BORTEZOMIB SANDOZ

Bortezomib treatment must be initiated under the supervision of a physician experienced in the treatment of cancer patients, however bortezomib may be administered by a healthcare professional experienced in the use of chemotherapeutic agents.

6). 3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11, in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. It is recommended that patients receive 2 cycles of bortezomib following a confirmation of a complete response.

It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of bortezomib therapy. At least 72 hours should elapse between consecutive doses of bortezomib. 4). 7 mg/m2). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib must be considered unless the benefit of treatment clearly outweighs the risk.

4). Patients with pre-existing severe neuropathy may be treated with bortezomib only after careful risk/benefit assessment. 3 mg/m2 once per week Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL***) Withhold bortezomib treatment until symptoms of toxicity have resolved.

7 mg/m2 once per week. Grade 4 (life-threatening consequences; urgent intervention indicated) and/or severe autonomic neuropathy Discontinue bortezomib * Based on posology modifications in Phase II and III multiple myeloma studies and post-marketing experience.

0. ** Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc; *** Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medicinal products, and not bedridden.

3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib. Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the bortezomib treatment cycle as a 1 hour intravenous infusion administered after the bortezomib injection.

Up to 8 cycles of this combination therapy can be administered as long as patients have not progressed and tolerate treatment. Patients achieving a 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.

Summary of the safety profile Serious adverse reactions uncommonly reported during treatment with bortezomib include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy.

The most commonly reported adverse reactions during treatment with bortezomib are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.

Tabulated summary of adverse reactions Multiple Myeloma Undesirable effects in Table 7 were considered by the investigators to have at least a possible or probable causal relationship to bortezomib. 3 mg/m2 and included in Table 7. Overall, bortezomib was administered for the treatment of multiple myeloma in 3,974 patients.

Adverse reactions are listed below by system organ class and frequency grouping.

Frequencies are defined as:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

1 of the MedDRA. Post-marketing adverse reactions not seen in clinical trials are also included.

Table 7:

Adverse reactions in patients with Multiple Myeloma treated with bortezomib in clinical trials, and all post-marketing adverse reactions regardless of indication#. System Organ Class Incidence Adverse reaction Common Herpes zoster (inc disseminated & ophthalmic), Pneumonia*, Herpes simplex*, Fungal infection* Uncommon Infection*, Bacterial infections*, Viral infections*, Sepsis (inc septic shock)*, Bronchopneumonia, Herpes virus infection*, Meningoencephalitis herpetic#, Bacteraemia (inc staphylococcal), Hordeolum, Influenza, Cellulitis, Device related infection, Skin infection*, Ear infection*, Staphylococcal infection, Tooth infection* Infections and infestations Rare Meningitis (inc bacterial), Epstein-Barr virus infection, Genital herpes, Tonsillitis, Mastoiditis, Post viral fatigue syndrome Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rare Neoplasm malignant, Leukaemia plasmacytic, Renal cell carcinoma, Mass, Mycosis fungoides, Neoplasm benign* Very Common Thrombocytopenia*, Neutropenia*, Anaemia* Common Leukopenia*, Lymphopenia* Uncommon Pancytopenia*, Febrile neutropenia, Coagulopathy*, Leukocytosis*, Lymphadenopathy, Haemolytic anaemia# Blood and lymphatic system disorders Rare Disseminated intravascular coagulation, Thrombocytosis*, Hyperviscosity syndrome, Platelet disorder NOS, Thrombocytopenic purpura, Blood disorder NOS, Haemorrhagic diathesis, Lymphocytic infiltration, Thrombotic microangiopathy (including Thrombocytopenic purpura)# Uncommon Angioedema#, Hypersensitivity*Immune system disorders Rare Anaphylactic shock, Amyloidosis, Type III immune complex mediated reaction Uncommon Cushing's syndrome*, Hyperthyroidism*, Inappropriate antidiuretic hormone secretion Endocrine disorders Rare Hypothyroidism Very Common Decreased appetite Common Dehydration, Hypokalaemia*, Hyponatraemia*, Blood glucose abnormal*, Hypocalcaemia*, Enzyme abnormality* Uncommon Tumour lysis syndrome, Failure to thrive*, Hypomagnesaemia*, Hypophosphataemia*, Hyperkalaemia*, Hypercalcaemia*, Hypernatraemia*, Uric acid abnormal*, Diabetes mellitus*, Fluid retention Metabolism and nutrition disorders Rare Hypermagnesaemia*, Acidosis, Electrolyte imbalance*, Fluid overload, Hypochloraemia*, Hypovolaemia, Hyperchloraemia *, Hyperphosphataemia*, Metabolic disorder, Vitamin B complex deficiency, Vitamin B12 deficiency, Gout, Increased appetite, Alcohol intolerance Common Mood disorders and disturbances*, Anxiety disorder*, Sleep disorders and disturbances* Uncommon Mental disorder*, Hallucination*, Psychotic disorder*, Confusion*, Restlessness Psychiatric disorders Rare Suicidal ideation*, Adjustment disorder, Delirium, Libido decreased Very Common Neuropathies*, Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia* Common Motor neuropathy*, Loss of consciousness (inc syncope), Dizziness*, Dysgeusia*, Lethargy, Headache* Nervous system disorders Uncommon Tremor, Peripheral sensorimotor neuropathy, Dyskinesia*, Cerebellar coordination and balance disturbances*, Memory loss (exc dementia)*, Encephalopathy*, Posterior Reversible Encephalopathy Syndrome#, Neurotoxicity, Seizure disorders*, Post herpetic neuralgia, Speech disorder*, Restless legs syndrome, Migraine, Sciatica, Disturbance in attention, Reflexes abnormal*, Parosmia Rare Cerebral haemorrhage*, Haemorrhage intracranial (inc subarachnoid)*, Brain oedema, Transient ischaemic attack, Coma, Autonomic nervous system imbalance, Autonomic neuropathy, Cranial palsy*, Paralysis*, Paresis*, Presyncope, Brain stem syndrome, Cerebrovascular disorder, Nerve root lesion, Psychomotor hyperactivity, Spinal cord compression, Cognitive disorder NOS, Motor dysfunction, Nervous system disorder NOS, Radiculitis, Drooling, Hypotonia, Guillain-Barré syndrome#, Demyelinating polyneuropathy# Common Eye swelling*, Vision abnormal*, Conjunctivitis* Uncommon Eye haemorrhage*, Eyelid infection*, Eye inflammation*, Diplopia, Dry eye*, Eye irritation*, Eye pain, Lacrimation increased, Eye discharge, Chalazion#, Blepharitis# Eye disorders Rare Corneal lesion*, Exophthalmos, Retinitis, Scotoma, Eye disorder (inc.

When bortezomib is given in combination with other medicinal products, the Summary of Product Characteristics of these other medicinal products must be consulted prior to initiation of treatment with bortezomib. 6). Intrathecal administration There have been fatal cases of inadvertent intrathecal administration of bortezomib.

5 mg powder for solution for injection is for intravenous or subcutaneous use. Bortezomib should not be administered intrathecally. Gastrointestinal toxicity Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with bortezomib treatment.

8). Therefore, patients who experience constipation should be closely monitored. Haematological toxicity Bortezomib treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed multiple myeloma treated with bortezomib and in patients with previously untreated MCL treated with bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP), one of the most common haematologic toxicity was transient thrombocytopenia.

Platelets were lowest at day 11 of each cycle of bortezomib treatment and typically recovered to baseline by the next cycle. There was no evidence of cumulative thrombocytopenia. The mean platelet count nadir measured was approximately 40% of baseline in the single-agent multiple myeloma studies and 50% in the MCL study.

In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts < 75,000/μl, 90% of 21 patients had a count ≤ 25,000/μl during the study, including 14% < 10,000/μl; in contrast, with a baseline platelet count > 75,000/μl, only 14% of 309 patients had a count ≤ 25,000/μl during the study.

8%) of Grade ≥ 3 thrombocytopenia in the bortezomib treatment group (BR-CAP) as compared to the non-bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R- CHOP]). 2%]). 9% of patients in the R-CHOP group.

1. Acute diffuse infiltrative pulmonary and pericardial disease. When bortezomib is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.