 to 5 seconds.
• Flush the intravenous line with a small amount of sterile sodium chloride injection.

Vortemyel 1 mg powder for solution for injection is for intravenous use only. Do not administer by any other route. Intrathecal administration has resulted in death.

• 3.Disposal

The vial is for single use only. Any unused solution should be discarded. Dispose of any unused product or waste material in accordance with local requirements.