Active ingredients: Bortezomib
VELCADE 3.5 mg powder for solution for injection.
Indications Why is Velcade used? What is it for?
VELCADE contains the active substance bortezomib, a so-called 'proteasome inhibitor'. Proteasomes play an important role in controlling cell function and growth. By interfering with their function, bortezomib can kill cancer cells.
VELCADE is used to treat multiple myeloma (a type of bone marrow malignancy) in patients over 18 years of age:
- alone or together with the medicines pegylated liposomal doxorubicin or dexamethasone, for patients with worsening (progressive) disease after receiving at least one previous treatment or in whom blood stem cell transplantation has failed or is not feasible
- in combination with the medicines melphalan and prednisone for patients with previously untreated disease who cannot receive high doses of chemotherapy with blood stem cell transplantation.
- in combination with dexamethasone or dexamethasone together with thalidomide, for patients with previously untreated disease and before receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment)
VELCADE is used to treat mantle cell lymphoma (a type of malignancy that affects the lymph nodes) in patients 18 years of age or older. In this case, VELCADE is used in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients with previously untreated disease and for whom blood stem cell transplantation is not feasible.
Contraindications When Velcade should not be used
Do not use VELCADE
- if you are allergic to bortezomib, boron or any of the other ingredients of this medicine (listed in section 6)
- if you have severe lung or heart problems.
Precautions for use What you need to know before taking Velcade
Tell your doctor if you have:
- low number of red blood cells or white blood cells
- bleeding problems and / or low blood platelet counts
- diarrhea, constipation, nausea or vomiting
- previous experiences of fainting, dizziness or light-headedness
- kidney problems
- moderate to severe liver problems
- previous complaints such as numbness, tingling or pain in the hands or feet (neuropathy)
- heart or blood pressure disorder
- shortness of breath or cough
- convulsions
- shingles (also located around the eyes or spreading to the rest of the body)
- symptoms of tumor lysis syndrome such as muscle cramps, muscle weakness, confusion, disturbed vision or vision loss and shortness of breath
- memory loss, difficulty thinking, difficulty walking or loss of vision. These can be signs of a serious brain infection, and your doctor may indicate further tests and checks.
You will need to have blood tests regularly before and during VELCADE therapy to constantly check your blood cell values.
If you have mantle cell lymphoma and are given rituximab together with VELCADE you should tell your doctor:
- if you think you have hepatitis or have had it in the past. In some cases, patients who have had hepatitis B may have a new attack of hepatitis, which can be fatal. If you have had a hepatitis B infection in the past, your doctor will need to monitor you closely for signs and symptoms of active hepatitis B.
Read the package leaflets of all medicines you take in combination with VELCADE for information on these medicines before starting treatment with VELCADE.
When VELCADE is co-administered with thalidomide, pay particular attention to the advice on pregnancy testing and the pregnancy prevention program (see "Pregnancy and breast-feeding" in this section).
Children and adolescents
VELCADE should not be used in children and adolescents because it is not known how the medicine works in these people.
Interactions Which drugs or foods can change the effect of Velcade
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines.
In particular, tell your doctor if you are using medicines containing any of the following active substances:
- ketoconazole, used to treat fungal infections
- ritonavir, used to treat HIV infection - rifampicin, an antibiotic used to treat bacterial infections
- carbamazepine, phenytoin or phenobarbital, used to treat epilepsy
- St. John's wort (Hypericum perforatum), used to treat depression or other conditions
- oral antidiabetic agents.
Warnings It is important to know that:
Pregnancy and breastfeeding
You should not use VELCADE if you are pregnant unless clearly necessary.
Men and women on VELCADE therapy should use effective contraceptive methods during and up to 3 months after treatment. If, despite these precautions, you become pregnant, tell your doctor immediately.
You should not breastfeed while taking VELCADE. Discuss with your doctor the best time to start breastfeeding again after the end of therapy.
The medicine thalidomide causes birth defects and fetal death. When VELCADE is co-administered with thalidomide, you must follow the thalidomide pregnancy prevention program (see thalidomide package leaflet).
Driving and using machines
VELCADE can cause fatigue, dizziness, fainting or blurred vision. Do not drive cars or use machines if you experience any of these symptoms. Also pay special attention if these effects do not occur.
Dose, Method and Time of Administration How to use Velcade: Posology
Your doctor will calculate the dose of VELCADE in proportion to your height and weight. The standard starting dose of VELCADE is 1.3 mg / m2 of body surface area twice weekly. Your doctor may change the dose and the total number of treatment courses depending on your response to treatment, the occurrence of certain side effects and your general health conditions (eg liver problems).
Multiple myeloma in progression
When VELCADE is given alone, you will receive 4 doses of VELCADE intravenously or subcutaneously on days 1, 4, 8 and 11. This is followed by a 10-day "off" period without treatment.
This 21-day (3-week) period corresponds to one course of treatment.
You could receive up to 8 cycles (24 weeks). You may also receive VELCADE together with the medicines pegylated liposomal doxorubicin or dexamethasone.
When VELCADE is given together with pegylated liposomal doxorubicin, you will receive a 21-day course of intravenous or subcutaneous VELCADE and 30 mg / m2 of pegylated liposomal doxorubicin will be given on day 4 of the 21-day treatment cycle of VELCADE as an infusion. intravenous after injection of VELCADE.
You could receive up to 8 cycles (24 weeks of treatment).
When VELCADE is co-administered with dexamethasone you will receive a 21-day course of treatment with intravenous or subcutaneous VELCADE and oral dexamethasone at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12, of the 21-day course of treatment with VELCADE.
You could receive up to 8 cycles (24 weeks of treatment).
Previously untreated multiple myeloma
If you have never been treated for multiple myeloma before and you are not a candidate for blood stem cell transplantation, you will receive VELCADE along with two other medicines: melphalan and prednisone.
In this case, the duration of a course of treatment is 42 days (6 weeks). He will receive 9 cycles (54 weeks).
- In cycles 1-4, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32.
- In cycles 5-9, VELCADE is administered once a week on days 1, 8, 22 and 29.
Melphalan (9 mg / m2) and prednisone (60 mg / m2) are administered by mouth on days 1, 2, 3 and 4 of the first week of each cycle.
If you have never been treated for multiple myeloma before and you are a candidate for blood stem cell transplantation, you will receive VELCADE intravenously or subcutaneously along with the medicines: dexamethasone, or dexamethasone and thalidomide, as induction treatment.
When VELCADE is co-administered with dexamethasone, you will receive a 21-day treatment course with intravenous or subcutaneous VELCADE and oral dexamethasone 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the cycle. 21-day VELCADE treatment.
You will receive 4 cycles (12 weeks of treatment).
When VELCADE is given together with thalidomide and dexamethasone, the duration of the treatment course 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 treatment cycle with VELCADE and thalidomide is administered orally at a dose of 50 mg daily until day 14 of the first cycle and, if tolerated, the thalidomide dose is increased to 100 mg on days 15-28 and may subsequently be increased up to 200 mg per day from the second cycle onwards. You could receive up to 6 cycles (24 weeks of treatment).
Previously untreated mantle cell lymphoma
If you have never received specific treatment for mantle cell lymphoma in the past, you will receive VELCADE intravenously or subcutaneously together with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone.
VELCADE is administered intravenously or subcutaneously on days 1, 4, 8 and 11, followed by a "rest" period without treatment. The duration of the treatment course is 21 days (3 weeks).
You could receive up to 8 courses of treatment (24 weeks).
The following medicinal products are administered on day 1 of each 21-day treatment cycle of VELCADE as an intravenous infusion: rituximab at 375 mg / m2, cyclophosphamide at 750 mg / m2 and doxorubicin at 50 mg / m2.
Prednisone is administered orally at a dose of 100 mg / m2 on days 1, 2, 3, 4 and 5 of the VELCADE treatment cycle.
How VELCADE is given
This medicine is for intravenous or subcutaneous use. VELCADE will be administered by a healthcare professional with experience in the use of cytotoxic medicines. The powder of VELCADE must be dissolved prior to administration. This will be done by a healthcare professional. The resulting solution is then quickly injected into a vein or subcutaneously. L " injection into a vein is rapid, over a period of 3 to 5 seconds. The subcutaneous injection can be made either in the thigh or in the abdomen.
Overdose What to do if you have taken too much Velcade
As this medicine is given by your doctor or nurse it is unlikely that you will take more than you should. In the unlikely event of an overdose, your doctor will monitor for side effects.
Side Effects What are the side effects of Velcade
Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects can be serious.
If you are given VELCADE for multiple myeloma or mantle cell lymphoma, tell your doctor right away if you notice any of the following symptoms:
- muscle cramps, muscle weakness
- confusion, disturbed vision or loss of vision, blindness, seizures, headache
- shortness of breath, swelling of the feet or changes in heart rate, high blood pressure, tiredness, fainting
- cough and difficulty breathing or tightness in the chest.
Treatment with VELCADE can very commonly cause a decrease in the number of red and white blood cells and blood platelets. Therefore, you will need to have blood tests regularly before and during treatment with VELCADE, to check your blood cell counts regularly. You may experience a reduction in the number of:
- platelets, which could make you more prone to bruising or bleeding without obvious injury (for example, bleeding in the intestines, stomach, mouth and gums or bleeding in the brain or liver)
- red blood cells, which can cause anemia, with symptoms such as fatigue and paleness
- white blood cells, which can make you more susceptible to infections or flu-like symptoms.
If you are given VELCADE for the treatment of multiple myeloma, the side effects that may occur are listed below.
Very common side effects (may affect more than 1 in 10 people)
- Sensitization, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, due to nerve damage.
- Reduction in the number of red and / or white blood cells (see above).
- Fever.
- Feeling of nausea or vomiting, loss of appetite.
- Constipation with or without excess gas (can be severe).
- Diarrhea: if this happens it is important that you drink a lot more water than usual. Your doctor may prescribe medications to control diarrhea.
- Tiredness (fatigue), feeling of weakness.
- Muscle pain, bone pain.
Common side effects (may affect up to 1 in 10 people)
- Low blood pressure, sudden drop in blood pressure when standing which can lead to fainting.
- Increased blood pressure.
- Reduced function of the kidneys.
- Headache.
- Feeling generally unwell, pain, dizziness, light-headedness, feeling of weakness or loss of consciousness.
- Chills.
- Infections, including pneumonia, respiratory infections, bronchitis, fungal infection, cough with phlegm, flu-like illness.
- Herpes zoster infection (localized, including around the eyes, or spread over the body).
- Chest pain or difficulty breathing during physical activity.
- Different types of skin rash (rash).
- Itchy skin, lumps on the skin or dry skin.
- Redness of the face or small breaks in the capillaries.
- Redness of the skin.
- Dehydration.
- Heartburn, bloating, belching, gas, stomach pain, intestinal or stomach bleeding.
- Alteration of liver function.
- Irritation of the mouth or lips, dry mouth, mouth ulcers or sore throat.
- Weight loss, loss of taste.
- Muscle cramps, muscle spasms, muscle weakness, pain in arms and legs.
- Blurred vision.
- Infection of the outermost layer of the eyes and the inner surface of the eyelids (conjunctivitis).
- Nasal haemorrhage (bleeding).
- Sleep disturbances or problems, sweating, anxiety, mood changes, depressed mood, restlessness or agitation, mental status changes, disorientation.
- Swelling of the body, including swelling around the eyes and other parts of the body.
Uncommon side effects (may affect up to 1 in 100 people)
- Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate.
- Kidney failure.
- Inflammation of a vein, blood clots in the veins and lungs.
- Blood clotting problems.
- Circulatory failure.
- Inflammation of the membrane surrounding the heart or the presence of fluid around the heart.
- Infections including urinary tract infections, the flu, herpes virus infections, ear infections and cellulitis.
- Blood in the stool, or bleeding of the mucous membranes e.g. mouth, vagina.
- Cerebrovascular disorders.
- Paralysis, convulsions, fall, movement disorders, abnormal, changed or reduced sensation (feeling, hearing, tasting, smelling), attention disturbance, tremor, spasms.
- Arthritis, including inflammation of the joints of the fingers, toes and jaw.
- Disorders that affect the lungs, preventing your body from getting enough oxygen. Some of these include difficulty in breathing, shortness of breath, wheezing even without physical activity, difficulty in shallow breathing or needing to stop, wheezing.
- Hiccups, speech disorders.
- Increased or decreased urine production (kidney damage), painful urination or blood / protein in the urine, fluid retention.
- Altered levels of consciousness, confusion, memory impairment or loss.
- Hypersensitivity.
- Loss of hearing, deafness or ringing in the ears, discomfort in the ear.
- Hormonal alterations that can affect the reabsorption of salts and water.
- Hyperactivity of the thyroid gland.
- Inability to produce enough insulin or resistance to normal insulin levels.
- Sore or inflamed eyes, excessively wet eyes, eye pain, dry eye, eye infections, eye discharge, vision disturbances, eye bleeding.
- Enlarged lymph nodes.
- Joint or muscle stiffness, feeling of heaviness, groin pain.
- Hair loss or abnormal hair texture.
- Allergic reactions.
- Redness or pain at the injection site.
- Pain in the mouth.
- Infection or inflammation of the mouth, ulcers of the mouth, esophagus, stomach and intestines sometimes associated with pain or bleeding, impaired bowel motility (including intestinal blockage), abdominal or esophageal discomfort, difficulty swallowing, vomiting blood.
- Skin infections.
- Bacterial and viral infections.
- Tooth infection.
- Inflammation of the pancreas, obstruction of the bile ducts.
- Pain in the genitals, erection problems.
- Weight gain.
- Feeling thirsty.
- Hepatitis.
- Disorders at the injection site or catheter site.
- Skin reactions or disorders (which can be serious and life-threatening), skin ulcerations.
- Bruises, falls and injuries.
- Inflammation or bleeding of blood vessels which may manifest as small red or purple dots (usually on the legs) which may become similar to large bruises on the skin or tissue.
- Benign cysts.
- A serious and reversible condition of the brain that includes seizures, high blood pressure, headache, fatigue, confusion, blindness or other vision problems.
Rare side effects (may affect up to 1 in 1,000 people)
- Heart problems including heart attack, angina.
- Flushes.
- Discoloration of the veins.
- Inflammation of the spinal nerve.
- Ear problems, bleeding from the ear.
- Reduced activity of the thyroid gland.
- Budd-Chiari syndrome (clinical signs are caused by blockage of the liver veins).
- Change or abnormal bowel function.
- Cerebral haemorrhage (bleeding).
- Yellow discoloration of the eyes and skin (jaundice).
- Severe allergic reaction (anaphylactic shock) signs include difficulty breathing, chest pain or chest tightness, and / or feeling dizzy / weak, severe itchy skin or lumps on the skin, swelling of the face, lips, tongue and / or throat which can cause difficulty in swallowing, collapse.
- Breast Disorders.
- Vaginal discharge.
- Swelling of the genitals.
- Inability to tolerate alcohol consumption.
- Wasting or loss of body mass.
- Increased appetite.
- Fistulas.
- Joint effusion.
- Cyst on the membrane that covers the joints (synovial cysts).
- Fractures.
- Breakdown of muscle fibers leading to other complications.
- Enlarged liver, liver haemorrhage.
- Kidney cancer.
- Skin condition similar to psoriasis.
- Skin cancer.
- Pallor of the skin.
- Increase in platelets or plasma cells (a type of white blood cell) in the blood.
- Abnormal reaction to blood transfusion.
- Partial or total loss of vision.
- Decreased libido.
- Loss of saliva.
- Eye protrusion.
- Photophobia (excessive sensitivity of the eye to light).
- Rapid breathing.
- Pain in the rectum.
- Gallstones.
- Hernia.
- Injuries.
- Brittle or weak nails.
- Abnormal protein deposition in vital organs.
- Coma.
- Intestinal ulcers.
- Damage to multiple organs.
- Death.
If you are given VELCADE together with other medicines to treat mantle cell lymphoma, the side effects that may occur are listed below.
Very common side effects (may affect more than 1 in 10 people)
- Pneumonia.
- Loss of appetite.
- Sensitization, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, due to nerve damage.
- Nausea and vomit.
- Diarrhea.
- Mouth ulcers.
- Intestinal constipation.
- Muscle pain, bone pain.
- Hair loss or abnormal hair texture.
- Tiredness, feeling of weakness.
- Fever.
Common side effects (may affect up to 1 in 10 people)
- Herpes zoster infection (localized, including around the eyes or spread over the body).
- Herpes virus infection.
- Bacterial and viral infections.
- Respiratory infections, bronchitis, cough with phlegm, flu-like illness.
- Fungal infections.
- Hypersensitivity (allergic reaction).
- Inability to produce enough insulin or resistance to normal insulin levels.
- Water retention.
- Difficulty or problems sleeping.
- Loss of consciousness.
- Altered levels of consciousness, confusional state.
- Feeling dizzy.
- Increased heart rate, high blood pressure, sweating.
- Visual disturbances, blurred vision.
- Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate.
- High or low blood pressure.
- Sudden drop in blood pressure when standing which can lead to fainting.
- Shortness of breath during physical activity.
- Cough.
- Hiccup.
- Ringing in the ears, discomfort in the ear.
- Intestinal or stomach bleeding.
- Stomach ache.
- Stomach pain, bloating.
- Difficulty swallowing.
- Infection or inflammation of the stomach and intestines.
- Stomach pain.
- Irritation of the mouth or lips, sore throat.
- Alteration of liver function.
- Itchy skin.
- Redness of the skin.
- Rash.
- Muscle spasms.
- Urinary tract infection.
- Pain in the limbs.
- Swelling of the body, including swelling around the eyes and other parts of the body.
- Chills.
- Redness and pain at the injection site.
- Feeling of general malaise.
- Loss of body weight.
- Body weight gain.
Uncommon side effects (may affect up to 1 in 100 people)
- Hepatitis.
- Severe allergic reaction (anaphylactic reaction) the signs of which may include difficulty in breathing, chest pain or chest tightness, and / or feeling dizzy / weak, severe itchy skin or lumps on the skin, swelling of the face, lips, tongue and / or throat which may cause difficulty in swallowing, collapse.
- Movement disorders, paralysis, contractions.
- Dizziness.
- Loss of hearing, deafness.
- Disorders that affect the lungs, preventing your body from getting enough oxygen. Some of these include difficulty in breathing, shortness of breath, wheezing even without physical activity, breathing that becomes shallow, difficult or stops, wheezing.
- Blood clots in the lungs.
- Yellow discoloration of the eyes and skin (jaundice).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
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 vial and carton after EXP.
Store at a temperature not exceeding 30 ° C. Keep the vial in the outer carton to protect the medicine from light.
The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, conditions and times of use are the responsibility of the preparer. However, the reconstituted solution is stable for 8 hours at 25 ° C prior to administration when stored in the original vial and / or in a syringe, with a maximum storage time for the reconstituted medicinal product not exceeding 8 hours.
VELCADE is for single use only. Unused product and waste must be disposed of in accordance with local regulations in force.
Deadline "> Other information
What VELCADE contains
- The active ingredient is bortezomib. Each vial contains 3.5 mg of bortezomib (as a boronic ester of mannitol). After reconstitution, 1 ml of solution for injection contains 1 mg of bortezomib.
- The other ingredients are mannitol (E421) and nitrogen.
Reconstitution for intravenous use: After reconstitution, 1 ml of solution for intravenous injection contains 1 mg of bortezomib.
Reconstitution for subcutaneous use: After reconstitution, 1 ml of solution for subcutaneous injection contains 2.5 mg of bortezomib.
Description of what VELCADE looks like and contents of the pack
VELCADE powder for solution for injection is white to creamy white.
Each pack of VELCADE 3.5 mg contains 1 glass vial of 10 ml with a blue cap, contained in a clear blister.
Deadline "> Information for healthcare professionals
The following information is intended for healthcare professionals only
RECONSTITUTION FOR INTRAVENOUS INJECTION
Note: VELCADE is a cytotoxic agent. Consequently, special care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing, to prevent contact with the skin.
DUE TO THE ABSENCE OF ANY KIND OF PRESERVATIVES, ASEPTIC TECHNICAL STANDARDS MUST BE FOLLOWED WHEN HANDLING VELCADE.
- Preparation of the 3.5 mg vial: Add 3.5 ml of sterile sodium chloride 9 mg / ml (0.9%) solution for injection to the vial containing the VELCADE powder. The lyophilized powder dissolves completely in less than 2 minutes.
The concentration of the solution obtained is equal to 1 mg / ml. The solution will be clear and colorless with a final pH between 4 and 7. It is not necessary to check the pH of the solution.
- The solution should be visually inspected prior to administration to check for any particulate matter or color change. In the presence of particulate matter or color change, the solution should not be used and should be discarded.
Confirm the concentration on the vial to ensure that the correct dose is administered intravenously (1 mg / ml).
- The reconstituted solution is preservative-free and should be used immediately after preparation while being chemically and physically stable for 8 hours at 25 ° C in the original vial and / or in a syringe with a maximum of 8 hours in the syringe. The total storage time of the reconstituted medicinal product cannot exceed 8 hours prior to administration. If the reconstituted solution is not used immediately after preparation, it is the user's responsibility to comply with the product's storage conditions and times prior to use.
It is not necessary to protect the reconstituted medicinal product from light.
ADMINISTRATION
- Once dissolved, withdraw the appropriate amount of the reconstituted solution in accordance with the dose calculated on the basis of the patient's body surface area.
- Confirm the dose and concentration in the syringe before use (check that the syringe is marked for intravenous administration).
- Inject the solution intravenously as a 3-5 second bolus, through a peripheral or central intravenous catheter.
- Flush the intravenous catheter with sterile sodium chloride 9 mg / ml (0.9%) solution for injection.
VELCADE 3.5 mg powder for solution for injection IS FOR SUBCUTANEOUS OR INTRAVENOUS USE. Do not administer by other routes. Intrathecal administration resulted in deaths.
DISPOSAL
The vial is for single use only and the remaining solution should be discarded.
Unused medicine and waste from this medicine must be disposed of in accordance with local regulations.
The following information is intended for healthcare professionals only:
Only the 3.5 mg vial can be administered subcutaneously as described below.
RECONSTITUTION FOR SUBCUTANEOUS INJECTION
Note: VELCADE is a cytotoxic agent. Consequently, special care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing, to prevent contact with the skin.
DUE TO THE ABSENCE OF ANY KIND OF PRESERVATIVES, ASEPTIC TECHNICAL STANDARDS MUST BE FOLLOWED DURING THE HANDLING OF VELCADE.
- Preparation of the 3.5 mg vial: Add 1.4 ml of sterile sodium chloride 9 mg / ml (0.9%) solution for injection to the vial containing the VELCADE powder. The lyophilized powder dissolves completely in less than 2 minutes.
The concentration of the solution obtained is equal to 2.5 mg / ml. The solution will be clear and colorless with a final pH between 4 and 7. It is not necessary to check the pH of the solution.
- The solution should be visually inspected prior to administration to check for any particulate matter or color change. In the presence of particulate matter or color change, the solution should not be used and should be discarded.
Confirm the concentration on the vial to ensure that the correct dose is administered subcutaneously (2.5 mg / ml).
- The reconstituted solution is preservative-free and should be used immediately after preparation while being chemically and physically stable for 8 hours at 25 ° C in the original vial and / or in a syringe with a maximum of 8 hours in the syringe. The total storage time of the reconstituted medicinal product cannot exceed 8 hours prior to administration. If the reconstituted solution is not used immediately after preparation, it is the user's responsibility to comply with the product's storage conditions and times prior to use.
It is not necessary to protect the reconstituted medicinal product from light.
ADMINISTRATION
- Once dissolved, withdraw the appropriate amount of the reconstituted solution in accordance with the dose calculated on the basis of the patient's body surface area.
- Confirm the dose and concentration in the syringe before use (check that the syringe is marked for subcutaneous administration).
- Inject the solution subcutaneously, at a 45-90 ° angle
- The reconstituted solution is administered subcutaneously into the thighs (right or left) or abdomen (right or left)
- In subsequent administrations it is necessary to change the injection site in rotation.
- If local reactions occur at the injection site after subcutaneous injection of VELCADE, a lower concentration of VELCADE 3.5 mg solution (1 mg / ml instead of 2.5 mg / ml) may be administered or it is recommended to switch to "intravenous injection.
VELCADE 3.5 mg powder for solution for injection IS FOR SUBCUTANEOUS OR INTRAVENOUS USE. Do not administer by other routes. Intrathecal administration resulted in deaths.
DISPOSAL
The vial is for single use only and the remaining solution should be discarded.
Unused medicine and waste from this medicine should be disposed of in accordance with local regulations.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
VELCADE 3,5 MG POWDER FOR SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each vial contains 3.5 mg of bortezomib (as a boronic ester of mannitol).
After reconstitution, 1 ml of solution for injection for subcutaneous use contains 2.5 mg of bortezomib.
After reconstitution, 1 ml of solution for injection for intravenous use contains 1 mg of bortezomib.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Powder for solution for injection.
White to creamy white powder (whether or not compacted).
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
VELCADE as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have already received at least one previous line of treatment and who have already undergone or are not eligible for stem cell transplantation. hematopoietic.
VELCADE in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are ineligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
VELCADE in combination with dexamethasone or with dexamethasone and thalidomide is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
VELCADE in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are not eligible for haematopoietic stem cell transplantation.
04.2 Posology and method of administration -
Treatment should be initiated and administered under the supervision of a physician trained and experienced in the use of chemotherapeutic agents. VELCADE should be reconstituted by a healthcare professional.
Posology for the treatment of progressive multiple myeloma (patients who have received at least one previous line of treatment)
Monotherapy
VELCADE 3.5 mg powder for solution for injection is administered intravenously or subcutaneously at the recommended dose of 1.3 mg / m² body surface area twice a week for two weeks on days 1, 4, 8 and 11 in one 21 day treatment cycle This 3 week period is considered a treatment cycle.
It is recommended that patients receive 2 courses of VELCADE after confirmation that a complete response is achieved.
Patients who respond to treatment but do not achieve complete remission are recommended to administer a total of 8 courses of VELCADE.
At least 72 hours should elapse between the administration of two consecutive doses of VELCADE.
Dose adjustments during treatment and its resumption as monotherapy
VELCADE therapy should be discontinued at the onset of any Grade 3 non-haematological toxicity or any Grade 4 haematological toxicity, excluding neuropathy, as indicated below (see also section 4.4). toxicity, VELCADE treatment can be resumed at a 25% lower dose (1.3 mg / m² reduced to 1.0 mg / m²; 1.0 mg / m² reduced to 0.7 mg / m²). where symptoms of toxicity have not resolved, or if they recur at a reduced dose, discontinuation of VELCADE should be considered unless the benefits of therapy clearly outweigh the risks.
Neuropathic pain and / or peripheral neuropathy
Patients who experience bortezomib-related neuropathic pain and / or peripheral neuropathy should be managed according to Table 1 (see section 4.4).
Patients with pre-existing severe neuropathy can only be treated with VELCADE after a "careful risk / benefit assessment."
Table 1: Recommended dose modifications * in case of neuropathy related to the administration of bortezomib
Combination therapy with pegylated liposomal doxorubicin
VELCADE 3.5 mg powder for solution for injection is administered intravenously or subcutaneously at the recommended dose of 1.3 mg / m² body surface area twice a week for two weeks on days 1, 4, 8 and 11 in one 21 day treatment cycle This 3 week period is considered a treatment cycle At least 72 hours should elapse between the administration of two consecutive doses of VELCADE.
Pegylated liposomal doxorubicin is administered at a dose of 30 mg / m² on day 4 of the VELCADE treatment cycle as an intravenous infusion lasting 1 hour following the injection of VELCADE.
Up to 8 cycles of this combination therapy can be given until patients show progression and tolerate treatment. Patients who achieve complete response can continue treatment for at least 2 cycles after the first evidence of complete response, even if this requires treatment for more than 8 cycles. Patients whose paraprotein levels continue to decline after 8 cycles can continue therapy as long as treatment is tolerated and continue to show a response.
For further information regarding pegylated liposomal doxorubicin, please refer to the respective Summary of Product Characteristics.
Combination with dexamethasone
VELCADE 3.5 mg powder for solution for injection is administered intravenously or subcutaneously at the recommended dose of 1.3 mg / m² body surface area twice a week for two weeks on days 1, 4, 8 and 11 in one 21 day treatment cycle This 3 week period is considered a treatment cycle At least 72 hours should elapse between the administration of two consecutive doses of VELCADE.
Dexamethasone is administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the VELCADE treatment cycle.
Patients who achieve disease response or stabilization after 4 cycles of this combination therapy can continue to receive the same combination for up to 4 additional cycles.
For further information regarding dexamethasone, please refer to the respective Summary of Product Characteristics.
Dose adjustment for combination therapy in patients with progressive multiple myeloma
For dose adjustments of VELCADE in combination therapy follow the dose modification recommendations described in the monotherapy section above.
Posology for the treatment of previously untreated multiple myeloma in patients not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
Combination therapy with melphalan and prednisone
VELCADE 3.5 mg powder for solution for injection is administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone as indicated in Table 2. A 6-week period is considered a course of treatment. In cycles 1-4 VELCADE is given twice a week on days 1, 4, 8, 11, 22, 25, 29 and 32. In cycles 5-9 VELCADE is given once a week on days 1, 8, 22 and 29. At least 72 hours should elapse between the administration of two consecutive doses of VELCADE.
Melphalan and prednisone should both be administered orally on days 1, 2, 3 and 4 of the first week of each VELCADE treatment cycle. 9 treatment cycles of this combination therapy are administered.
Table 2: Scheme of the recommended posology of VELCADE in combination with melphalan and prednisone
Dose adjustments during treatment and its resumption in combination with melphalan and prednisone
Before starting a new course of therapy:
• platelet count should be ≥ 70 x 109 / L and Absolute Neutrophil Count (ANC) ≥ 1.0 x 109 / L
• Non-haematological toxicities must have decreased to Grade 1 or baseline
Table 3: Changes in posology during subsequent courses of VELCADE therapy in combination with melphalan and prednisone
For more information regarding melphalan and prednisone, refer to their respective Summaries of Product Characteristics.
Posology for the treatment of previously untreated multiple myeloma in patients eligible for haematopoietic stem cell transplantation (induction therapy).
Combination therapy with dexamethasone
VELCADE 3.5 mg powder for solution for injection is administered intravenously or subcutaneously at the recommended dose of 1.3 mg / m² body surface area twice a week for two weeks on days 1, 4, 8 and 11 in one 21 day treatment cycle This 3 week period is considered a treatment cycle At least 72 hours should elapse between the administration of two consecutive doses of VELCADE.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.
Four treatment cycles of this combination therapy are administered.
Combination therapy with thalidomide and dexamethasone
VELCADE 3.5 mg powder for solution for injection is administered intravenously or subcutaneously at the recommended dose of 1.3 mg / m² body surface area twice a week for two weeks on days 1, 4, 8 and 11 in one 28 day treatment cycle This 4 week period is considered a treatment cycle.
At least 72 hours should elapse between the administration of two consecutive doses of VELCADE.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.
Thalidomide is administered orally at a daily dose of 50 mg on days 1-14; if tolerated, the dose is increased to 100 mg on days 15-28 and can subsequently be further increased to 200 mg per day from cycle 2 (see Table 4).
Four treatment cycles of this combination therapy are administered.
For patients who achieve at least a partial response, an additional 2 courses of treatment are recommended.
Table 4: Posology of combination therapy with VELCADE for the treatment of previously untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation.
Dose adjustment for transplant candidates
For VELCADE dose adjustment in case of neuropathy, refer to Table 1.
In addition, when VELCADE is administered in combination with other chemotherapeutic agents, appropriate dose reduction of these medicinal products should be considered in case of toxicity according to the recommendations in the relevant Summary of Product Characteristics.
Posology for patients with previously untreated mantle cell lymphoma (MCL)
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP)
VELCADE 3.5 mg powder for solution for injection is administered intravenously or subcutaneously at the recommended dose of 1.3 mg / m² body surface area twice weekly for two weeks on days 1, 4, 8 and 11, followed by from a 10 day rest period on days 12 to 21. This 3 week period is considered a course of treatment At least 72 hours should elapse between the administration of two consecutive doses of VELCADE.
6 treatment cycles with this combination therapy are recommended. Patients with a documented first response to cycle 6 may be given 2 additional courses of treatment.
The following medicinal products are administered as an intravenous infusion on day 1 of each 3-week treatment cycle with VELCADE: 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 each treatment cycle with VELCADE.
Dose adjustment during treatment of patients with previously untreated MCL
Before starting a new course of therapy:
• The platelet count must be ≥ 100,000 cells / mcL and the absolute neutrophil count (ANC) must be ≥ 1,500 cells / mcL
• Platelet counts should be ≥ 75,000 cells / mcL in patients with bone marrow infiltration or splenic sequestration
• Hemoglobin must be ≥ 8 g / dL
• Non-haematological toxicities should be reduced to Grade 1 or baseline.
VELCADE treatment should be discontinued at the onset of any Grade ≥ 3 VELCADE-related non-haematological toxicities (excluding neuropathy) or Grade ≥ 3 haematological toxicities (see also section 4.4). For dose adjustment, see Table 5 below.
In case of haematological toxicity, granulocyte growth factors can be administered according to local standard practice. Preventive use of granulocyte growth factors should be considered in the event of repeated delays in administering courses of therapy. When clinically appropriate, transfusion of platelets should be considered for the treatment of thrombocytopenia.
Table 5: Dose adjustment during treatment of patients with previously untreated MCL
Furthermore, when VELCADE is administered in combination with other chemotherapeutic agents, an "appropriate dose reduction of these medicinal products should be considered in the event of toxicity, in accordance with the recommendations contained in the respective Summary of Product Characteristics".
Special populations
Elderly patients
There is no clinical evidence to suggest a need for dose adjustment in patients over 65 years of age with multiple myeloma or mantle cell lymphoma.
There are no studies on the use of VELCADE in elderly patients with previously untreated multiple myeloma who are candidates for high-dose chemotherapy with haematopoietic stem cell transplantation.
Therefore, no dose recommendations can be made in this population.
In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patients exposed to VELCADE were in the range of 65-74 years and ≥ 75 years of age, respectively. In patients ≥ 75 years of age, both regimens, VELCADE in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), were less tolerated (see paragraph 4.8).
Hepatic dysfunction
Patients with mild hepatic impairment require no dose adjustment and should be treated with the recommended dosage.Patients with moderate or severe hepatic impairment should start treatment with VELCADE at a reduced dose of 0.7 mg / m² per injection during the first course of treatment, and a subsequent dose increase to 1.0 mg / m² or a further dose reduction to 0.5 mg / m² may be considered based on patient tolerance (see Table 6 and sections 4.4 and 5.2).
Table 6: Recommended initial dose modifications of VELCADE for patients with hepatic impairment
Renal dysfunction
The pharmacokinetics of bortezomib are unaffected in patients with mild to moderate renal impairment (creatinine clearance [CrCL]> 20 ml / min / 1.73 m²); therefore no dose adjustments are required in these patients. It is unknown whether the pharmacokinetics of bortezomib are altered in patients with severe renal impairment not on dialysis (CrCL
Pediatric population
The safety and efficacy of VELCADE in patients below 18 years of age have not been established (see sections 5.1 and 5.2). No data are available.
Method of administration
VELCADE 3.5 mg powder for solution for injection is for intravenous or subcutaneous administration.
VELCADE 1 mg powder for solution for injection is for intravenous administration only.
VELCADE must not be administered by other routes. Intrathecal administration caused death.
Intravenous injection
The reconstituted solution of VELCADE 3.5 mg is administered intravenously as a 3-5 second bolus, through a peripheral or central intravenous catheter, followed by flushing with sodium chloride 9 mg / ml (0, 9%). There should be at least 72 hours between two consecutive doses of VELCADE.
Subcutaneous injection
The reconstituted solution of VELCADE 3.5 mg is administered subcutaneously in the thighs (right or left) or abdomen (right or left). The solution is to be injected subcutaneously at a 45-90 ° angle.
Injection sites must be changed in rotation for subsequent injections.
If injection site reactions occur after subcutaneous administration of VELCADE, a less concentrated solution of VELCADE (VELCADE 3.5 mg reconstituted at 1 mg / ml instead of 2.5 mg / ml) may be administered subcutaneously or Switching to intravenous administration is recommended.
When VELCADE is administered in combination with other medicinal products, refer to the Summary of Product Characteristics of these medicinal products for instructions on administration.
04.3 Contraindications -
Hypersensitivity to the active substance, to boron or to any of the excipients listed in section 6.1.
Acute diffuse infiltrative pulmonary disease and pericardiopathy.
When VELCADE is given in combination with other medicinal products, refer to the relevant Summary of Product Characteristics for additional contraindications.
04.4 Special warnings and appropriate precautions for use -
When VELCADE is administered in combination with other medicinal products, the relevant Summary of Product Characteristics should be consulted before starting treatment with VELCADE. Particular attention should be paid to pregnancy testing and pregnancy prevention regulations when thalidomide is administered. see section 4.6).
Intrathecal administration
There have been cases of death following inadvertent intrathecal administration of VELCADE. VELCADE 1 mg powder for solution for injection is intended for intravenous use only, while VELCADE 3.5 mg powder for solution for injection is intended for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
Gastrointestinal toxicity
Gastrointestinal toxic effects, including nausea, diarrhea, vomiting and constipation, are very common during treatment with VELCADE. Cases of paralytic ileus have been reported uncommonly (see section 4.8). Therefore, patients experiencing constipation should be monitored closely.
Hematological toxicity
Treatment with VELCADE is very often associated with haematological toxic effects (thrombocytopenia, neutropenia and anemia). In studies conducted in patients with relapsed multiple myeloma treated with VELCADE and in patients with previously untreated MCL treated with VELCADE in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP), one of the most common haematological toxicities was transient thrombocytopenia . Platelets were at their lowest level on Day 11 of each VELCADE treatment cycle and returned to baseline levels usually on the next cycle. There was no evidence of cumulative thrombocytopenia. The mean platelet value nadir was approximately 40% of the baseline value in the multiple myeloma studies with VELCADE used as monotherapy and 50% in the MCL study. In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet values: for platelet values at baseline 75,000 / mcl, only 14% of 309 patients had platelet counts ≤ 25,000 / mcl during the study.
In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus 5.8%) Grade ≥ 3 thrombocytopenia in the VELCADE treatment group (VcR-CAP) versus the non-VELCADE group (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]). The two treatment groups were similar in both the overall incidence of bleeding events of all grades (6.3% in the VcR-CAP group and 5.0% in the R-CHOP group) and Grade 3 and major bleeding (VcR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the VcR-CAP group, 22.5% of patients received a platelet transfusion compared with 2.9% of patients in the R-CHOP group.
Gastrointestinal and intracerebral haemorrhage have been reported in association with VELCADE treatment. Therefore, platelet levels should be monitored prior to the administration of each dose of VELCADE. VELCADE therapy should be discontinued when the platelet count reaches values
Complete blood counts, with differential counts and including platelet counts, should be monitored frequently during treatment with VELCADE. When clinically appropriate, platelet transfusion should be considered (see section 4.2).
In MCL patients without evidence of cumulative neutropenia, transient reversible neutropenia was observed between treatment courses. Neutrophils were at their lowest level on Day 11 of each VELCADE treatment cycle and usually returned to baseline in the next cycle. In study LYM-3002, growth factor support was employed in 78% of patients in the VcR-CAP arm and 61% of patients in the R-CHOP arm. As patients with neutropenia are at increased risk of infections, they should be monitored for signs and symptoms of infection and treated promptly. Granulocyte growth factors can be administered to treat haematological toxicity according to local standard practice. In the event of repeated delays in the administration of courses of therapy, the preventive use of granulocyte growth factors should be considered (see section 4.2).
Reactivation of the Herpes zoster virus
Administration of antiviral prophylaxis is recommended in patients receiving VELCADE. In the Phase III study conducted in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with VELCADE + Melphalan + Prednisone than in patients treated with Melphalan + Prednisone (respectively 14 % versus 4%).
In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6.7% in the VcR-CAP arm and 1.2% in the R-CHOP arm (see section 4.8).
Reactivation and infection with hepatitis B virus (HBV)
When rituximab is used in combination with VELCADE, screening for HBV should always be performed prior to initiation of treatment in patients at risk of HBV infection. Carriers of hepatitis B and patients with a history of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection during and after treatment with rituximab in combination with VELCADE. Antiviral prophylaxis should be considered. For more information, refer to the Summary of Product Characteristics for rituximab.
Progressive multifocal leukoencephalopathy (PML)
Very rare cases of John Cunningham virus (JC) infection resulting in PML and death have been reported in patients treated with VELCADE, with unknown causality. Patients diagnosed with PML had previously taken immunosuppressive therapy or were taking it concomitantly. Most cases of PML were diagnosed within 12 months of taking the first dose of VELCADE. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may indicate PML among the differential diagnoses of central nervous system problems. If a diagnosis of PML is suspected, patients should be referred to a physician who specializes in the management of PML and appropriate diagnostic measures for PML implemented. In the event of a confirmed diagnosis of PML, treatment with VELCADE should be discontinued.
Peripheral neuropathy
Treatment with VELCADE is most often associated with the onset of peripheral, primarily sensory neuropathy. However, cases of severe motor neuropathy with or without peripheral sensory neuropathy have been reported.
The incidence of peripheral neuropathy increases early in treatment and peaks at cycle 5.
Patients are advised to be closely monitored for symptoms of neuropathy such as burning sensation, hyperesthesia, hypoesthesia, paraesthesia, malaise, neuropathic pain or weakness.
In the Phase III clinical study comparing VELCADE administered intravenously to the subcutaneous route, the incidence of Grade? 2 peripheral neuropathy events was 24% in the subcutaneous administration group and 41% in the intravenous injection group (p = 0.0124). Grade? 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group compared with 16% in the intravenous treatment group (p = 0.0264). all grades of peripheral neuropathy with intravenously administered VELCADE was lower in previous studies where VELCADE was administered intravenously than in study MMY-3021.
Neurological evaluation is recommended in patients with onset or worsening of peripheral neuropathy, for whom a change in dose or regimen or a change in route of administration to the subcutaneous route may be required (see section 4.2). Neuropathy was managed with supportive or other therapies.
Early and regular monitoring for symptoms of treatment-related neuropathy with a neurological evaluation should be considered in patients receiving VELCADE in combination with medicinal products known to be associated with neuropathy (e.g. thalidomide) and appropriate consideration should be given to dose reduction or discontinuation of treatment.
In addition to peripheral neuropathy, autonomic neuropathy may contribute to the onset of some adverse reactions, such as postural hypotension and severe ileus constipation. There is still limited information available on autonomic neuropathy and its contribution to these side effects. .
Convulsions
Seizures have been reported uncommonly in patients with no history of seizures or epilepsy. Special care is required when treating patients at risk for seizures.
Hypotension
VELCADE treatment is commonly associated with orthostatic / postural hypotension. Most adverse reactions are mild to moderate in severity and have been observed during treatment. Patients who experienced orthostatic hypotension with VELCADE (injected intravenously) had no previous episodes of orthostatic hypotension prior to treatment. Therapy for the treatment of orthostatic hypotension was required in most patients. A minority of patients with orthostatic hypotension experienced syncope episodes. Orthostatic / postural hypotension was not acutely related to bolus infusion of VELCADE.
The mechanism of this event is unknown, although a component may be determined by autonomic neuropathy. Autonomic neuropathy may be related to bortezomib, or it is possible that the drug may aggravate a pre-existing condition, such as diabetic or amyloidotic neuropathy. The utmost caution should be used in the treatment of patients with a history of syncope being treated with drugs known to be related to hypotension, or patients who exhibit dehydration resulting from recurrent diarrhea or vomiting. Orthostatic / postural hypotension may be treated with dosage adjustment of antihypertensive drugs, rehydration or administration of mineralocorticosteroids and / or sympathomimetic drugs. Patients should be advised to consult their physician if dizziness, light-headedness or brief episodes of fainting.
Posterior reversible encephalopathy syndrome (PRES)
There have been reports of PRES in patients receiving VELCADE. PRES is a rare neurological form characterized by rapid, often reversible evolution that can manifest itself with seizures, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological changes. The diagnosis is confirmed by radiological images of the brain structures, preferably obtained with Nuclear Magnetic Resonance (MRI). In patients developing PRES, VELCADE therapy should be discontinued.
Heart failure
Acute onset or aggravation of congestive heart failure, and / or development of decreased left ventricular ejection fraction has been observed during treatment with bortezomib. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with heart failure or with risk factors for heart failure should be carefully monitored.
Electrocardiographic investigations
Isolated cases of QT interval prolongation have been observed in clinical studies, the causality of which has not been established.
Pulmonary alterations
Rare cases of acute diffuse infiltrative pulmonary disease of unknown aetiology, such as pneumonia, interstitial pneumonia, pulmonary infiltration and acute respiratory distress syndrome (ARDS), have been reported in patients receiving VELCADE (see section 4.8). Some of these episodes have been fatal. A chest radiograph prior to treatment is recommended as a baseline reference for potential pulmonary changes following treatment.
In case of onset or worsening of pulmonary symptoms (eg cough, dyspnoea), a prompt diagnostic evaluation of the patient and consequent appropriate treatment must be carried out. The risk / benefit balance should be considered before continuing VELCADE therapy.
During a clinical study, two out of two patients receiving high-dose cytarabine (2 g / m² per day) as a 24-hour continuous infusion in combination with daunorubicin and VELCADE for the treatment of relapsed acute myeloid leukemia died due to ARDS. in the initial phase of therapy, the study was stopped. This specific combination therapy regimen with high dose cytarabine (2 g / m² per day) in continuous 24 hour infusion is therefore not recommended.
Impaired renal function
Renal complications are common in patients with multiple myeloma. Patients with renal insufficiency should be carefully monitored (see sections 4.2 and 5.2).
Impaired liver function
Bortezomib is metabolised by liver enzymes. In patients with moderate or severe hepatic impairment, exposure to bortezomib is increased; such patients should be treated with a reduced dose of VELCADE and should be carefully monitored for any onset of toxicity (see sections 4.2 and 5.2. ).
Hepatic reactions
Rare cases of hepatic failure have been reported in patients receiving VELCADE and concomitant drug therapies and with severe underlying disease.Other hepatic reactions such as increased liver enzymes, hyperbilirubinaemia and hepatitis have been reported. These changes may be reversible after discontinuation of bortezomib treatment (see section 4.8).
Tumor lysis syndrome
Since bortezomib is a cytotoxic substance and is therefore capable of rapidly destroying malignant plasma cells and MCL cells, complications from tumor lysis syndrome may be observed. Patients at risk of developing tumor lysis syndrome are those who have shown a high tumor burden before starting treatment. These patients should be carefully monitored and precautions taken.
Concomitant administration of other drugs
Patients on concomitant treatment with bortezomib and potent CYP3A4 inhibitors should be carefully monitored. Particular care should be taken when co-administering bortezomib and CYP3A4 or CYP2C19 substrates (see section 4.5).
Normal hepatic function should be confirmed in patients receiving oral hypoglycaemics and treated with caution (see section 4.5).
Potentially immune-complex mediated reactions
Potential immune complex related reactions, such as serum sickness, polyarthritis with rash and proliferative glomerulonephritis, have been reported uncommonly. Administration of bortezomib should be discontinued in case of serious events.
04.5 Interactions with other medicinal products and other forms of interaction -
Education in vitro indicate that bortezomib is a weak inhibitor of cytochrome P450 isoenzymes (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4. Given the limited contribution (7%) of the CYP2D6 isoenzyme to the metabolism of bortezomib, this low metabolising phenotype is not expected to affect the overall availability of bortezomib.
A clinical drug-drug interaction study, based on data from 12 patients, to investigate the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously) showed a mean increase in AUC. bortezomib by 35% (90% CI [1.032-1.772)] Therefore, patients on concomitant treatment with bortezomib and potent CYP3A4 inhibitors (eg ketoconazole, ritonavir) should be closely monitored.
In a clinical drug-drug interaction study, based on data from 17 patients, to verify the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously) there was no evidence of an effect. significant on the pharmacokinetics of bortezomib.
A drug-drug interaction study, based on data from 6 patients, to investigate the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously) showed a mean reduction in AUC. 45% bortezomib. Therefore, concomitant use of bortezomib with potent CYP3A4 inducers (eg rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort) is not recommended as efficacy may be reduced.
In the same drug-drug interaction study, on data from 7 patients, to verify the effect of dexamethasone, a weak inducer of CYP3A4, on the pharmacokinetics of bortezomib (injected intravenously) there was no significant effect on the bortezomib pharmacokinetics.
A drug-drug interaction study, based on data from 21 patients, to evaluate the effect of melphalan-prednisone on the pharmacokinetics of bortezomib (injected intravenously), showed an increase in the AUC of bortezomib by 17%.
This was not considered clinically relevant.
In clinical trials, hypoglycaemia and hyperglycemia were reported uncommonly in diabetic patients receiving oral hypoglycemic drugs. Patients on oral antidiabetic therapy receiving VELCADE may require careful blood glucose monitoring and dosage adjustment of antidiabetic drugs.
04.6 Pregnancy and breastfeeding -
Contraception in men and women
Men and women of childbearing potential must use adequate contraceptive measures during administration and for 3 months following treatment.
Pregnancy
No clinical data on bortezomib exposure during pregnancy are available. The teratogenic potential of bortezomib has not been fully investigated.
In preclinical studies, administration of bortezomib at the maximum tolerated doses by the mother showed no effect on embryofoetal development in rats and rabbits. Animal studies have not been conducted to determine any effects on parturition and postnatal development (see section 5.3). VELCADE should not be used during pregnancy unless the clinical condition of the patient requires its use.
The patient should be informed of the potential risks to the fetus if VELCADE is administered during pregnancy, or if the patient becomes pregnant during treatment.
Thalidomide is a potent teratogen in humans and induces severe, life-threatening birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all conditions of the thalidomide pregnancy prevention program are met. Patients receiving VELCADE in combination with thalidomide must adhere to the thalidomide Pregnancy Prevention Program Refer to the Summary of Product Characteristics of thalidomide for additional information.
Feeding time
It is unknown whether bortezomib is excreted in human milk. Due to the potential for serious adverse reactions of VELCADE in breastfed infants, breastfeeding should be discontinued during VELCADE therapy.
Fertility
Fertility studies have not been conducted with VELCADE (see section 5.3).
04.7 Effects on ability to drive and use machines -
VELCADE may moderately affect the ability to drive or use machines.
VELCADE may be associated very commonly with fatigue, commonly with dizziness, uncommonly with syncope, commonly with orthostatic / postural hypotension, or blurred vision. Patients should exercise extreme caution when driving vehicles or using machines (see section 4.8).
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: antineoplastic drugs, other antineoplastic drugs.
ATC code: L01XX32.
Mechanism of action
Bortezomib is a proteasome inhibitor. It is specifically indicated to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large polypeptide complex, responsible for the degradation of ubiquinated proteins. The ubiquitin-proteasome metabolic pathway plays an essential role in controlling the turnover of specific proteins, thus maintaining homeostasis in the cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects signal transmission within the cell, which results in cancer cell death.
Bortezomib is highly selective for the proteasome. At concentrations of 10 mcM, bortezomib does not inhibit any of the numerous receptors and proteases evaluated and is more than 1,500 times more selective for the proteasome than the second target enzyme. Proteosome inhibition kinetics were evaluated in vitro and bortezomib dissociates from the proteasome with a t½ of 20 minutes, thus demonstrating that bortezomib inhibition is reversible.
Bortezomib-mediated inhibition of the proteasome has numerous effects on cancer cells, including, but not limited to, the "alteration of regulatory proteins that control cell cycle progression and" activation of nuclear factor kB (NF-kB). L " inhibition of the proteasome leads to cell cycle arrest and apoptosis.
NF-kB is a transcription factor whose activation is required in many stages of carcinogenesis, including cell growth and survival, angiogenesis, cell interaction and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
Trials have shown that bortezomib is cytotoxic to numerous types of cancer cells and that these cells are much more sensitive to the proapoptotic effects of proteasome inhibition than normal ones. Bortezomib causes reduction in tumor growth. in vivo in many preclinical cancer models, including multiple myeloma.
Data in vitro, ex vivo and in animal models suggest that bortezomib increases osteoblastic differentiation and activity and inhibits osteoclastic function. These effects have been observed in multiple myeloma patients with advanced osteolytic disease and treated with bortezomib.
Clinical efficacy in previously untreated multiple myeloma
An international, randomized (1: 1), open-label, prospective Phase III (MMY-3002 VISTA) clinical study was conducted in 682 patients to evaluate whether VELCADE (Vc) (1.3 mg / m² injected intravenously) in combination with melphalan (M) (9 mg / m²) and prednisone (P) (60 mg / m²) improved time to progression (TTP) compared to melphalan (9 mg / m²) and prednisone (60 mg / m²) in patients with previously untreated multiple myeloma. Treatment was given for up to 9 cycles (approximately 54 weeks) and was stopped early in case of disease progression or unacceptable toxicity. In the study, the median age of the patients was 71 years, 50% were male, 88% were Caucasian, and the patients' median Karnofsky performance status score was 80. Patients had IgG / IgA / Light Chain myeloma in 63% / 25% / 8% of cases, a median hemoglobin of 105 g / l and a median platelet count of 221.5 x 109 / l. In the two groups, the percentage of patients who had a creatinine clearance ≤ 30 was similar. ml / min (3% in each arm).
At the time ofinterim analysis planned, the primary endpoint, time to progression, had been reached and patients in the M + P arm were offered Vc + M + P treatment. Median follow-up was 16.3 months. After a median follow-up The final survival figure was updated for 60.1 months. A statistically significant survival benefit was observed in favor of the Vc + M + P treatment group (HR = 0.695, p = 0.00043) despite subsequent therapies including VELCADE-based regimens. Median survival in the Vc + M + P treatment group was 56.4 months compared to 43.1 months in the M + P treatment group. Efficacy results are shown in Table 11.
Table 11: Efficacy Results After Final Update of VISTA Survival Data
Candidate patients for stem cell transplantation
Two randomized, open-label Phase III multicentre clinical trials (IFM-2005-01, MMY-3010) were conducted to demonstrate the safety and efficacy of VELCADE in double and triple combination with other chemotherapeutic agents as induction therapy before stem cell transplantation in patients previously untreated for multiple myeloma.
In study IFM-2005-01 VELCADE in combination with dexamethasone [VcDx, n = 240] was compared with vincristine-doxorubicin-dexamethasone [VDDx, n = 242]. Patients in the VcDx group received four 21-day cycles, each of which consisted of VELCADE (1.3 mg / m² administered intravenously twice weekly on days 1, 4, 8, and 11) and oral dexamethasone (40 mg / m2). day on days 1 to 4 and on days 9 to 12, in Cycles 1 and 2, and on days 1 to 4 in Cycles 3 and 4).
One hundred ninety-eight patients (82%) and 208 patients (87%) in the VDDx and VcDx groups, respectively, had undergone autologous stem cell transplantation; most patients underwent a single transplant. Patient demographics and baseline disease characteristics were similar between the two treatment groups. In the study, the median age of the patients was 57 years, 55% were male and 48% of the patients had high cytogenetic risk. The median duration of treatment was 13 weeks for the VDDx group and 11 weeks for the VDDx group. VcDx The median number of cycles received by both groups was 4 cycles.
The study's primary efficacy endpoint was post-induction response rate (CR + nCR). A statistically significant difference in CR + nCR was observed in favor of the VELCADE group in combination with dexamethasone. Secondary efficacy endpoints included rates response (CR + nCR, CR + nCR + VGPR + PR) post-transplant, progression-free survival and overall survival The main efficacy results are presented in Table 12.
Table 12: Efficacy results in IFM-2005-01 study
In study MMY-3010 VELCADE in combination with thalidomide and dexamethasone [VcTDx, n = 130] was compared with thalidomide-dexamethasone [TDx, n = 127]. Patients in the VcTDx group received six 4-week cycles, each of which consisted of VELCADE (1.3 mg / m² administered twice weekly on days 1, 4, 8 and 11, followed by a rest period of 17 days 12 through 28), dexamethasone (40 mg given orally on days 1 to 4 and days 8 through 11), and thalidomide (50 mg daily given orally on days 1-14, with dose increased up to at 100 mg on days 15-28 and thereafter at 200 mg per day).
One hundred and five patients (81%) and 78 patients (61%) in the VcTDx and TDx groups, respectively. they had undergone a single autologous stem cell transplant. Patient demographics and baseline disease characteristics were similar between the two treatment groups. Patients in the VcTDx and TDx groups, respectively, had a median age of 57 and 56 years, 99% and 98% of the patients were Caucasian; 58% and 54% were male. In the VcTDx group 12% of patients were cytogenetically classified as high risk compared with 16% of patients in the TDx group. The median duration of treatment was 24.0 weeks and the median number of treatment cycles received was 6.0 and was consistent across treatment groups.
The primary efficacy endpoints of the study were post-induction and post-transplant response rates (CR + nCR). A statistically significant difference in CR + nCR was observed in favor of the treatment group with VELCADE in combination with dexamethasone and thalidomide. Secondary efficacy endpoints included progression-free survival and overall survival. The main efficacy results are presented in Table 13.
Table 13: Efficacy results from study MMY-3010
Clinical efficacy in patients with relapsed or refractory multiple myeloma
The safety and efficacy profiles of VELCADE (injected intravenously) were evaluated in two studies at the recommended dose of 1.3 mg / m²: a randomized, controlled dexamethasone (Dex) Phase III (APEX) study conducted in 669 patients with relapsed and refractory multiple myeloma, who have undergone 1 to 3 previous treatment lines and a single-arm Phase II study, conducted in 202 patients with relapsed and refractory multiple myeloma, who have undergone at least two previous treatment lines with disease progression after the last therapy.
In the Phase III study, in all patients, including those who had received only one prior line of therapy, treatment with VELCADE resulted in a significant lengthening of time to progression, a significant prolongation of survival, and a significant increase in the response rate. compared to dexamethasone treatment (see Table 14).
Based on the data emerging from the "interim analysis pre-planned, the Monitoring Committee recommended discontinuation of dexamethasone treatment in favor of VELCADE treatment for all patients randomized to dexamethasone treatment, regardless of disease status. Due to this early crossover, the median duration of Live patient follow-up was 8.3 months. In the VELCADE treatment arm, overall survival was longer and the response rate was higher in both patients who were refractory to their last therapy and those who did not. they were.
Of the 669 patients enrolled, 245 (37%) were 65 years of age or older. Response parameters as well as TTP were significantly better for VELCADE regardless of age. All efficacy parameters (time to progression, overall survival and response rate) were significantly improved in the VELCADE arm, regardless of levels. of b2-microglobulin at baseline.
In the refractory population of the Phase II study, the responses were evaluated by an independent committee and the response criteria applied are those established. by the European Bone Marrow Transplant Group. The mean overall survival of all patients enrolled in the study was 17 months (range Performance Status, from the deletion status of chromosome 13, or from the number or type of previous therapies. The response rate of patients already undergoing 2-3 or to more than 7 lines of treatment it was 32% (10/32) and 31% (21/67), respectively.
Table 14: Summary of efficacy results from Phase III (APEX) and II studies
In the Phase II study, patients who did not achieve optimal response to VELCADE monotherapy were treated with high doses of dexamethasone and VELCADE. The protocol allowed patients who achieved a less than optimal response to VELCADE monotherapy to receive dexamethasone.
A total of 74 evaluable patients were treated with dexamethasone and VELCADE. The combined treatment made it possible to obtain a response or an improvement in the response [MR 11% or PR 7%] in 18% of patients.
Clinical efficacy in patients with relapsed / refractory multiple myeloma with subcutaneous administration of VELCADE
A non-inferiority, open-label, randomized Phase III clinical trial compared the efficacy and safety of subcutaneous administration of VELCADE versus intravenous administration. This study included 222 patients with relapsed / refractory multiple myeloma, randomized in a ratio of 2: 1 to receive 1.3 mg / m² of VELCADE subcutaneously or intravenously for 8 cycles. For those patients who did not achieve optimal response to VELCADE alone (less than Complete Response [CR]) after 4 cycles, they were allowed to receive 20 mg of dexamethasone on the day of VELCADE administration and the day after. Patients with baseline grade ≥ 2 peripheral neuropathy or platelet counts
This study met the primary objective of non-inferiority assessed on response rate (CR + PR) after 4 cycles of VELCADE monotherapy for both subcutaneous and intravenous routes of administration, with a response rate of 42% in both. In addition, secondary efficacy endpoints related to response and time to event showed consistent results for both the subcutaneous and intravenous routes (Table 15).
Table 15: Summary of efficacy analyzes comparing subcutaneous and intravenous administrations of VELCADE
Treatment with VELCADE in combination with pegylated liposomal doxorubicin (study DOXIL-MMY-3001)
An open-label, randomized, parallel-group Phase III multicenter study was conducted in 646 patients comparing the safety and efficacy of VELCADE plus pegylated liposomal doxorubicin versus VELCADE monotherapy in multiple myeloma patients who had received at least 1 therapy in previously and who had not shown disease progression during anthracycline therapy. The primary efficacy endpoint was time to progression (TTP) while the secondary efficacy endpoints were overall survival (OS) and overall response rate ( ORR: (complete response + partial response) using the criteria of the "European Group for Blood and Marrow Transplantation (EBMT).
The results of the "interim analysis protocol-defined (based on 249 TTP events) led to early termination of the study for efficacy. This interim analysis showed a 45% risk reduction of TTP (95% CI; 29-57%, p
The final analysis for overall survival (OS) performed after a median follow-up of 8.6 years showed no significant difference in OS between the two treatment arms. Median OS was 30.8 months (95% CI; 25.2-36.5 months) for patients on VELCADE monotherapy and 33.0 months (95% CI; 28.9-37.1 months) for patients on combination therapy with VELCADE and pegylated liposomal doxorubicin.
Treatment with VELCADE in combination with dexamethasone
In the absence of a direct comparison between VELCADE and VELCADE in combination with dexamethasone in patients with progressive multiple myeloma, a "paired statistical analysis" was performed to compare the results of the non-randomized arm of VELCADE in combination with dexamethasone (study Phase II open label MMY-2045), with results obtained in the VELCADE monotherapy treatment arms from different Phase III randomized trials (M34101-039 [APEX] and DOXIL MMY-3001) in the same indication.
Matched-Pair Analysis is a statistical method in which patients in the treatment group studied (eg. VELCADE in combination with dexamethasone) and patients in the comparison group (eg. VELCADE) are comparable with respect to confounding factors through individual pairing of study subjects. This method minimizes the effects of confounding factors observed when estimating treatment effects using non-randomized data.
127 paired patient pairs were identified. The analysis showed an improvement in the overall response rate (ORR: CR + PR) (odds ratio 3.769; 95% CI 2.045-6.947; p
There is limited information available on retreatment with VELCADE in relapsed multiple myeloma.
The Phase II MMY-2036 (RETRIEVE), single-arm open label study was conducted to determine the efficacy and safety of retreatment with VELCADE. One hundred and thirty patients (age ≥ 18 years) with multiple myeloma who previously had at least one partial response to a regimen containing VELCADE was retreated after progression. At least 6 months after previous therapy, VELCADE was initiated at the last tolerated dose of 1.3 mg / m² (n = 93) or ≤ 1.0 mg / m² (n = 37) and administered on days 1, 4, 8 and 11 every 3 weeks for up to 8 cycles, either as monotherapy or in combination with dexamethasone according to standard of therapy. Dexamethasone was administered in combination with VELCADE to 83 patients in cycle 1 and an additional 11 patients received dexamethasone during the following VELCADE retreatment cycles.
The primary endpoint was the best confirmed response to retreatment according to EBMT criteria. The best overall response rate (CR + PR) for retreatment in 130 patients was 38.5% (95% CI: 30.1; 47). , 4).
Clinical efficacy in previously untreated patients with mantle cell lymphoma (MCL)
LYM-3002 is a Phase III, randomized, open-label study comparing the efficacy and safety of the combination of VELCADE, rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP; n = 243) to those of rituximab. cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP; n = 244) in previously untreated adult patients with MCL (Stage II, III or IV). Patients in the VcR-CAP treatment arm received VELCADE (1.3 mg / m²; on days 1, 4, 8, 11, rest period 12-21), rituximab 375 mg / m² IV on day 1; cyclophosphamide 750 mg / m² IV on day 1; doxorubicin 50 mg / m² IV on day 1 and prednisone 100 mg / m² orally on days 1 to 5 of the 21-day VELCADE treatment cycle. Patients with a documented first response to cycle 6 were given two further courses of treatment.
The primary efficacy endpoint was progression-free survival based on an Independent Review Committee (IRC) assessment. Secondary endpoints included time to progression (TTP), time to next anti-lymphoma treatment (TNT), duration of "treatment-free interval (TFI), overall response rate (ORR) and complete response rate (CR / CRu), overall survival (OS) and duration of response.
Demographics and baseline disease characteristics were generally well balanced between the two treatment arms: the median age of the patients was 66 years, 74% were male, 66% were Caucasian and 32% Asian, 69% of patients. patients had positive bone marrow aspirate and / or MCL positive bone marrow biopsy, 54% of patients had an International Prognostic Index (IPI) score ≥ 3, and 76% had Stage IV disease. Duration of treatment (median = 17 weeks) and duration of follow-up (median = 40 months) were comparable in both treatment arms. Patients in both treatment arms received a median of 6 cycles with 14% of subjects in the VcR-CAP group and 17% of patients in the R-CHOP group receiving the additional 2 cycles. Most patients in both groups completed treatment, 80% in the VcR-CAP group and 82% in the R-CHOP group. The efficacy results are presented in Table 16:
Table 16: Efficacy results from LYM-3002 study
The median PFS as determined by the investigator was 30.7 months in the VcR-CAP group and 16.1 months in the R-CHOP group (Hazard Ratio [HR] = 0.51; p
The median duration of complete response was 42.1 months in the VcR-CAP group compared to 18 months in the R-CHOP group. Overall response duration was 21.4 months longer in the VcR-CAP group (median 36.5 months versus 15.1 months in the R-CHOP group). At a median follow-up duration of 40 months, the median overall survival (OS) favored VcR-CAP (56.3 months in the R-CHOP group and not achieved in the VcR-CAP group), (HR estimate = 0.80; p = 0.173). There was a trend towards prolonged overall survival in favor of the VcR-CAP group; the estimated 4-year survival rate was 53.9% in the R-CHOP group and 64.4% in the VcR-CAP group.
Patients with previously treated light chain (AL) amyloidosis
An open-label, non-randomized Phase I / II study was conducted to determine the safety of VELCADE in patients with previously treated light chain (AL) amyloidosis. No new safety concerns were observed during the study and, in particular, VELCADE did not lead to worsening of organ damage (heart, kidney and liver).
In an exploratory efficacy analysis, for the two associated dose cohorts, a response rate of 67.3% (of which 28.6% complete response) was reported in terms of haematological response (protein M), in 49 evaluable patients treated with the maximum permitted doses of 1.6 mg / m² once weekly and 1.3 mg / m² twice weekly. For the two associated dose courses, 1-year survival was 88 , 1%.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with VELCADE in all subsets of the pediatric population with multiple myeloma and mantle cell lymphoma (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties -
Absorption
Following intravenous bolus administration of 1.0 mg / m² and 1.3 mg / m² to 11 patients with multiple myeloma and creatinine clearance values greater than 50 ml / min, the mean maximum plasma concentrations of bortezomib at first doses were 57 and 112 ng / mL, respectively. At subsequent doses, the mean maximum observed plasma concentrations ranged from 67 to 106 ng / mL for the 1.0 mg / m² dose and between 89 and 120 ng / mL for the 1.3 mg / m² dose.
After repeated intravenous bolus or subcutaneous injection of a dose of 1.3 mg / m² in patients with multiple myeloma (n = 14 in the intravenous group, n = 17 in the subcutaneous group), total systemic drug exposure (AUClast) was equivalent for the subcutaneous and intravenous routes of administration. Cmax after subcutaneous administration (20.4 ng / ml) was lower than intravenous (223 ng / ml). The geometric mean ratio AUC was 0.99 and with the 90% confidence intervals they were 80.18% - 122.80%.
Distribution
In patients with multiple myeloma, the mean volume of distribution (Vd) of bortezomib ranged from 1659 to 3294 l following single or repeated intravenous dosing at 1.0 mg / m² or 1.3 mg / m². This suggests that bortezomib is widely distributed in peripheral tissues. At a bortezomib concentration range of 0.01 to 1.0 μg / ml, binding to human plasma proteins in vitro it stood at an average of 82.9%. The plasma protein bound fraction of bortezomib was not concentration dependent.
Biotransformation
Education in vitro on human liver microsomes and on cytochrome P450 isoenzymes expressed by human c-DNA indicate that bortezomib mainly undergoes oxidative metabolism via cytochrome P450, 3A4, 2C19 and 1A2 enzymes. The main metabolic pathway consists of deboronation which leads to two deboronated metabolites which are subsequently hydroxylated to different metabolites. The deboronated metabolites of bortezomib are inactive as inhibitors of the 26S proteasome.
Elimination
The mean elimination half-life (t1 / 2) of bortezomib during multiple-dose treatment ranges from 40 to 193 hours. Bortezomib is cleared more rapidly after the first dose than at the following doses. The mean total clearance was 102 and 112 l / h after the first dose of 1.0 mg / m² and 1.3 mg / m², respectively, and between 15 and 32 l / h and between 18 and 32 l / h for subsequent doses of 1.0 mg / m² and 1.3 mg / m², respectively.
Special populations
Hepatic insufficiency
The effect of hepatic insufficiency on the pharmacokinetics of bortezomib was studied in a Phase I clinical study in 61 patients with primary solid tumors with varying degrees of hepatic impairment and treated with dosages of bortezomib including between 0.5 and 1.3 mg / m².
Mild hepatic impairment did not alter the dose-normalized AUC of bortezomib when compared to that seen in patients with normal hepatic function. However, dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment. , and such patients should be closely monitored (see section 4.2, Table 6).
Kidney failure
A pharmacokinetic study was conducted in patients with varying degrees of renal impairment, which were classified by creatinine clearance (CrCL) values into the following groups: Normal (CrCL ≥60 ml / min / 1.73 m² , n = 12), Mild (CrCL = 40-59 mL / min / 1.73 m², n = 10), Moderate (CrCL = 20-39 mL / min / 1.73 m², n = 9), and Severe (Intravenous CrCL at doses ranging from 0.7 to 1.3 mg / m² twice weekly. VELCADE exposure (dose normalized AUC and Cmax) was similar in all patient groups (see section 4.2).
05.3 Preclinical safety data -
At concentrations
Bortezomib did not show genotoxicity in the mutagenicity test in vitro (Ames test), nor in the micronucleus test in vivo carried out in mice.
In developmental toxicity studies conducted in rats and rabbits, embryofoetal mortality was shown at maternally toxic doses, but no embryofoetal toxicity below the maternal toxic dose. Fertility studies have not been conducted, however an evaluation of reproductive tissues was performed in general toxicity studies. In the six-month study in rats, degenerative effects on both the testes and the ovaries were found. It is therefore likely that bortezomib may have a potential effect on male and female fertility. Perinatal and postnatal development studies have not been conducted.
Multiple cycle general toxicity studies conducted in rats and monkeys revealed that the main target organs were: the gastrointestinal tract, resulting in vomiting and / or diarrhea; hematopoietic and lymphatic tissues, resulting in cytopenia in the peripheral blood, atrophy of the lymphatic tissue and hematopoietic hypocellularity of the bone marrow; peripheral neuropathy (seen in monkeys, mice and dogs) affecting the axons of the sensory nerves; and slight changes in the kidney. After discontinuation of treatment, all of these target organs showed partial to complete recovery.
Based on animal studies, the passage of bortezomib across the blood brain barrier appears limited and the relevance in humans is unknown.
Cardiovascular safety pharmacological studies conducted in monkeys and dogs show that intravenous administration of mg / m2 doses 2 to 3 times the clinically recommended dose results in increased heart rate, decreased cardiac contractility, hypotension and death. In dogs, decreased cardiac contractility and hypotension were controlled by acute treatment with positive inotropic agents or vasopressors and a slight increase in corrected QT interval was observed.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Mannitol (E421)
Nitrogen
06.2 Incompatibility "-
This medicinal product must not be mixed with other products except those mentioned in section 6.6.
06.3 Period of validity "-
Unopened vial
3 years.
Reconstituted solution
The reconstituted solution should be used immediately after preparation.
If not used immediately, it is the user's responsibility to comply with the conditions and storage times of the medicinal product prior to use.
However, the physical and chemical stability of the reconstituted solution has been demonstrated for 8 hours at 25 ° C when stored in the original vial and / or in a syringe. The total storage time of the reconstituted medicinal product prior to administration should not exceed 8 hours.
06.4 Special precautions for storage -
Store at a temperature not exceeding 30 ° C.
Keep the vial in the outer carton to protect the medicine from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package -
Type I glass 10 ml vial, with a gray bromobutyl stopper and an aluminum seal, with a royal blue cap contains 3.5 mg bortezomib.
The vial is contained in a transparent blister consisting of a tray with a lid.
Each pack contains 1 single-use vial.
06.6 Instructions for use and handling -
General Precautions
Bortezomib is a cytotoxic agent. Therefore, special care should be taken when handling and preparing VELCADE. It is recommended to wear gloves and other protective clothing to prevent contact with the skin.
The handling of VELCADE must be done with strict adherence to aseptic techniques due to the absence of preservatives.
There have been cases of death following inadvertent intrathecal administration of VELCADE. VELCADE 1 mg powder for solution for injection is intended for intravenous use only, while VELCADE 3.5 mg powder for solution for injection is intended for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
Instructions for reconstitution
VELCADE must be reconstituted by a healthcare professional.
Intravenous injection
Each 10 ml vial containing VELCADE 3.5 powder for solution for injection must be reconstituted with 3.5 ml of sodium chloride 9 mg / ml (0.9%) solution for injection. Dissolution of the lyophilized powder occurs in less than 2 minutes. After reconstitution, each ml of solution contains 1 mg of bortezomib. The reconstituted solution is clear and colorless, with a final pH between 4 and 7. The reconstituted solution should be visually inspected prior to administration to check for any particulate matter or discolouration. In the presence of particulate matter or change in color. color the reconstituted solution should not be used and should be discarded.
Subcutaneous injection
Each 10 ml vial containing VELCADE 3.5 powder for solution for injection must be reconstituted with 1.4 ml of sodium chloride 9 mg / ml (0.9%) solution for injection. Dissolution of the lyophilized powder takes less than 2 minutes. After reconstitution, each ml of solution contains 2.5 mg of bortezomib. The reconstituted solution is clear and colorless, with a final pH between 4 and 7. The reconstituted solution should be visually inspected prior to administration to check for any particulate matter or discolouration. In the presence of particulate matter or change in color. color the reconstituted solution should not be used and should be discarded.
Disposal
VELCADE is for single use only.
Unused medicine and waste from this medicine should be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
JANSSEN-CILAG INTERNATIONAL N.V.
Turnhoutseweg, 30
B-2340 Beerse
Belgium
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/04/274/001
036559019
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 26 April 2004
Date of the last renewal of the authorization: 26 April 2014
10.0 DATE OF REVISION OF THE TEXT -
04/2015
