Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Reconstitution and dosing for subcutaneous and IV administration INDICATIONS: VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma and patients with mantle cell lymphoma. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. Please see Important Safety Information within the Safety tab and accompanying full Prescribing Information. FOR HEALTHCARE PROFESSIONALS ONLY Storage DESCRIPTION UNOPENED VIALS ▼ VELCADE (bortezomib) is an antineoplastic agent ▼ Store unopened vials of VELCADE® (bortezomib) at a controlled room temperature of 25ºC (77ºF); excursions are permitted from 15ºC to 30ºC (59ºF to 86ºF). Retain vials in original package to protect from light ▼ VELCADE is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells ▼ Procedures for proper handling and disposal should be considered. Please see the information on the following page HOW SUPPLIED ▼ VELCADE is supplied as individually cartoned 10-mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder ▼ Each carton of VELCADE contains a glass vial with a royal blue cap in a transparent blister pack ▼ Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package and protected from light ▼ Do not use VELCADE after the date stated on the vial and carton RECONSTITUTED VELCADE ▼ VELCADE contains no antimicrobial preservative. Administer reconstituted VELCADE within 8 hours of preparation ▼ When reconstituted as directed, VELCADE may be stored at 25ºC (77ºF). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting Disposal ▼ Each vial of VELCADE is for only a single use. Dispose of any unused product or waste material in accordance with local requirements ▼ Consider handling and disposing of VELCADE according to guidelines issued for cytotoxic drugs, including using gloves and other protective clothing to prevent skin contact1-4 A vial of VELCADE can be used for either subcutaneous or intravenous (IV) administration, but reconstitution is different NDC 63020-049-01 Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY ABOUT VELCADE About VELCADE® (bortezomib) Dosing ▼ The recommended starting dose of VELCADE® (bortezomib) is 1.3 mg/m2 for both subcutaneous and IV administrations ▼ Please see the Dose Modifications tab for dosing with hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy ▼ The drug quantity contained in 1 vial (3.5 mg) may exceed the dose required. Use caution when calculating the dose to prevent overdose OVERDOSAGE ▼ There is no specific antidote known for overdosage with VELCADE. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia ▼ The volume of 0.9% sodium chloride solution used to reconstitute VELCADE (bortezomib) for subcutaneous administration is different from the volume for IV administration. Use caution when calculating the volume to be administered ▼ The reconstituted concentration for subcutaneous administration is greater than the reconstituted concentration for IV administration – For subcutaneous reconstitution, add 1.4 mL of sterile 0.9% sodium chloride solution to the powder contained in the vial of VELCADE. This reconstitution will result in a final concentration of 2.5 mg/mL VELCADE – For IV reconstitution, add 3.5 mL of sterile 0.9% sodium chloride solution to the powder contained in the vial of VELCADE. This reconstitution will result in a final concentration of 1 mg/mL VELCADE – The reconstituted product should be a clear and colorless solution free of particulate matter ▼ Apply stickers to the vial and syringe that identify the intended route of administration ▼ VELCADE contains no antimicrobial preservative ▼ Reconstituted VELCADE should be administered within 8 hours of preparation BECAUSE EACH ROUTE OF ADMINISTRATION HAS A DIFFERENT RECONSTITUTED CONCENTRATION, USE CAUTION WHEN CALCULATING THE VOLUME TO BE ADMINISTERED ▼ VELCADE is for subcutaneous or IV use only. VELCADE should not be administered by any other route ▼ Fatal events have occurred with intrathecal administration SUBCUTANEOUS injection only IV injection only ADD CALCULATING VELCADE VOLUME (mL) VELCADE dose (mg/m2) × patient BSA* (m2) Reconstituted concentration† † Total VELCADE = volume (mL) to be administered 2.5 mg/mL for subcutaneous administration and 1 mg/mL for IV administration. *Sample BSA calculation: BSA = BSA=square root of ([height in Ht (cm) × Wt (kg) centimeters multiplied by body weight 3600 in kilograms] divided by 3600).5 1.4 mL 0.9% sodium chloride ADD 0.9% NaCl 0.9% NaCl TO MAKE 2.5 mg/mL final concentration 3.5 mL 0.9% sodium chloride TO MAKE 1 mg/mL final concentration ▼ The recommended starting dose of VELCADE is 1.3 mg/m2 for both subcutaneous and IV administrations ▼ Please see the Dose Modifications tab for dosing with hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy FOR ALL SUBCUTANEOUS INJECTIONS, IT IS IMPORTANT TO USE PROPER ASEPTIC TECHNIQUE Please see section 2 of the full Prescribing Information for dosage, reconstitution, and administration instructions. Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY DOSING & RECONSTITUTION ▼ The amount (in mg) of VELCADE to be administered is based on body surface area (BSA) calculations* using a standard nomogram5 or according to institutional policy Reconstitution of subcutaneous VELCADE® (bortezomib) is different Subcutaneous administration INJECTION-SITE REACTIONS AS OBSERVED IN A CLINICAL TRIAL ▼ In a clinical trial of patients with relapsed multiple myeloma, the most common reaction was redness, occurring in 57% of patients.6 Injection-site reactions were reported in 6% of patients as an adverse reaction, with 1% being serious and leading to dose modification or discontinuation. All events resolved in a median of 6 days ▼ If local injection-site reactions occur following administration of VELCADE® (bortezomib) subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously. Alternatively, consider the IV route of administration ▼ Please see Administration Precautions (section 2.9) in the full Prescribing Information Techniques that may minimize injection-site reactions with subcutaneous administration START CLEAN ▼ Ensure a new, clean, sharp, dry needle before administration7 ▼ Inspect solution for particulate matter and discoloration ▼ If any discoloration or particulate matter is observed, do not use the reconstituted product. File a product complaint by calling 1-866-VELCADE ▼ VELCADE is for subcutaneous or IV use only. VELCADE should not be administered by any other route ▼ Verify correct dose ▼ Fatal events have occurred with intrathecal administration ▼ Inject slowly and steadily (≈1.0 mL for 10 seconds)7 SLOW AND STEADY ▼ Allow absorption by the surrounding tissue8 ▼ Avoid fluid backtrack up the needle into the skin8 ALWAYS FOLLOW BEST PRACTICES ▼ Wash hands before and following administration8 Rotate injection sites Use the abdomen or thighs as sites for subcutaneous injections ▼ Wear gloves; however, they may not protect from needlestick injuries8 ▼ Carefully and immediately dispose of sharps at the point of administration8 Generally, when using a 25-gauge needle that is 5/8 inch in length, insert needle at a 45-degree angle9,10 Skin Administer new injections at least 1 inch from an old site and never into areas where the skin is tender, bruised, erythematous, or indurated Subcutaneous tissue Muscle 1/2-inch needle9 5/8-inch needle9 Generally, when using a 26- to 30-gauge needle that is 1/2 inch in length, insert needle at a 90-degree angle9,10 Please see the MM Trial Designs & Adverse Reactions tab for safety information in the subcutaneous vs IV clinical trial. Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY Ensure that the medication is deposited in the subcutaneous tissue9 SUBCUTANEOUS ADMINISTRATION ▼ Maintain aseptic procedures In previously untreated multiple myeloma In previously untreated multiple myeloma Dosing schedule TWICE-WEEKLY FOLLOWED BY WEEKLY DOSING FOR 1 YEAR (54 WEEKS PLANNED) Cycles 1-4 TWICE WEEKLY, 6-WEEK CYCLES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 MP orally on days 1 to 4 every 6 weeks. VELCADE® (bortezomib) Oral melphalan+prednisone (MP) Administration of concomitant medications ▼ In the VISTA trial, concomitant medications for certain conditions were permitted for patients receiving VELCADE® (bortezomib)12 Condition Concomitant treatment Prophylaxis for herpes zoster reactivation Antiviral prophylaxis recommended. Acceptable therapies include: • Acyclovir (400 mg orally, 3 times daily) • Famciclovir (125 mg orally, twice daily) • Valacyclovir (500 mg orally, twice daily) Hematologic-related events • Colony-stimulating factors • Erythropoietin • Transfusion of platelets and red blood cells, per standard practice Prevention of myeloma-related kidney disease • Adequate hydration Osteopenia or lytic destruction of bone • Bisphosphonates in accordance with ASCO clinical practice guidelines • Bisphosphonate therapy may be initiated within 1 week of starting VELCADE for those patients who were not on it previously Constipation • Adequate hydration • High-fiber diet • Stool softeners, if needed Diarrhea • Loperamide as needed, per standard practice. Prophylactic loperamide was not recommended Prevention of tumor lysis syndrome • Allopurinol treatment, per standard practice • Special attention should be given to ensure adequate hydration Cycles 5-9 ONCE WEEKLY, 6-WEEK CYCLES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 MP orally on days 1 to 4 every 6 weeks. ▼ Administer VELCADE (1.3 mg/m ) as a subcutaneous injection or as a 3- to 5-second bolus IV injection in combination with oral MP (melphalan 9 mg/m2 and prednisone 60 mg/m2). VELCADE is contraindicated for intrathecal administration; fatal events have occurred 2 ▼ Prior to initiating any cycle with VELCADE in combination with MP, platelet count should be at least 70 × 109/L and absolute neutrophil count (ANC) should be at least 1.0 × 109/L ▼ At least 72 hours should elapse between each VELCADE dose ▼ Dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. In patients undergoing dialysis, VELCADE should be administered after the dialysis procedure The above medications and supportive therapies are examples of appropriate supportive care that were permitted in the phase 3 trial. ▼ In the VISTA trial, discontinuations due to adverse reactions were 11% for VELCADE combination and 10% for MP alone11 Please see the MM Trial Designs & Adverse Reactions tab for clinical trial information. Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY MM DOSING SCHEDULES ▼ Please see the Dose Modifications tab for dosing with hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy In relapsed multiple myeloma In relapsed multiple myeloma RETREAT TWICE WEEKLY AT THE LAST TOLERATED DOSE INITIAL THERAPY FOLLOWED BY WEEKLY MAINTENANCE SCHEDULE OR STANDARD SCHEDULE Dosing schedule for retreatment with VELCADE® (bortezomib) Retreatment cycles 1-8 TWICE WEEKLY, 3 WEEKS x8 (MAXIMUM) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Dosing schedule for VELCADE® (bortezomib)-naïve patients FOR INITIAL THERAPY Cycles 1-8 Patients may be retreated with VELCADE (bortezomib) if they: ✓ Responded to prior VELCADE-based therapy ✓ Relapsed ≥6 months after completing that therapy VELCADE ▼ Administer VELCADE (1.3 mg/m2) as a subcutaneous injection or as a 3- to 5-second bolus IV injection. VELCADE is contraindicated for intrathecal administration; fatal events have occurred ▼ VELCADE may be administered as a single agent or in combination with dexamethasone ▼ At least 72 hours should elapse between each VELCADE dose ▼ Dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. In patients undergoing dialysis, VELCADE should be administered after the dialysis procedure ▼ Please see the Dose Modifications tab for hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy ▼ In the RETRIEVE trial, adverse reactions leading to discontinuation occurred in 13% of patients FOR EXTENDED THERAPY TWICE WEEKLY, 3 WEEKS x8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Cycle 9 and beyond WEEKLY MAINTENANCE SCHEDULE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 VELCADE (bortezomib) OR TWICE-WEEKLY STANDARD SCHEDULE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 ▼ At least 72 hours should elapse between each VELCADE dose ▼ Dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. In patients undergoing dialysis, VELCADE should be administered after the dialysis procedure ▼ Please see the Dose Modifications tab for dosing with hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy ▼ In the APEX trial, responding patients received a median of 31 weeks of therapy (39 weeks planned) using twice-weekly followed by weekly dosing13 ▼ In the APEX trial, discontinuations due to adverse reactions were 25% for VELCADE and 18% for dexamethasone Please see the MM Trial Designs & Adverse Reactions tab for clinical trial information. Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY MM DOSING SCHEDULES ▼ Administer VELCADE (1.3 mg/m2) as a subcutaneous injection or as a 3- to 5-second bolus IV injection. VELCADE is contraindicated for intrathecal administration; fatal events have occurred Multiple myeloma trial designs Adverse reactions in multiple myeloma PREVIOUSLY UNTREATED MULTIPLE MYELOMA: VISTA PREVIOUSLY UNTREATED MULTIPLE MYELOMA A randomized, open-label, international, phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE® (bortezomib) administered intravenously in combination with melphalan+prednisone (MP) vs MP in previously untreated multiple myeloma. After progressive disease was established, all patients were eligible to receive subsequent therapies. The primary endpoint was time to progression (TTP). Secondary endpoints were complete response (CR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). At a prespecified interim analysis (median follow-up: 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median: 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, OS, and ORR. Further enrollment was halted, and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. ▼ The most commonly reported adverse reactions (ARs) for VELCADE® (bortezomib)+ melphalan+prednisone (MP) vs MP alone were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), and leukopenia (32% vs 28%) RELAPSED MULTIPLE MYELOMA: SUBCUTANEOUS VS IV A non-inferiority, phase 3, randomized (2:1), open-label trial that compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed multiple myeloma. Patients who did not obtain a CR after 4 cycles were allowed oral dexamethasone. The primary endpoint was ORR at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP, and PFS (months), 1-year OS, and safety. RELAPSED MULTIPLE MYELOMA (VELCADE-NAÏVE): APEX A randomized, open-label trial (N=669) evaluating the efficacy and safety of VELCADE administered intravenously vs dexamethasone in patients with relapsed/refractory multiple myeloma. The primary endpoint was TTP. Secondary endpoints were OS, ORR, and safety. The APEX trial was terminated at a preplanned interim analysis of TTP. All dexamethasone patients were offered VELCADE. Median TTP was 6.2 months with VELCADE vs 3.5 months with dexamethasone (p<0.0001). An updated analysis was performed. RETREATMENT OF RELAPSED MULTIPLE MYELOMA: RETRIEVE A single-arm, open-label study in patients with relapsed multiple myeloma (N=130). Patients with multiple myeloma who had previously achieved ≥partial response (PR) on a VELCADE-containing regimen (median of 2 prior lines of therapy [range: 1-7]) and progressed ≥6 months after completing that regimen were retreated with IV VELCADE±dexamethasone. Patients received VELCADE on days 1, 4, 8, and 11 q 3 weeks for 24 weeks. The primary endpoint was best confirmed response to treatment as assessed by the European Group for Blood and Marrow Transplantation criteria. The secondary endpoints were duration of response (DOR) and safety. RELAPSED MULTIPLE MYELOMA: SUBCUTANEOUS VS IV ▼ In the phase 3 study of VELCADE administered subcutaneously vs intravenously in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported ARs in the subcutaneous vs IV treatment groups were peripheral neuropathy (37% vs 50%) and thrombocytopenia (30% vs 34%). The incidence of serious ARs was similar in the subcutaneous and IV treatment groups (20% vs 19%, respectively). The most commonly reported serious ARs in the subcutaneous treatment group were pneumonia and pyrexia (2% each); in the IV treatment group, pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) ▼ Dose reductions due to ARs occurred in 31% of patients in the subcutaneous group vs 43% in the IV group RELAPSED MULTIPLE MYELOMA ▼ The most commonly reported ARs with VELCADE vs dexamethasone were nausea (52% vs 9%), diarrhea NOS (52% vs 11%), fatigue (39% vs 25%), PN NEC (35% vs 4%), thrombocytopenia (33% vs 3%), and constipation (30% vs 8%) ▼ The most commonly reported serious ARs in the VELCADE treatment group were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious ARs were pneumonia (4%), hyperglycemia (3%), and pyrexia and psychotic disorder (2% each) ADDITIONAL SAFETY CONSIDERATION ▼ Antiviral prophylaxis should be considered for patients treated with VELCADE. Herpes zoster reactivation was more common in patients treated with VELCADE FOR HEALTHCARE PROFESSIONALS ONLY MM TRIAL DESIGNS & ADVERSE REACTIONS Please see Important Safety Information for VELCADE within the Safety tab. ▼ A total of 25% of patients in the treatment group receiving VELCADE+MP experienced serious ARs vs 18% in the treatment group receiving MP. The most commonly reported serious ARs with VELCADE+MP vs MP alone included pneumonia (5% vs 4%), diarrhea (4% vs 0%), thrombocytopenia (3% vs 1%), vomiting (3% vs <1%), nausea (2% vs <1%), anemia (2% vs 2%), herpes zoster (2% vs <1%), and dehydration (2% vs <1%)14 In previously untreated mantle cell lymphoma Dosing schedule Administration of concomitant medications REPLACE VINCRISTINE IN R-CHOP* WITH TWICE-WEEKLY VELCADE® (bortezomib) TWICE WEEKLY, 6-8 CYCLES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 VELCADE (bortezomib) Rituximab, cyclophosphamide, and doxorubicin ▼ In the phase 3 trial, concomitant medications for certain conditions were permitted for patients receiving VELCADE® (bortezomib)15 Condition Concomitant treatment Prophylaxis for herpes zoster (mandated in the clinical trial) Antiviral prophylaxis. Acceptable therapies include: • Acyclovir (400 mg orally, 3 times daily) • Famciclovir (125 mg orally, twice daily) • Valacyclovir (500 mg orally, twice daily) Prophylaxis for hepatitis B re-activation • Lamivudine (100 mg/day orally or equivalent prophylaxis) recommended until 8 weeks after the last dose of treatment Thrombocytopenia • Platelet transfusions as needed, per standard practice Anemia • Red blood cell transfusions as needed, per standard practice Prevention of neutropenia and management of treatment-emergent toxicities • Colony-stimulating growth factors, per standard practice Management of hematologic toxicities associated with cyclophosphamide or doxorubicin • Granulocyte colony-stimulating factors Prevention of hemorrhagic cystitis • Mesna, as clinically indicated Infusion reactions to rituximab Premedication before each infusion as clinically indicated: • Acetaminophen • Diphenhydramine • Steroids Diarrhea • Loperamide as needed, per standard practice. Prophylactic loperamide was not recommended Prevention of tumor lysis syndrome • Allopurinol treatment, per standard practice • Special attention should be given to ensure adequate hydration Prednisone ▼ Administer VELCADE (1.3 mg/m2) as a 3- to 5-second bolus IV injection in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and prednisone (100 mg/m2). VELCADE is contraindicated for intrathecal administration; fatal events have occurred ▼ Prior to the first day of each VR-CAP cycle (other than cycle 1): † – Platelet count should be at least 100 × 109/L and absolute neutrophil count (ANC) should be at least 1.5 × 109/L – Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L) – Nonhematologic toxicity should have recovered to grade 1 or baseline ▼ At least 72 hours should elapse between each VELCADE (bortezomib) dose ▼ Please see the Dose Modifications tab for dosing with hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy ▼ In a phase 3 study of VR-CAP vs R-CHOP in adult patients with previously untreated mantle cell lymphoma – For patients with a response first documented at cycle 6, two additional treatment cycles were allowed. Median number of cycles received by patients in both treatment arms was 6, with 17% of patients in the R-CHOP group and 14% of patients in the VR-CAP group receiving up to 2 additional cycles The above medications and supportive therapies are examples of appropriate supportive care that were permitted in the phase 3 trial. – Discontinuations due to adverse reactions were 8% with VR-CAP and 6% with R-CHOP *R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. † VR-CAP=VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone. Please see the MCL Trial Designs & Adverse Reactions tab for clinical trial information. Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY MCL DOSING SCHEDULES In previously untreated mantle cell lymphoma In relapsed mantle cell lymphoma Dosing schedule for VELCADE® (bortezomib) patients Mantle cell lymphoma trial designs INITIAL THERAPY FOLLOWED BY WEEKLY MAINTENANCE SCHEDULE OR STANDARD SCHEDULE A randomized, open-label, phase 3 study (N=487) evaluating the efficacy and safety of VELCADE® (bortezomib) administered intravenously in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle cell lymphoma (stage II, III, or IV) who were ineligible or not considered for bone marrow transplantation. The primary endpoint was progression-free survival (PFS). FOR INITIAL THERAPY FOR EXTENDED THERAPY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 RELAPSED MANTLE CELL LYMPHOMA: PINNACLE Cycle 9 and beyond WEEKLY MAINTENANCE SCHEDULE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 VELCADE® (bortezomib) OR TWICE-WEEKLY STANDARD SCHEDULE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 ▼ Administer VELCADE (1.3 mg/m2) as a subcutaneous injection or as a 3- to 5-second IV injection. VELCADE is contraindicated for intrathecal administration; fatal events have occurred ▼ At least 72 hours should elapse between each VELCADE dose ▼ Please see the Dose Modifications tab for dosing with hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy ▼ In the PINNACLE trial, 23% of patients discontinued VELCADE due to treatment-related adverse reactions16 A single-arm, multicenter, phase 2, open-label trial (N=155) evaluating the efficacy and safety of VELCADE in patients with mantle cell lymphoma who had received at least 1 prior therapy. Primary endpoint was time to progression (TTP) and secondary endpoints were objective response rate (ORR), complete response (CR), duration of response (DOR), and overall survival (OS). As an appropriate cohort of historical controls could not be found for comparison to the results of this study, the formal statistical comparisons of TTP and survival specified in the protocol could not be performed. Adverse reactions in mantle cell lymphoma PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA ▼ The most commonly reported adverse reactions with VR-CAP vs R-CHOP were neutropenia (87% vs 71%), thrombocytopenia (72% vs 17%), leukopenia (48% vs 36%), anemia (44% vs 29%), peripheral neuropathy (30% vs 27%), lymphopenia (28% vs 12%), diarrhea (25% vs 5%), nausea (23% vs 12%), and pyrexia (20% vs 10%) ▼ A total of 38% of patients receiving VR-CAP experienced serious adverse reactions vs 30% of patients receiving R-CHOP. The most commonly reported serious adverse reactions included febrile neutropenia (11% vs 8%), pneumonia (8% vs 3%), neutropenia (5% vs 5%), and pyrexia (4% vs 2%), respectively17 RELAPSED MANTLE CELL LYMPHOMA ▼ The most commonly reported adverse reactions were peripheral neuropathy NEC (54%), fatigue (52%), diarrhea NOS (39%), nausea (36%), constipation (34%), and vomiting and rash NOS (23% each) ▼ The most commonly reported serious adverse reactions were nausea, vomiting NOS, abdominal pain NOS, and syncope (3% each); pyrexia, pneumonia NOS, and sepsis NOS (2% each)18 ▼ Treatment-related deaths were reported in 3% of patients19 Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY MCL TRIAL DESIGNS & ADVERSE REACTIONS Cycles 1-8 TWICE WEEKLY PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA: LYM-3002 Dose modifications for hematologic and nonhematologic toxicities Previously untreated multiple myeloma Toxicity Dose modification or delay Neutropenia/thrombocytopenia If prolonged grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding, is observed in the previous cycle Consider reduction of the melphalan dose by 25% in the next cycle Thrombocytopenia during a cycle If platelet count is not above 30 × 109/L or absolute neutrophil count (ANC) is not above 0.75 × 109/L on a VELCADE dosing day (other than day 1) VELCADE® (bortezomib) dose should be withheld If several doses in consecutive cycles are withheld due to toxicity, VELCADE dose should be reduced by 1 dose level* Grade 3 or higher nonhematologic toxicities VELCADE therapy should be withheld until symptoms of the toxicity have resolved to grade 1 or baseline Then VELCADE may be reinitiated with 1 doselevel reduction* Relapsed multiple myeloma Once the symptoms of the toxicity have resolved, VELCADE therapy may be reinitiated at a dose reduced by 25%* Dose modifications on days 4, 8, and 11 for previously untreated mantle cell lymphoma Toxicity Dose modification or delay Grade 3 or higher neutropenia, or a platelet count not at or above 25 × 109/L Withhold VELCADE® (bortezomib) therapy for up to 2 weeks until the patient has an absolute neutrophil count (ANC) at or above 0.75 × 109/L and a platelet count at or above 25 × 109/L • If, after VELCADE has been withheld, the toxicity does not resolve, discontinue VELCADE • If toxicity resolves such that the patient has an ANC at or above 0.75 x 109/L and a platelet count at or above 25 × 109/L, VELCADE dose should be reduced by 1 dose level* Grade 3 or higher nonhematologic toxicities Withhold VELCADE therapy until symptoms of the toxicity have resolved to grade 2 or better. Then, VELCADE may be reinitiated with one dose level reduction* For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE, as per guidelines Relapsed mantle cell lymphoma VELCADE therapy should be withheld at the onset of any grade 3 nonhematologic or grade 4 hematologic toxicities, excluding neuropathy Once the symptoms of the toxicity have resolved, VELCADE therapy may be reinitiated at a dose reduced by 25%* *From 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2. *From 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2. ▼ Prior to initiating any cycle of therapy with VELCADE in combination with melphalan+prednisone (MP): — Platelet count should be at least 70 × 109/L and ANC should be at least 1.0 × 109/L — Nonhematologic toxicities should have resolved to grade 1 or baseline ▼ Dosing adjustments of VELCADE are not necessary for patients with renal insufficiency ▼ In patients undergoing dialysis, VELCADE should be administered after the dialysis procedure ▼ Prior to the first day of each VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) cycle (other than cycle 1): – Platelet count should be at least 100 × 109/L and ANC should be at least 1.5 × 109/L – Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L) – Nonhematologic toxicity should have recovered to grade 1 or baseline ▼ Interrupt VELCADE treatment at the onset of any grade 3 hematologic or nonhematologic toxicities Please review all dosing guidelines for hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy throughout the Dose Modifications tab. Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY DOSE MODIFICATIONS VELCADE therapy should be withheld at the onset of any grade 3 nonhematologic or grade 4 hematologic toxicities, excluding neuropathy Dose modifications for hematologic and nonhematologic toxicities (cont.) Dose modifications for peripheral neuropathy (PN) Dose modifications for hepatic impairment Bilirubin and SGOT (AST) levels Modification of starting dose Severity of PN signs/symptoms* Dose modification or delay Mild Bilirubin level less than or equal to 1.0× ULN* and SGOT† (AST‡) levels more than ULN or bilirubin level more than 1.0-1.5× ULN and any SGOT (AST) level Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia without pain or loss of function) No action None Grade 1 with pain or grade 2 (moderate symptoms; limiting instrumental activities of daily living [ADL]†) Reduce VELCADE® (bortezomib) to 1 mg/m2 Grade 2 with pain or grade 3 (severe symptoms; limiting self-care ADL‡) • Withhold VELCADE therapy until toxicity resolves • When toxicity resolves, reinitiate with a reduced dose of 0.7 mg/m2 once per week Grade 4 (life-threatening consequences; urgent intervention indicated) Discontinue VELCADE Moderate Bilirubin level more than 1.5-3× ULN and any SGOT (AST) level Severe Bilirubin level more than 3× ULN and any SGOT (AST) level Reduce VELCADE (bortezomib) to 0.7 mg/m2 in the first cycle Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability ® *Upper limit of normal range. † Serum glutamic oxaloacetic transaminase. ‡ Aspartate aminotransferase. ▼ Patients with mild hepatic impairment do not require a starting-dose adjustment ▼ Patients with moderate or severe hepatic impairment should be started on VELCADE at a reduced dose of 0. 7 mg/m2 per injection during the first cycle — Subsequent dose escalation to 1. 0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance *Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. † Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. ‡ Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not being bedridden. ▼ Treatment-emergent PN is generally manageable and reversible with VELCADE dose modification ▼ Compromised hepatic function may occur in patients with multiple myeloma20 — In VISTA, 79% of patients who received a dose modification experienced improvement within a median of 1.9 months21 ▼ Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. In such cases, interrupt therapy with VELCADE to assess reversibility — In APEX, 64%§ of patients experienced resolution or improvement within a median of 3.6 months22 ▼ Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness ▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less dose-intense schedule, or discontinuation ▼ Starting VELCADE subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN ▼ The long-term outcome of PN has not been studied in mantle cell lymphoma § Peripheral neuropathy grade ≥2 (n=91).22 Please review all dosing guidelines for hematologic and nonhematologic toxicities, moderate to severe hepatic impairment, and peripheral neuropathy throughout the Dose Modifications tab. Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY DOSE MODIFICATIONS ▼ Monitor hepatic enzymes during treatment. Upon occurrence, interrupt therapy with VELCADE to assess reversibility GO Frequently asked questions Frequently asked questions (cont.) Q: The powder contained in the vial of VELCADE looks the same for subcutaneous and IV. Is it the same vial? Q: Is there any information on accidental overdosage of VELCADE? A: Yes, a vial of VELCADE can be used for either subcutaneous or IV administration. VELCADE is available in individual vials, each containing 3.5 mg of powdered product. However, the reconstitution of VELCADE for subcutaneous and IV administrations differs. The reconstituted concentration of VELCADE for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL). Stickers that indicate the route of administration are provided within the carton. Q: What do I add to the 3.5-mg vial of VELCADE to reconstitute it for subcutaneous administration? A: In the event of an overdosage, monitor the patient’s vital signs and give appropriate supportive care. There is no specific antidote known for overdosage with VELCADE. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia. Q: Is there any information on use in special populations, such as older patients? A: No overall differences in safety or effectiveness were observed between patients aged 65 years or older and younger patients receiving VELCADE, but greater sensitivity of some older individuals cannot be ruled out. A: For subcutaneous reconstitution, add 1.4 mL of sterile 0.9% sodium chloride solution to the powder contained in the vial of VELCADE. Q: Not all of the reconstituted VELCADE was used. Can it be stored for future use? A: Each vial of VELCADE is for only a single use. VELCADE contains no antimicrobial preservative. Administer reconstituted VELCADE within 8 hours of preparation. When reconstituted as directed, VELCADE may be stored at 25ºC (77ºF). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting. Dispose of any unused product or waste material in accordance with local requirements. Q: How far ahead of use can I reconstitute VELCADE for subcutaneous injection? A: VELCADE contains no antimicrobial preservative. Administer reconstituted VELCADE within 8 hours of preparation. Q: How common are injection-site reactions with subcutaneous administration of VELCADE® (bortezomib)? Please see Important Safety Information for VELCADE within the Safety tab. FOR HEALTHCARE PROFESSIONALS ONLY FAQs A: In a clinical trial, the most common reaction was redness, occurring in 57% of patients.6 Injection-site reactions were reported in 6% of patients as an adverse event, with 1% being serious and leading to dose modification or discontinuation. All events resolved in a median of 6 days. If local injection-site reactions occur following administration of VELCADE subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered. Alternatively, consider the IV route of administration. References: 1. US Department of Health and Human Services. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. Cincinnati, OH: US Dept of Health and Human Services; 2004. DHHS (NIOSH) publication 2004-165. 2. US Department of Labor. Controlling occupational exposure to hazardous drugs (section VI, chapter 2). In: US Dept of Labor. OSHA Technical Manual (OTM). Washington, DC: Occupational Safety and Health Administration; 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html. 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharmacists. 2006;63:1172-1191. 4. Polovich M, Whitford JM, Olsen M, eds. Fundamentals of administration. In: Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society. 2009;73-104. http://ons. metapress.com/content/r14224/?p= f24648586d21451f8fe672fed78a5511&pi=0. 5. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317(17):1098. 6. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440. 7. Workman B. Safe injection techniques. Nurs Stand. 1999;13(39):47-53. 8. Hunter J. Subcutaneous injection technique. Nurs Stand. 2007;22(21):41-44. 9. Ostendorf W. Administration of parenteral medications. In: Perry AG, Potter PA, Elkin MK, eds. Nursing Interventions and Clinical Skills. 5th ed. St Louis, MO: Elsevier Mosby; 2012:541583. 10. Smith SF, Duell DJ, Martin BC. Parenteral medication administration. In: Clinical Nursing Skills Basic to Advanced Skills. 8th ed. Upper Saddle River, NJ: Pearson Education, Inc; 2012:607-630. 11. Data on file 53, Millennium Pharmaceuticals, Inc. 12. Data on file 72, Millennium Pharmaceuticals, Inc. 13. Data on file 12, Millennium Pharmaceuticals, Inc. 14. Data on file 48, Millennium Pharmaceuticals, Inc. 15. Data on file 73, Millennium Pharmaceuticals, Inc. 16. Data on file 55, Millennium Pharmaceuticals, Inc. 17. Data on file 66, Millennium Pharmaceuticals, Inc. 18. Data on file 51, Millennium Pharmaceuticals, Inc. 19. Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24(30):4867-4874. 20. Thomas FB, Clausen KP, Greenberger NJ. Liver disease in multiple myeloma. Arch Intern Med. 1973;132(2):195-202. 21. Dimopoulos MA, Mateos M-V, Richardson PG, et al. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol. 2011;86(1):23-31. 22. Richardson PG, Sonneveld P, Schuster MW, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol. 2009;144(6):895-903. Indications and Important Safety Information for VELCADE® (bortezomib) Important Safety Information for VELCADE® (bortezomib) (cont.) INDICATIONS: VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma and patients with mantle cell lymphoma. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment. Upon occurrence, interrupt therapy with VELCADE (bortezomib) to assess reversibility. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. ▼ Embryo-fetal risk: Women should avoid breast-feeding or becoming pregnant while on VELCADE. WARNINGS AND PRECAUTIONS: VELCADE is for subcutaneous or IV administration only. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered. DRUG INTERACTIONS: Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ▼ Peripheral neuropathy, including severe cases, may occur. Patients should be monitored for symptoms and managed with dose modification or discontinuation. Patients with preexisting symptoms may experience worsening peripheral neuropathy (including ≥Grade 3). Starting with VELCADE subcutaneously may be considered for patients who either have preexisting or are at high risk for peripheral neuropathy. ▼ Hypotension: Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated. ▼ Cardiac toxicity, including acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction, has occurred. Isolated cases of QT-interval prolongation have been reported. Patients with risk factors for, or existing, heart disease should be closely monitored. ▼ Pulmonary toxicity: Acute respiratory distress syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology have occurred (sometimes fatal). Pulmonary hypertension, in the absence of left heart failure or significant pulmonary disease, has been reported. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt and comprehensive diagnostic evaluation is conducted. ▼ Posterior reversible encephalopathy syndrome has occurred. Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting, has occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement. Interrupt VELCADE for severe symptoms. ▼ Thrombocytopenia/Neutropenia: Manage with dose and/or schedule modifications. Complete blood counts should be monitored frequently during treatment. There have been reports of gastrointestinal and intracerebral hemorrhage. Support with transfusions and supportive care, according to published guidelines. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden and take appropriate precautions. A vi for e but ▼ The both ▼ Bec conc ▼ Patients with diabetes may require close monitoring and adjustment of the antidiabetic medications. –V –V a ▼ Visit and ADVERSE REACTIONS ▼ Previously untreated multiple myeloma (MM): In the phase 3 study of VELCADE administered intravenously with melphalan and prednisone (MP) vs MP alone, the most commonly reported adverse reactions (ARs) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), and leukopenia (32% vs 28%). Please Please at VELC ▼ Relapsed MM subcutaneous vs IV: In the phase 3 study of VELCADE administered subcutaneously vs intravenously in relapsed MM, safety data were similar between the two treatment groups. The most commonly reported ARs in the subcutaneous vs IV treatment groups were peripheral neuropathy (37% vs 50%) and thrombocytopenia (30% vs 34%). The incidence of serious ARs was similar in the subcutaneous treatment group (20%) and the IV treatment group (19%). The most commonly reported serious ARs were pneumonia and pyrexia (each 2%) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (each 3%) in the IV treatment group. ▼ Previously untreated mantle cell lymphoma (MCL): In a phase 3 study of VELCADE administered intravenously with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) vs vincristine, rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), the most commonly reported ARs were neutropenia (87% vs 71%), thrombocytopenia (72% vs 17%), leukopenia (48% vs 36%), anemia (44% vs 29%), lymphopenia (28% vs 12%), peripheral neuropathy (30% vs 27%), diarrhea (25% vs 5%), nausea (23% vs 12%), and pyrexia (20% vs 10%). ▼ Relapsed MM and MCL: In the integrated analysis of 1163 patients in phase 2 and 3 studies of VELCADE administered intravenously, the most commonly reported ARs were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathy NEC (38%), and thrombocytopenia (32%). A total of 26% of patients experienced serious ARs. The most commonly reported serious ARs included diarrhea, vomiting, and pyrexia (each 3%); nausea, dehydration, and thrombocytopenia (each 2%); and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (each 1%). FOR HE Please see accompanying full Prescribing Information, also available at VELCADE-hcp.com. SAFETY FOR HEALTHCARE PROFESSIONALS ONLY Takeda Oncol Other tradem Copyright © 2 All rights rese A vial of VELCADE® (bortezomib) can be used for either subcutaneous or IV administration, but reconstitution is different ▼ The recommended starting dose of VELCADE (bortezomib) is 1.3 mg/m2 for both subcutaneous and IV administrations ▼ Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered – VELCADE is administered subcutaneously at a concentration of 2.5 mg/mL – VELCADE is administered intravenously at a concentration of 1 mg/mL as a 3- to 5-second bolus IV injection ▼ Visit the VELCADE Nurse Portal at VELCADE-rn.com for educational tools and resources to help support you and your patients Please see Important Safety Information for VELCADE within the Safety tab. Please see accompanying full Prescribing Information, also available at VELCADE-hcp.com. FOR FINANCIAL, TREATMENT, OR PERSONAL SUPPORT FOR YOUR PATIENTS, CONTACT A CASE MANAGER AT 1-866-VELCADE (OPTION 2) FOR HEALTHCARE PROFESSIONALS ONLY Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited. Other trademarks are the property of their respective owners. Copyright © 2014, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in the USA USO/BOR/14/0055 1/15 Please see full Prescribing Information at velcade.com/Files/PDFs/VELCADE_PRESCRIBING_INFORMATION.pdf