Bortezomib^®

• VELBORTE® 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 received at least 1 prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation.
• VELBORTE® in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
• VELBORTE® 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 high­dose chemotherapy with haematopoietic stem cell transplantation.
• VELBORTE® in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation.

• Sensitivity to the bortezomib, boron or mannitol.
• Acute diffuse infiltrative pulmonary disease and pericardial disease.

• VELBORTE® should not be administered intrathecally.
• Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with VELBORTE® Therefore, patients who experience constipation should be closely monitored.
• VELBORTE® treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia andanaemia). Gastrointestinal and intracerebral haemorrhage, have been reported in association with VELBORTE® treatment. Therefore, Complete blood counts (CBC) with differential and including platelet counts should be frequently monitored throughout treatment with VELBORTE®. VELBORTE® therapy should be withheld when the platelet count is < 25,000/μl or, in the case of combination with melphalan and prednisone, when the platelet count is ≤30,000/μl. Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs and symptoms of infection and treated promptly. Granulocyte colony stimulating factors may be administered for haematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeated delays in cycle administration.
• the overall incidence of herpes zoster reactivation was more common in patients treated with VELBORTE®+Melphalan+Prednisone. Therefore, antiviral prophylaxis is recommended in patients being treated with VELBORTE®.
• When rituximab is used in combination with VELBORTE®, HBV screening must always be performed in patients at risk ofinfection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must beclosely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combinationtreatment with VELBORTE®. Antiviral prophylaxis should be considered.
• Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in Progressive multifocal leukoencephalopathy (PML) and death, have been reported in patients treated with VELBORTE®. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. Discontinue VELBORTE® if PML is diagnosed.
• Treatment with VELBORTE® is very commonly associated with peripheral neuropathy, which is predominantly sensory.However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5. In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus. It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose, schedule or route of administration to subcutaneous. Neuropathy has been managed with supportive care and other therapies. Early and regular monitoring for symptoms of treatment­emergent neuropathy with neurological evaluation should be considered in patients receiving VELBORTE® in combination with medicinal products known to be associated with neuropathy (e.g., thalidomide) and appropriate dose reduction or treatment discontinuation should be considered.
• Special care is required when treating patients with any risk factors for seizures.
• VELBORTE® treatment is commonly associated with orthostatic/postural hypotension. Most adverse reactions are mild tomoderate in nature and are observed throughout treatment. Patients who developed orthostatic hypotension on VELBORTE® (Injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with VELBORTE®. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of VELBORTE®. Caution is advised when treating patients with a history of syncope receiving medicinal products known to be associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.
• Posterior Reversible Encephalopathy Syndrome (PRES) is a rare, often reversible, rapidly evolving neurological condition, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably Magnetic Resonance Imaging (MRI), is used to confirm the diagnosis. In patients developing PRES, VELBORTE® should be discontinued.
• Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib treatment. Patients with risk factors for or existing heart disease should be closely monitored.
• There have been rare reports of pulmonary disorders. Some of these events have been fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potential post­treatment pulmonary changes. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing VELBORTE® therapy.
• Rare cases of hepatic failure have been reported in patients receiving VELBORTE® and concomitant medicinal products and with serious underlying medical conditions. Other reported hepatic reactions may be reversible upon discontinuation of bortezomib.
• The patients those with high tumour burden prior to treatment are at risk of tumour lysis syndrome, since bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells. These patients should be monitored closely and appropriate precautions taken.
• Patients should be closely monitored when given bortezomib in combination with potent CYP3A4­inhibitors. Cautionshould be exercised when bortezomib is combined with CYP3A4­ or CYP2C19 substrates. Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycaemics.
• Bortezomib should be discontinued if potentially immunocomplex-mediated reactions occur.
• VELBORTE® may be associated with fatigue very commonly, dizziness commonly, syncope uncommonly and orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious when driving or using machines and should be advised not to drive or operate machinery if they experience these symptoms.

VELBORTE^® treatment must be initiated under supervision of a physician experienced in the treatment of cancer patients, however VELBORTE^® may be administered by a healthcare professional experienced in use of chemotherapeutic agents. VELBORTE^® must be reconstituted by a healthcare professional. when VELBORTE® is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these products should be considered in the event of toxicities according to the recommendations in the Summary of Product Characteristics.

• Dosage:

treatment of progressive multiple myeloma (patients who have received at least one prior therapy)
Monotherapy
VELBORTE^® 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection recommended dose is 1.3 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 VELBORTE^®. It is recommended that patients receive 2 cycles of VELBORTE^® 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 VELBORTE^® therapy.

Dose adjustments during treatment and re­initiation of treatment for monotherapy
VELBORTE^® treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below. Once the symptoms of the toxicity have resolved, VELBORTE^® treatment may be re-initiated at a 25% reduced dose (1.3 mg/m² reduced to 1.0 mg/m² ; 1.0 mg/m² reduced to 0.7 mg/m²). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of VELBORTE^® must be considered unless the benefit of treatment clearly outweighs the risk.

Neuropathic pain and/or peripheral neuropathy

Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1. Patients with pre-existing severe neuropathy may be treated with VELBORTE^® only after careful risk/benefit assessment.

* 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.

Combination therapy with pegylated liposomal doxorubicin

VELBORTE^® treatment cycles are the same as described in monotherapy. Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the VELBORTE^® treatment cycle as a 1-hour intravenous infusion administered after the VELBORTE^®. 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. Patients whose levels of paraprotein continue to decrease after 8 cycles can also continue for as long as treatment is tolerated and they continue to respond.

Combination with dexamethasone

VELBORTE^® treatment cycles are the same as described in monotherapy. Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the VELBORTE^® treatment cycle. Patients achieving a response or a stable disease after 4 cycles of this combination therapy can continue to receive the same combination for a maximum of 4 additional cycles. For Dose adjustments for combination therapy for patients with progressive multiple myeloma follow dose modification guidelines described under monotherapy above.

Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplantation

Combination therapy with melphalan and prednisone

VELBORTE^® in combination with oral melphalan and oral prednisone as shown in Table 2. A 6-week period is considered a treatment cycle. Nine treatment cycles of this combination therapy are administered.

Dose adjustments during treatment and re­initiation of treatment for combination therapy with melphalan and prednisone

Prior to initiating a new cycle of therapy:
• Platelet counts should be ≥ 70 × 10⁹/l and the absolute neutrophils count should be ≥ 1.0 × 10⁹/l

• Non-haematological toxicities should have resolved to Grade 1 or baseline

Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy)

Combination therapy with dexamethasone

VELBORTE^® dosing is same as monotherapy treatment. Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELBORTE^® treatment cycle. Four treatment cycles of this combination therapy are administered.

Combination therapy with dexamethasone and thalidomide

VELBORTE^® recommended dose is 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 28-day treatment cycle. Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELBORTE^® treatment cycle. Thalidomide is administered orally at 50 mg daily on days 1­14 and if tolerated the dose is increased to 100 mg on days 15­28, and thereafter may be further increased to 200 mg daily from cycle 2. Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles. For VELBORTE^® dosage adjustments, dose modification guidelines described for monotherapy should be followed.

Posology for patients with previously untreated mantle cell lymphoma (MCL)

Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP)

VELBORTE^® dosing is same as monotherapy treatment. Six VELBORTE^® cycles are recommended, although for patients with a response first documented at cycle 6, two additional VELBORTE^® cycles may be given. The following medicinal products are administered on day 1 of each VELBORTE^® 3-week treatment cycle as intravenous infusions: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m² and doxorubicin at 50 mg/m². Prednisone is administered orally at 100 mg/m² on days 1, 2, 3, 4 and 5 of each VELBORTE^® treatment cycle.

Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma

Prior to initiating a new cycle of therapy:

– Platelet counts should be ≥ 100,000 cells/μL and the absolute neutrophils count (ANC) should be ≥ 1,500 cells/μL

– Platelet counts should be ≥ 75,000 cells/μL in patients with bone marrow infiltration or splenic sequestration – Haemoglobin ≥ 8 g/dL

– Non­haematological toxicities should have resolved to Grade 1 or baseline.

VELBORTE^® treatment must be withheld at the onset of any ≥ Grade 3 VELBORTE^®­related non­haematological toxicities (excluding neuropathy) or ≥ Grade 3 haematological toxicities. For dose adjustments, see Table 3 below.

Granulocyte colony stimulating factors may be administered for haematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeated delays in cycle administration. Platelet transfusion for the treatment of thrombocytopenia should be considered when clinically appropriate.

In addition, when VELBORTE^® is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these medicinal products should be considered in the event of toxicities, according to the recommendations in the respective Summary of Product Characteristics.

• Administration Precautions:

VELBORTE® is a cytotoxic agent. To avoid skin contact, use of gloves and other protective coatings is recommended. Aseptic technique must be strictly observed throughout the handling of VELBORTE®, since it contains no preservative.

The drug quantity contained in one 3.5-mg vial, may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose. When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated. If local injection site reactions occur following BORTEZOMIB administration subcutaneously, a less concentrated BORTEZOMIB solution (1 mg/ mL instead of 2.5 mg/mL) may be administered.

• Preparation and Administration:

VELBORTE® is a cytotoxic agent. To avoid skin contact, use of gloves and other protective coatings is recommended. Aseptic technique must be strictly observed throughout the handling of VELBORTE®, since it contains no preservative.

Intravenous injection

For intravenous injections add each VELBORTE® vial 3.5ml of 0.9% sodium chloride solution until the solution is clear, colorless and devoid of visible particles at a concentration of 1 mg/ml can be achieved. Bolus intravenous solution should be administered within 3 to 5 seconds into the peripheral or central veins. The veins should be washed by sodium chloride solution 0.9%. At least 72 hours should elapse between consecutive doses of VELBORTE®.

Subcutaneous injection

For subcutaneous injection, add each VELBORTE® vial 1.4ml of 0.9% sodium chloride solution until the solution is clear, colorless and devoid of visible particles at a concentration of 2.5 mg/ml can be achieved. Inject the prepared solution subcutaneously into the thigh (right or left) and abdomen (right or left) at a 90-45 degree angle. Injection sites should be changed in successive injections.

If any changes in color or particulate matter are present in the pre-injected solution, the product should be discarded.

VELBORTE® adverse reaction report by incidence:

>10%:

Central nervous system: Peripheral neuropathy, fatigue, neuralgia, headache, paresthesia, dizziness

Dermatologic: Skin rash

Gastrointestinal: Diarrhoea, nausea, constipation, vomiting, anorexia,

abdominal pain, decreased appetite

Hematologic & oncologic: Thrombocytopenia, neutropenia, anaemia, leukopenia

Infection: Herpes zoster infection

Neuromuscular & skeletal: Asthenia

Respiratory: Dyspnoea

Miscellaneous: Fever

1% to 10%:

Cardiovascular: Hypotension, cardiac disease, acute pulmonary edema, cardiac failure, cardiogenic shock, pulmonary edema

Endocrine & metabolic: Dehydration

Hematologic & oncologic: Haemorrhage

Infection: Herpes simplex infection, herpes zoster

Local: Injection site reaction, irritation at injection site

Respiratory: Pneumonia

Frequency not defined:
Cardiovascular: Aggravated atrial fibrillation, angina pectoris, atrial flutter, atrioventricular block, bradycardia, cerebrovascular accident, deep vein thrombosis, edema, embolism (peripheral), facial edema, haemorrhagic stroke, hypersensitivity angiitis, hypertension, ischemic heart disease, myocardial infarction, pericardial effusion, pericarditis, peripheral edema, phlebitis, portal vein thrombosis, pulmonary embolism, septic shock, sinoatrial arrest, subdural hematoma, torsades de pointes, transient ischemic attacks, ventricular tachycardia

Central nervous system: Agitation, anxiety, ataxia, brain disease, cerebral haemorrhage, chills, coma, confusion, cranial nerve palsy, dysarthria, dysautonomia, dysesthesia, insomnia, malaise, mental status changes, motor dysfunction, paralysis, psychosis, seizure, spinal cord compression, suicidal ideation, vertigo

Dermatologic: Pruritus, urticaria

Endocrine and metabolic: Amyloid heart disease, hyperglycaemia (diabetic patients), hyperkalaemia, hypernatremia, hyperuricemia, hypocalcaemia, hypoglycaemia (diabetic patients), hypokalaemia, hyponatremia, weight loss

Gastrointestinal: Cholestasis, duodenitis (haemorrhagic), dysphagia, faecal impaction, gastritis (haemorrhagic), gastroenteritis, gastroesophageal reflux disease, hematemesis, intestinal obstruction, intestinal perforation, melena, oral candidiasis, pancreatitis, paralytic ileus, peritonitis, stomatitis

Genitourinary: Bladder spasm, haematuria, haemorrhagic cystitis, urinary incontinence, urinary retention, urinary tract infection

Hematologic & oncologic: Disseminated intravascular coagulation, febrile neutropenia, lymphocytopenia, oral mucosal petechiae

Hepatic: Ascites, hepatic failure, hepatic haemorrhage, hepatitis, hyperbilirubinemia

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction

Infection: Aspergillosis, bacteraemia, listeriosis, toxoplasmosis

Local: Catheter infection

Neuromuscular and skeletal: Arthralgia, back pain, bone fracture, limb pain, myalgia, ostealgia

Ophthalmic: Blurred vision, conjunctival infection, conjunctival irritation, diplopia

Otic: Auditory impairment

Renal: Bilateral hydronephrosis, nephrolithiasis, proliferative glomerulonephritis, renal failure

Respiratory: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, bronchitis, chronic obstructive pulmonary disease (exacerbation), cough, epistaxis, haemoptysis, hypoxia, laryngeal edema, nasopharyngitis, pleural effusion, pneumonitis, pulmonary hypertension, pulmonary infiltrates (including diffuse), respiratory tract infection, sinusitis

<1%, Post marketing or case reports:

Amyloidosis, blepharitis, blindness, cardiac tamponade, chalazion, deafness (bilateral), decreased left ventricular ejection fraction, dysgeusia, dyspepsia, haemolytic-uremic syndrome, herpes meningoencephalitis, increased serum transaminases, interstitial pneumonitis, intestinal obstruction, ischemic colitis, ocular herpes simplex, optic neuritis, optic neuropathy, progressive multifocal leukoencephalopathy, prolonged QT interval on ECG, pulmonary disease, respiratory insufficiency, reversible posterior leukoencephalopathy syndrome, sepsis, Stevens-Johnson syndrome, Sweet syndrome, syncope, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, tumour lysis syndrome

• Co-administration with enzyme inhibitors CYP3A4 (e.g., ketoconazole, ritonavir) Increase the side effects of the drug.
• Co-administration with enzyme inducers CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort) Reduce the effectiveness of the drug.
• Patients on oral antidiabetic agents receiving VELBORTE® treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

Pregnancy

 VELBORTE® should not be used during pregnancy unless the clinical condition of the woman requires treatment with VELBORTE®. Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.

Breast feeding

Because of the potential for serious adverse reactions in breast­fed infants, breast­feeding should be discontinued during treatment with VELBORTE®.

• Keep the medicine in the box until it is consumed.
• store the medicine at temperatures below 30° C and stored away from light and moisture.
• Keep the medicine out of the reach of children
• The solution prepared for injection should be taken immediately. The maximum storage time of the prepared solution at room temperature (25° C) should not exceed 8 hours.