Bertred Solution

The active substance, bortezomib, is an anticancer medicine. BERTRED 3,5 is used for the treatment of:

Multiple Myeloma (a cancer of the bone marrow) in adults:

• alone or together with the medicines pegylated liposomal doxorubicin or dexamethasone, for patients whose disease is worsening (progressive) after receiving at least one prior treatment and for whom blood stem cell transplantation was not successful or is unsuitable.
• in combination with other medicines (melphalan and prednisone), for patients who have not been previously treated and are unsuitable for high-dose chemotherapy with blood stem cell transplantation.
• in combination with the medicines dexamethasone or dexamethasone together with thalidomide, for patients whose disease has not been previously treated and before receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment).

Mantle Cell Lymphoma (a blood cancer in the lymph glands) in adults:

• whose disease is worsening (progressive) after receiving at least one prior treatment, one of which should have included the medicine anthracycline (or mitoxantrone) and/or rituximab as part of their chemotherapy treatment.
• in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously treated and for whom blood stem cell transplantation is unsuitable.

You should not be given BERTRED 3,5:

• if you are hypersensitive (allergic) to bortezomib, boron or any of the other ingredients of BERTRED 3,5.
• if you have acute diffuse interstitial lung disease (lung disorders in which the tissues of the lungs become inflamed).
• if you have pericardial disease (disease that affects the sac that encloses the heart).

Warnings and precautions

Take special care BERTRED 3,5:

Tell your doctor or healthcare professional, before you are given a BERTRED 3,5 injection if you have or ever had any of the following conditions:

• liver problems.
• diabetes or high blood sugar (doses of medicines for diabetes may have to be changed if you receive BERTRED 3,5).
• low numbers of red or white blood cells.
• numbness, burning feeling, tingling, or pain in the hands or feet (neuropathy).
• bleeding problems and/or low number of platelets in your blood.
• diarrhoea, constipation, nausea or vomiting.
• fits (seizures) or epilepsy.
• dizziness/light-headedness or fainting when rising from a sitting or lying position (postural low blood pressure).
• heart or blood pressure problems.
• lung problems, shortness of breath.
• kidney problems.
• shingles (localised including around the eyes or spread across the body).
• hepatitis B virus infection.
• symptoms of tumor lysis syndrome such as muscle cramping, muscle weakness, confusion, visual loss or disturbances and shortness of breath.
• memory loss, trouble thinking, difficulty with walking or loss of vision. These may be signs of a serious brain infection and your doctor may suggest further testing and follow-up.
• a rare disease called amyloidosis which occurs when a substance called amyloid builds up in your organs.
• a history of allergies and a type of arthritis called polyarthritis.

Use in children

BERTRED 3,5 has not been studied, and should therefore not be used in children and adolescents.

Blood monitoring

Your doctor will do regular blood tests before and during your treatment with BERTRED 3,5 to check your blood cells, including the number of platelets in your blood. Platelets are responsible for normal clotting of blood. BERTRED 3,5 often lowers the platelet numbers and this can cause severe bleeding.

Other medicines with BERTRED 3,5

Always tell your healthcare professional if you are taking any other medicine. (This includes complementary or traditional medicines). In particular, tell your doctor if you are using medicines containing any of the following with BERTRED 3,5:

• ketoconazole used to treat fungal infections.
• ritonavir used to treat HIV infection.
• rifampicin, chloramphenicol, clarithromycin - antibiotics used to treat bacterial infections.
• pain medicines e.g., codeine (will increase risk of constipation, nausea and vomiting).
• carbamazepine, phenytoin or phenobarbitone used to treat epilepsy.
• oral anti-diabetic medicines.
• St. John’s Wort (Hypericum perforatum) used to treat depression or other conditions.
• medication for high blood pressure or for heart problems (such as angiotensin inhibitors, beta-blockers, antihypertensive medicine, calcium channel blockers, angiotensin receptor blockers and diuretics (water pills)).
• amiodarone used for heart rhythm problems.
• isoniazid, an antibiotic used in the treatment of tuberculosis (TB).
• nitrofurantoin, an antibiotic used in the treatment of bladder infections.
• statins, used to control blood cholesterol levels.

BERTRED 3,5 with food and drink

BERTRED 3,5 is not known to be affected by food. Drinking of alcohol with BERTRED 3,5 is not advised as the risk of liver damage can increase.

- BERTRED 3,5 is for intravenous and subcutaneous use.

- You will not be expected to give yourself injections of BERTRED 3,5. It will be given to you by a person who is qualified to do so.

- Always go for your injection of BERTRED 3,5 exactly as your doctor has instructed you. You should check with your doctor, pharmacist or healthcare professional if you are unsure. BERTRED 3,5 is for single use only and discard any unused portions.

BERTRED 3,5 lyophilised powder has to be dissolved before administration. The resulting solution is then either injected into a vein or injected into the thighs or abdomen. Your doctor will work out your dose of BERTRED 3,5 according to your height and weight (body surface area) and determine further treatment.

Monotherapy

Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

When BERTRED 3,5 is given alone, you will receive 4 doses of BERTRED 3,5 intravenously on days 1, 4, 8 and 11, followed by a 10-day ‘rest period’ without treatment. This 21-day period (3 weeks) corresponds to one treatment cycle. You might receive up to 8 cycles (24 weeks) of treatment.

Combination therapy

Previously untreated multiple myeloma

If you have not been treated before for multiple myeloma, and you are not suitable for blood stem cell transplantation you will receive BERTRED 3,5 intravenously together with two other medicines; melphalan and prednisone. In this case, the duration of a cycle is 42 days (6 weeks). The treatment consists of a total of 9 cycles (54 weeks).

• In cycles 1 to 4, BERTRED 3,5 is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32.
• In cycles 5 to 9, BERTRED 3,5 is administered once weekly on days 1, 8, 22 and 29. Melphalan and prednisone are both given orally on days 1, 2, 3 and 4 of the first week of each cycle.

If you have not been treated before for multiple myeloma, and you are suitable for blood stem cell transplantation you will receive BERTRED 3,5 intravenously together with the medicines dexamethasone, or dexamethasone and thalidomide, as induction treatment.

The recommended starting dose of BERTRED 3,5 in combination with other medicines used for the treatment of multiple myeloma is 1,3 mg/m2 to be administered twice weekly on Days 1, 4, 8, and 11, followed by a rest period of 10 to 18 days, which is considered a treatment cycle. Three to six cycles should be administered. At least 72 hours should elapse between consecutive doses of BERTRED 3,5.

Relapsed Multiple Myeloma

If you have been treated before for multiple myeloma and you are unsuitable for blood stem cell transplantation or if you have already received a blood stem cell transplantation, you will receive BERTRED 3,5 together with a medicine called pegylated liposomal doxorubicin or a medicine called dexamethasone.

When BERTRED 3,5 is given together with pegylated liposomal doxorubicin, you will receive BERTRED 3,5 as a 21-day treatment cycle and pegylated liposomal doxorubicin 30 mg/m2 is given on day 4 of the BERTRED 3,5 21-day treatment cycle as an intravenous infusion after the BERTRED 3,5 injection. You might receive up to 8 cycles (24 weeks).

When BERTRED 3,5 is given together with dexamethasone, you will receive BERTRED 3,5 as a 21-day treatment cycle and dexamethasone 20 mg is given orally on the day of and the day after the BERTRED 3,5 injection.

Retreatment for Multiple Myeloma

If you have previously responded to treatment with BERTRED 3,5 (either alone or in combination) and if you have relapsed you should be started on retreatment at the last tolerated dose. Refer to “Monotherapy” for dosing schedule.

Previously untreated Mantle Cell Lymphoma

If you have not been treated before for Mantle Cell Lymphoma you will receive BERTRED 3,5 intravenously together with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone. BERTRED 3,5 is given intravenously on days 1, 4, 8 and 11, followed by a ‘rest period’ without treatment. The duration of a treatment cycle is 21 days (3 weeks). You might receive up to 8 cycles (24 weeks).

The following medicines are given on day 1 of each BERTRED 3,5 21-day treatment cycle as intravenous infusions: Rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 and doxorubicin at 50 mg/m2. Prednisone is given orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of the BERTRED 3,5 treatment cycle.

Your doctor will tell you how long your treatment with BERTRED 3,5 will last. Do not stop treatment early without discussing this with your doctor.

If you have the impression that the effect of BERTRED 3,5 is too strong or too weak, tell your doctor or pharmacist.

If you receive more BERTRED 3,5 than you should

Since a healthcare professional will administer BERTRED 3,5 he/she will control the dosage. However, in the event of overdosage your doctor will manage the overdosage.

If you forget to receive BERTRED 3,5

If you forget to receive BERTRED 3,5 for any reason, discuss this with your doctor as soon as possible.

If you stop taking BERTRED 3,5

Do not stop taking BERTRED 3,5 unless your doctor tells you to.

BERTRED 3,5 can have side effects. Not all side effects reported for BERTRED 3,5 are included in this leaflet. Should your general health worsen or if you experience any untoward effects while taking BERTRED 3,5, please consult your doctor, pharmacist or other health care professional for advice.

If any of the following happens, stop taking BERTRED 3,5 and tell your doctor immediately or go to the casualty department at your nearest hospital:

• Swelling and redness of the hands, feet, ankles, face, mouth, lips, gums, tongue, throat and neck which may cause difficulty in swallowing or breathing or throat tightness;
• Shortness of breath and wheezing;
• Rash, hives (raised bumps), blisters or itching;
• Fainting;
• A serious hypersensitivity reaction causing kidney problems or failure, joint pain, fever and a rash. Allergic reactions can happen in patients taking BERTRED 3,5 even after only one dose. These are all very serious side effects. If you have them, you may have had a serious allergic reaction to BERTRED 3,5. You may need urgent medical attention or hospitalisation.

Tell your doctor immediately or go to the casualty department at your nearest hospital if you notice any of the following:

• Difficulty passing stools (constipation), inability to pass gas, belching, vomiting, feeling sick (nausea), severe stomach pain.
• Numbness, prickling or tingling sensations in your toes, fingers, feet or hands and burning, freezing, throbbing and/or shooting pain that is often worse at night.
• Loss of the ability to move and to feel anything in one or more parts of the body (paralysis).
• Confusion, visual loss or disturbances, blindness, fits (seizures), headaches.
• Abnormal tiredness, changes in heartbeat (faster or irregular), chest pain which may indicate heart problems.
• Rapid breathing or gasping for breath, coughing, wheezing, restlessness, confusion and rapid pulse. These are symptoms of a medical emergency as a result of fluid accumulating and/or inflammation in the lungs, and which may indicate lung problems.
• Feeling sick (nausea), vomiting, passing only small amounts of urine or no urine, pain in the back and swelling may indicate kidney problems. Sudden or gradual change in kidney functioning can lead to kidney failure and death.
• High fever, shaking, chills, confusion, joint aches, stiff neck, severe headaches, extreme tiredness, rapid pulse, flu-like symptoms, or any general feeling of being unwell due to infection in any part of the body that can be fatal.
• Blood clot in the leg (thrombosis) or bleeding throughout the body leading to organ failure, due to a life-threatening condition that prevents normal blood clotting.
• Severe pain in the upper middle or upper left part of the belly, nausea, fever or chills, swollen abdomen and tender to touch which may indicate problems with your pancreas.
• Bruising or bleeding anywhere in your body without obvious injury e.g., bleeding from your bowels, mouth, gums, vomiting blood, blood in your urine or stools.
• Muscle cramping, muscle weakness.

You may experience a reduction in the number of:

• platelets, which may make you be more prone to bruising, or to bleeding without obvious injury (e.g., bleeding from your bowels, stomach, mouth and gum or bleeding in the brain or bleeding from the liver).
• red blood cells, which can cause anaemia, with symptoms such as tiredness and paleness.
• white blood cells may make you more prone to infections or flu-like symptoms.

These are all serious side effects. You may need urgent medical attention.

Tell your doctor if you notice any of the following:

If you are given BERTRED 3,5 for the treatment of multiple myeloma the side-effects you may get are listed below:

Frequent:

• Shingles (itching, tingling or severe burning pain with painful, rash that develops into blisters on one side of the body and may occur on the forehead, cheek, nose, and around the eye and may also spread throughout the body).
• Cold sores.
• Pneumonia (infection in lungs).
• Bacterial and fungal infections.
• Decreased appetite.
• Dehydration.
• Low levels of potassium, salt, and calcium in the circulating blood.
• Abnormal sugar and enzyme levels in the blood (picked up in blood tests).
• Problems with your mood and sleep.
• Feeling anxious, troubled/nervous.
• Weakness, numbness and pain, usually in the hands and feet.
• A sensation which is painful, itchy, burning, or restrictive.
• Nerve pain.
• Muscle weakness of the arms and legs.
• Fainting.
• Dizziness.
• Sour, sweet, bitter or metallic taste in mouth.
• Tiredness.
• Headache.
• Swelling or bulging of the eye.
• Vision problems.
• “Pink eye” (conjunctivitis).
• Vertigo (the sensation of spinning while stationary).
• High or low blood pressure.
• A drop in blood pressure on standing or sitting up.
• Shortness of breath.
• Nose bleeds.
• sneezing, nasal discharge and congestion, persistent watery runny nose.
• Cough.
• Nausea (feeling sick) vomiting (throwing up).
• Vomiting of blood.
• Runny tummy (loose watery stools).
• Inflamed and sore lips and mouth.
• Reflux or indigestion.
• Sensation of elevated abdominal pressure and volume.
• Pain in the throat/upper airway.
• Stomach pain.
• Passing of gas/belching.
• Liver problems.
• Rash.

Less frequent:

• Various types of bacterial and viral infections which include urinary tract infections, the flu, ear infections, tooth infections, skin infections, cold sores, sexually transmitted infection marked by genital pain and sores.
• Inflammation of the tonsils.
• Inflammation of the mastoid bone, located behind the ear.
• Extreme tiredness, sleep abnormalities, pain and other symptoms that are made worse by exertion which is experienced after having a viral infection.
• Severe reversible brain condition caused by a virus which includes seizures, high blood pressure, headaches, tiredness, confusion, blindness or other vision problems.
• An infection of the brain and brain covering (meninges) caused by the herpes simplex virus.
• Different types of cancers of the blood and cancer of the kidneys.
• Fever when your white blood cell are very low.
• Swelling of your lymph nodes.
• Inflammation or bleeding of the blood vessels that can appear as small red or purple dots (usually on the legs) to large bruise-like patches under the skin or tissue.

Store at or below 30 ºC. Keep the vial in the outer carton in order to protect from light.

Reconstituted solution: The reconstituted solution should be used immediately after preparation. From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8° C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions. However, the chemical and physical in-use stability of reconstituted/diluted solution has been demonstrated for 8 hours at 30 °C and for 15 days at 2 °C to 8 °C, stored in the original vial and/or a syringe prior to administration.

Do not use this medicine after the expiry date. Keep this medicine out of the sight and reach of children. Do not dispose medicines in drains or sewerage systems (e.g., toilets).