pms-Bortezomib

PMS-BORTEZOMIB powder for solution for injection is a white to off-white cake or powder.
The active substance is bortezomib. Each vial contains 3.5 mg of bortezomib.
Intravenous reconstitution: After reconstitution, 1 ml of solution for intravenous injection contains 1 mg bortezomib.
Subcutaneous reconstitution: After reconstitution, 1 ml of solution for subcutaneous injection contains 2.5 mg bortezomib.
Excipients/Inactive Ingredients: The other ingredients are mannitol.

PMS-BORTEZOMIB 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.

PMS-BORTEZOMIB is used for the treatment of multiple myeloma (a cancer of the bone marrow) in patients older than 18 years: 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 the medicines melphalan and prednisone, for patients whose disease has 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).

The dose of PMS-BORTEZOMIB will be worked out according to the patient's height and weight (body surface area). The usual starting dose of PMS-BORTEZOMIB is 1.3 mg/m² body surface area twice a week.
The dose and total number of treatment cycles may be changed, depending on the patient's response to the treatment on the occurrence of certain side effects and on the underlying conditions (e.g. liver problems).
Progressive multiple myeloma: When PMS-BORTEZOMIB is given alone, the patient will receive 4 doses of PMS-BORTEZOMIB intravenously or subcutaneously on days 1, 4, 8 and 11, followed by a 10-day 'rest period' without treatment. This 21-day period (3 weeks) corresponds to one treatment cycle. The patient might receive up to 8 cycles (24 weeks).
The patient may also be given PMS-BORTEZOMIB together with the medicines pegylated liposomal doxorubicin or dexamethasone.
When PMS-BORTEZOMIB is given together with pegylated liposomal doxorubicin, the patient will receive PMS-BORTEZOMIB intravenously or subcutaneously as a 21-day treatment cycle and pegylated liposomal doxorubicin 30 mg/m² is given on day 4 of the PMS-BORTEZOMIB 21-day treatment cycle as an intravenous infusion after the PMS-BORTEZOMIB injection.
The patient might receive up to 8 cycles (24 weeks).
When PMS-BORTEZOMIB is given together with dexamethasone, the patient will receive PMS-BORTEZOMIB intravenously or subcutaneously as a 21-day treatment cycle and dexamethasone 20 mg is given orally on days 1, 2, 4, 5, 8, 9, 11, and 12, of the PMS-BORTEZOMIB, 21-day treatment cycle.
The patient might receive up to 8 cycles (24 weeks).
Previously untreated multiple myeloma: If the patient has not been treated before for multiple myeloma, and is not suitable for blood stem cell transplantation, the patient will receive PMS-BORTEZOMIB together with two other medicines; melphalan and prednisone.
In this case, the duration of a treatment cycle is 42 days (6 weeks). The patient will receive 9 cycles (54 weeks).
In cycles 1 to 4, PMS-BORTEZOMIB is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32.
In cycles 5 to 9, PMS-BORTEZOMIB is administered once weekly on days 1, 8, 22 and 29.
Melphalan (9 mg/m²) and prednisone (60 mg/m²) are both given orally on days 1, 2, 3 and 4 of the first week of each cycle.
If the patient has not been treated before for multiple myeloma, and is suitable for blood stem cell transplantation, the patient will receive PMS-BORTEZOMIB intravenously or subcutaneously together with the medicines dexamethasone, or dexamethasone and thalidomide, as induction treatment.
When PMS-BORTEZOMIB is given together with dexamethasone, the patient will receive PMS-BORTEZOMIB intravenously or subcutaneously as a 21-day treatment cycle and dexamethasone 40 mg is given orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the PMS-BORTEZOMIB 21-day treatment cycle.
The patient will receive 4 cycles (12 weeks).
When PMS-BORTEZOMIB is given together with thalidomide and dexamethasone, the duration of a treatment cycle is 28 days (4 weeks).
Dexamethasone 40 mg is given orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the PMS-BORTEZOMIB 28-day treatment cycle and thalidomide is given orally daily at 50 mg up to day 14 of the first cycle, and if tolerated the thalidomide dose is increased to 100 mg on days 15-28 and may be further increased to 200 mg daily from the second cycle onwards.
The patient might receive up to 6 cycles (24 weeks).
How PMS-BORTEZOMIB is given: This medicine is for intravenous or subcutaneous use. PMS-BORTEZOMIB will be administered by a health care professional experienced in the use of cytotoxic medicines. PMS-BORTEZOMIB powder has to be dissolved before administration. This will be done by a healthcare professional. The resulting solution is then either injected into a vein or under the skin. Injection into a vein is rapid, taking 3 to 5 seconds. Injection under the skin is in either the thighs or the abdomen.
Only the 3.5 mg vial can be administered subcutaneously.
Reconstitution for Intravenous Injection and Subcutaneous Injection: Note: PMS-BORTEZOMIB is a cytotoxic agent. Therefore, caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout handling of PMS-BORTEZOMIB since no preservative is present.
1. Preparation of the 3.5 mg vial: Intravenous Injection: carefully add 3.5 ml of sterile, 9 mg/ml (0.9%) sodium chloride solution for injection to the vial containing the PMS-BORTEZOMIB powder by using a syringe of the appropriate size without removing the vial stopper. Dissolution of the lyophilized powder is completed in less than 2 minutes.
The concentration of the resulting solution will be 1 mg/ml. The solution will be clear and colourless, with a final pH of 4 to 7. There is no need to check the pH of the solution.
Subcutaneous Injection: carefully add 1.4 ml of sterile, 9 mg/ml (0.9%) sodium chloride solution for injection to the vial containing the PMS-BORTEZOMIB powder by using a syringe of the appropriate size without removing the vial stopper. Dissolution of the lyophilised powder is completed in less than 2 minutes.
The concentration of the resulting solution will be 2.5 mg/ml. The solution will be clear and colourless, with a final pH of 4 to 7. There is no need to check the pH of the solution.
2. Before administration, visually inspect the solution for particulate matter and discolouration. If any discolouration or particulate matter is observed, the solution should be discarded. Be sure that the correct dose is being given for the intravenous route of administration (1 mg/ml) or for the subcutaneous route of administration (2.5 mg/ml).
3. The reconstituted solution/product is preservative free and should be used immediately after preparation. However, the chemical and physical in-use stability has been demonstrated for 8 hours at 25°C stored in the original vial and/or a syringe. The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration. If the reconstituted solution is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
It is not necessary to protect the reconstituted medicinal product from light.
Administration: Once dissolved, withdraw the appropriate amount of the reconstituted solution according to calculated dose based upon the patient´s Body Surface Area.
Confirm the dose and concentration in the syringe prior to use (check that the syringe is marked as intravenous/subcutaneous administration).
Intravenous Injection: Inject the solution as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter into a vein.
Flush the peripheral or intravenous catheter with sterile, 9 mg/ml (0.9%) sodium chloride solution.
Subcutaneous Injection: Inject the solution subcutaneously, under a 45-90° angle.
The reconstituted solution is administered subcutaneously through the thighs (right or left) or abdomen (right or left).
Injection sites should be rotated for successive injections.
If local injection site reactions occur following PMS-BORTEZOMIB injection subcutaneously, either a less concentrated PMS-BORTEZOMIB solution (1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously or a switch to intravenous injection is recommended.
PMS-BORTEZOMIB 3.5 mg powder for solution for injection IS FOR SUBCUTANEOUS OR INTRAVENOUS USE. Do not give by other routes. Intrathecal administration has resulted in death.

As this medicine is being given by a doctor or nurse, it is unlikely that the patient will be given too much. In the unlikely event of an overdose, the doctor will monitor the patient for side effects.

PMS-BORTEZOMIB should not be used: if the patient is allergic to bortezomib, boron or to any of the other ingredients of this medicine (listed in Description); if the patient has certain severe lung or heart problems.

Patients must be advised to inform the doctor if they have any of the following: low numbers of red or white blood cells; bleeding problems and/or low number of platelets in the blood; diarrhoea, constipation, nausea or vomiting; fainting, dizziness or light-headedness in the past; kidney problems; moderate to severe liver problems; numbness, tingling, or pain in the hands or feet (neuropathy) in the past; heart or blood pressure problems; shortness of breath or cough; seizures; shingles (localized including around the eyes or spread across the body); 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 further testing and follow-up may be suggested).
The patient will have to take regular blood tests before and during the treatment with PMS-BORTEZOMIB, to check the blood cell counts regularly.
The package leaflets of all medicinal products to be taken in combination with PMS-BORTEZOMIB must be read for information related to these medicines before starting treatment with PMS-BORTEZOMIB. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed (see Use in Pregnancy & Lactation).
Driving and using machines: PMS-BORTEZOMIB might cause tiredness, dizziness, fainting, or blurred vision. Patients must be advised not to drive or operate tools or machines if they experience such side effects; even if they do not, they should still be cautious.
Use in Children: PMS-BORTEZOMIB should not be used in children and adolescents because it is not known how the medicine will affect them.

The patient should not use PMS-BORTEZOMIB if she is pregnant, unless clearly necessary.
Both men and women receiving PMS-BORTEZOMIB must use effective contraception during and for up to 3 months after treatment. If, despite these measures, pregnancy occurs, the patient must be advised to inform the doctor immediately.
The patient should not breast-feed while using PMS-BORTEZOMIB. She must be advised to discuss with the doctor when it is safe to restart breast-feeding after finishing the treatment.
Thalidomide causes birth defects and fetal death. When PMS-BORTEZOMIB is given in combination with thalidomide, the patient must be advised to follow the pregnancy prevention programme for thalidomide (see package leaflet for thalidomide).

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these effects may be serious.
If the patient is given PMS-BORTEZOMIB for multiple myeloma, they must be advised to inform the doctor straight away if they notice any of the following symptoms: muscle cramping, muscle weakness; confusion, visual loss or disturbances, blindness, seizures, headaches; shortness of breath, swelling of the feet or changes in the heart beat, high blood pressure, tiredness, fainting; coughing and breathing difficulties or tightness in the chest.
Treatment with PMS-BORTEZOMIB can very commonly cause a decrease in the numbers of red and white blood cells and platelets in the blood. Therefore, the patient will have to take regular blood tests before and during the treatment with PMS-BORTEZOMIB, to check the blood cell counts regularly. The patient may experience a reduction in the number of: platelets, which may make the patient be more prone to bruising, or to bleeding without obvious injury (e.g., bleeding from the 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 the patient more prone to infections or flu-like symptoms.
If the patient is given PMS-BORTEZOMIB for the treatment of multiple myeloma, the side effects the patient may get are listed as follows: Very common side effects (may affect more than 1 in 10 people): Sensitivity, 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 blood cells and or white blood cells (see previously mentioned); Fever; Feeling sick (nausea) or vomiting, loss of appetite; Constipation with or without bloating (can be severe); Diarrhoea (If this happens, it is important that the patient drinks more water than usual. Another medicine may be given to control diarrhoea.); Tiredness (fatigue), feeling weak; Muscle pain, bone pain.
Common side effects (may affect up to 1 in 10 people): Low blood pressure, sudden fall of blood pressure on standing which may lead to fainting; High blood pressure; Reduced functioning of the kidneys; Headache; General ill feeling, pain, vertigo, light-headedness, a feeling of weakness or loss of consciousness; Shivering; Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, coughing with phlegm, flu like illness; Shingles (localized including around the eyes or spread across the body); Chest pains or shortness of breath with exercise; Different types of rash; Itching of the skin, lumps on the skin or dry skin; Facial blushing or tiny broken capillaries; Redness of the skin; Dehydration; Heartburn, bloating, belching, wind, stomach pain, bleeding from the bowels or stomach; Alteration of liver functioning; A sore mouth or lip, dry mouth, mouth ulcers or throat pain; Weight loss, loss of taste; Muscle cramps, muscle spasms, muscle weakness, pain in the limbs; Blurred vision; Infection of the outermost layer of the eye and the inner surface of the eyelids (conjunctivitis); Nose bleeds; Difficulty or problems in sleeping, sweating, anxiety, mood swings, depressed mood, restlessness or agitation, changes in the mental status, disorientation; Swelling of body, to include around 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 reduced heart rate; Failing of the kidneys; Inflammation of a vein, blood clots in the veins and lungs; Problems with blood clotting; Insufficient circulation; Inflammation of the lining around the heart or fluid around the heart; Infections including urinary tract infections, the flu, herpes virus infections, ear infection and cellulitis; Bloody stools, or bleeding from mucosal membranes, e.g., mouth, vagina; Cerebrovascular disorders; Paralysis, seizures, falling, movement disorders, abnormal or change in, or reduced sensation (feeling, hearing, tasting, smelling), attention disturbance, trembling, twitching; Arthritis, including inflammation of the joints in the fingers, toes, and the jaw; Disorders that affect the lungs, preventing the body from getting enough oxygen (some of these include difficulty breathing, shortness of breath, shortness of breath without exercise, breathing that becomes shallow, difficult or stops, wheezing); Hiccups, speech disorders; Increased or decreased urine production (due to kidney damage), painful passing of urine or blood/proteins in the urine, fluid retention; Altered levels of consciousness, confusion, memory impairment or loss; Hypersensitivity; Hearing loss, deafness or ringing in the ears, ear discomfort; Hormone abnormality which may affect salt and water absorption; Overactive thyroid gland; Inability to produce enough insulin or resistance to normal levels of insulin; Irritated or inflamed eyes, excessively wet eyes, painful eyes, dry eyes, eye infections, lump in the eyelid (chalazion), red and swollen eyelids, discharge from the eyes, abnormal vision, bleeding of the eye; Swelling of the lymph glands; Joint or muscle stiffness, sense of heaviness, pain in the groin; Hair loss and abnormal hair texture; Allergic reactions; Redness or pain at the injection site; Mouth pain; Infections or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestines, sometimes associated with pain or bleeding, poor movement of the intestines (including blockage), abdominal or oesophageal discomfort, difficulty swallowing, vomiting of blood; Skin infections; Bacterial and viral infections; Tooth infection; Inflammation of the pancreas, obstruction of the bile duct; Genital pain, problem having an erection; Weight increase; Thirst; Hepatitis; Injection site or injection device related disorders; Skin reactions and disorders (which may be severe and life threatening), skin ulcers; Bruises, falls and injuries; Inflammation or haemorrhage 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; Benign cysts; A severe reversible brain condition which includes seizures, high blood pressure, headaches, tiredness, confusion, blindness or other vision problems.
Rare side effects (may affect up to 1 in 1,000 people): Heart problems to include heart attack, angina; Serious nerve inflammation, which may cause paralysis and difficulty breathing (Guillain-Barré syndrome); Flushing; Discoloration of the veins; Inflammation of the spinal nerve; Problems with the ear, bleeding from the ear; Underactivity of the thyroid gland; Bleeding in the brain; Budd-Chiari syndrome (the clinical symptoms caused by blockage of the hepatic veins); Changes in or abnormal bowel function; Yellow discoloration of eyes and skin (jaundice); Serious allergic reaction (anaphylactic shock) signs of which may include difficulty breathing, chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin or raised lumps on the skin, swelling of the face, lips, tongue and /or throat, which may cause difficulty in swallowing, collapse; Breast disorders; Vaginal tears; Genital swelling; Inability to tolerate alcohol consumption; Wasting, or loss of body mass; Increased appetite; Fistula; Joint effusion; Cysts in the lining of joints (synovial cysts); Fracture; Breakdown of muscle fibers leading to other complications; Swelling of the liver, bleeding from the liver; Cancer of the kidney; Psoriasis like skin condition; Cancer of the skin; Paleness of the skin; Increase of platelets or plasma cells (a type of white cell) in the blood; Blood clot in small blood vessels (thrombotic microangiopathy); Abnormal reaction to blood transfusions; Partial or total loss of vision; Decreased sex drive; Drooling; Bulging eyes; Sensitivity to light; Rapid breathing; Rectal pain; Gallstones; Hernia; Injuries; Brittle or weak nails; Abnormal protein deposits in the vital organs; Coma; Intestinal ulcers; Multi-organ failure; Death.
Reporting: If the patient gets any side effects, the patient must be advised to talk to the doctor or pharmacist. This includes any possible side effects not listed in this monograph.
Reporting side effects can help provide more information on the safety of this medicine.

Patients must be advised to inform the doctor, or pharmacist if they are taking, have recently taken or might take any other medicines.
In particular, patients must be advised to inform the doctor if they 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 for depression or other conditions; oral antidiabetics.

Disposal: A vial is for single use only and the remaining solution must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store below 25°C. Keep the vial in the outer carton in order to protect from light.
The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
However, the reconstituted solution is stable for 8 hours at 25°C stored in the original vial and/or a syringe, with a total storage time for the reconstituted medicine not exceeding 8 hours prior to administration.

Targeted Cancer Therapy

L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.

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